Targeted Therapy in Cancer

7182019 Targeted Therapy in Cancer

httpslidepdfcomreaderfulltargeted-therapy-in-cancer 151

Targeted therapy in Cancer

Dr TRI WIDYAWATI MSi

Bagian Farmakologi dan Terapeutik

Fakultas Kedokteran

Universitas Sumatera Utara



Introductionbull Surgery radiation and chemotherapy have led to

increase survival rates for certain types of cancer

However there are some types of cancer eg lung andGIT (liver cancer) cancers often do not respond well tosuch type of treatment in addition to the marked sideeffects that have been observedTherefore additionalcancer thera is stron l recommendedThe latter

should be targeting therapy based on biochemical andbiological approachbull Novel promissing biological ndashbiochemical therapy for

cancer

bull 1-Bio-immunotherapybull 2-Anti-angiogenesis amp anti-metastasis inducerbiomolecules

bull 3-Apoptosis inducer therapy

bull 4-Gene therapy 5-differentiation inducer therapy



ChemotherapyShortcomingsA Nature of cytotoxin

B Lack of in vivo selectivity

C The mechanism of anti-proliferation on cells cycle rather than

specific toxicity directed towards particular cancer cell

D Host toxixity treatment discontinued most of them had badside-effects such as no appetites omit lose hair

Side Effects of Chemotherapy

Immediate Early Delayed Late(hours - days) (days - weeks) (weeks- months) (months - yrs)

Extravasation Myelosuppression Cardiotoxicity Second CancerEmesis Mucositis Lung fibrosis EncephalopathyHypersensitivity Alopecia P Neuropathy SterilityTumour lysis Cystitis Hepatotoxicity Teratogenicity

Nephrotoxicity



Changing of the Guard

bull There is a paradigm shift in thetreatment of cancer

bull with DNA to prevent cell replication butare not specific to cancer cells

bull We are moving to targeted therapieswhich specifically target cancer cells



The Paradigm Shift

bull The use of these drugs is giving

clinicians a glimmer of the paradigmshift that will occur in the treatment of

bull One or several new targeted therapiesoffer the prospect of cancer being

treated as a chronic disease



Targeted Therapy A definitionbull Drugs targeted at pathways processes and

physiology which are uniquely disrupted incancer cells

ndash Receptors

ndash Genes ndash Angiogenesis

ndash Tumor pH

bull Get real these pathways etc are not so distinct



Targeted therapiesbull With targeted therapy the specific

mechanism of action of the drug results in anincrease in its therapeutic index

bull However the advantages of the specificity

and safety of the are offset by the smallernumber of susceptible tumour types

bull Increasing numbers of these innovative and

expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them



The Need to Identify the Targetbull Appropriate use of newly approved and

expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample

bull urren y e wo ma or c asses o arge etherapy are

= the small molecule tyrosine kinase

inhibitors (TKIs) and= monoclonal antibodies (mAbs)





Six Essential Alterations

in Cell Physiology in Malignancy

Insensitivity to

anti-growth signals

Self-sufficiency in

growth signals

Evading

apoptosis

Targets for classical drugs

Hanahan amp WeinbergCell 10057 (2000)

Limitless replicativepotential

Tissue invasionamp metastasis

Sustained

angiogenesis

Targets for novel drugs



Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium

bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication



Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For

example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint

cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)



Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting

vasculature

Epidermal growth factor receptor (EGFR also known as HER1)

A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]

Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens

Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin



HER2neu A tyrosine kinase related to epidermal growth

factor receptor it has a role in the pathogenesis of

breast cancer and is a target of treatment (with the

monoclonal antibody trastuzumab [Herceptin] and the

small molecule inhibitor lapatinib [Tykerb]) in the 25

percent of persons with breast cancer in which

HER2neu is associated with disease recurrence and

worse prognosis HER2 is named because it has

similar structure to human epidermal growth factor

receptor (HER1) neu is so named because it was

derived from a neuroglioblastoma cell line



Ligand A molecule that binds to a specific receptor

Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells

Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases

Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling

Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the

monoclonal antibody bevacizumab (Avastin)



What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign

objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target

Monoclonal antibodies (mAb) are antibodies that are identical because they were

produced by one type of immune cell all clones of a single parent cell

Polyclonal antibodies are antibodies that are derived from different cell lines

Isot es

According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE

IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid

IgAIgA1 (90) and IgA2 (10) stomach and intestines

IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds

IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown

IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite



Monoclonal Antibodies

bull Action of the mAbs rituximab

(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for

reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth



The structure of antibodies

bull httpwwwpathcamacuk~mrc7igsmikeimageshtml



The types of mAb designed

AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities

BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)

CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human

variable region framework



Monoclonal antibodies for cancer

treatment

Mechanisms that could be responsible for the

cancer treatmentA mAbs act directely when binding to a cancer

specific antigens and induce immunological

response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function

B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates

C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell



mAbs treatment for cancer cells

ADEPT antibody directed enzyme prodrug therapy ADCC antibody

dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment

Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer

20011118-129



Mabthera

bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma

bull CD20 is a protein on the surface of malignantlymphoma cells

bull CD20 expressed on 90 of B-cells in

Side effects includeInfusion related fever chills rigors

N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days



HER2

= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor

= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome

=overexpressing cells

As a single agent 15 chance of shrinking metastatic

breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents

Can combine with chemotherapy



Figure 3 Acneiform rash on (A) the face and (B) back of

patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor



Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib

bullbull GefitinibGefitinib

bullbull ZD6474ZD6474

bullbull SunitinibSunitinibbullbull SorafenibSorafenib







The Angiogenic Switchis Necessary for Tumor Growth and Metastasis

Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor

Tumor secretion ofangiogenic factors

stimulatesangiogenesis

Rapid tumor growth andmetastasis

Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401

bull Allows rapid tumor

growth by providingoxygen nutrientsand waste removal

bull Facilitatesmetastasis



On

The Angiogenic Switch


The Balance Hypothesis

Hanahan and Folkman Cell 1996 86353

= Activators (eg VEGF bFGF IL-8)

= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)

Off

VEGF = Vascular endothelial growth factor



Agents targeting the

VEGF pathway


VEGF pathway

SolubleVEGF

receptors

VEGFAnti-VEGFantibodies

(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)

Ribozymes(angiozyme)

Anti-VEGFRantibodies(IMC-2C7)

(VEGF-Trap)



Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor

(EGFR)(EGFR)

bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor

progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block

intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR

bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired

bullbull Inhibits production of VEGFInhibits production of VEGF



GefitinibGefitinib

bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung

cancercancer

bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of

10 response rate in clinical study10 response rate in clinical study

bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage



ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21

bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after

chemotherapychemotherapy

bullbull r o n mg ay vs ace or o n mg ay vs ace o

bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)

bullbull One year survival 297 vs 205One year survival 297 vs 205

bullbull Quality of life improvementQuality of life improvement

bullbullFDA indication for locally advancedFDA indication for locally advanced

bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one

bullbullor more chemotherapy regimensor more chemotherapy regimens



STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor

and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST

bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma

tumours which over express c-kit

bull Side effects ndash Nausea myalgia oedema diarrhoea

myelosuppression LFTrsquos early ldquostormrdquo



PET Before and after Glivec

for GIST

7120071200 91019101





Table 3 Small Molecule Inhibitors for Cancer Treatment




Drug Target

FDA-approved

indications

Toxicities side

effects and

precautions Monitoring

Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion

fluid retentionmucositis

myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries

weight signs andsymptoms of fluid

retention

Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries



Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of

appetite nausea andvomiting fatigue

conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of

inflammatory orinfectious sequelae

in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of

appetite interstitial

lung disease (rare)

elevated liverchemistries

Liver chemistries

signs of

inflammatory or

infectious sequelae

in patients withdermatologic

toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver

chemistriesweight signs

and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting

arthralgiasand myalgias

myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries

Sorafenib BRAF Renal cell Hypertension Blood



Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer

hepatocellularcarcinoma

Hypertensionalopecia bleeding

rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting

Bloodpressure

dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot

e eva e amy ase

and lipase levelsmyelosuppressionwound-healingcomplications

Discontinuetreatmenttemporarily forsurgicalprocedures

syn rome

amylaselipase andphosphatelevels CBC



note

= All small molecule inhibitors are administeredorally except bortezomib which is administered

intravenously

= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are

=anticonvulsants azole antifungals dexamethasone

isoniazid [Nydrazid] macrolide antibiotics nefazodone

[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St

Johns wort verapamil [Calan] and warfarin

[Coumadin])

Molecularly targeted therapy for hepatocellular



carcinoma

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983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

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983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155




Molecularly targeted therapy for hepatocellularcarcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

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Sorafenib in the treatment of advanced



Sorafenib in the treatment of advancedhepatocellular carcinoma

bull Hepatocellular carcinoma (HCC) is the

most common primary liver tumorresponsible for about 90 of liver cancers

challenge to physicians

bull Many chemotherapeutic agents have been

tried but none had shown a significantresult of improved survival or quality of life





bull Sorafenib reg is a multikinase inhibitor that has

recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)

bull It has been tried in several solid tumorsincluding HCC

bull A recent phase III trial has shown that sorafenib

significantly extends survival for patients withadvanced HCC

S f ib



Sorafenib

bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf

VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by

Ras membrane localized rotein stimulates ene

transcription in the nucleus leading to a variety of tumor-promoting cellular effects

bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through

several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging



Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)

present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated

PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the

receptors has several effects on endothelial cellmotility and apoptosis



Conclusionsbull Targeted therapies which improve

the therapeutic index are the futureof anti-cancer therapy

provide the means to identify thetargets and will be used to subtypetumours and will provide predict

response to therapy and provideprognostic information



Introductionbull Surgery radiation and chemotherapy have led to

increase survival rates for certain types of cancer

However there are some types of cancer eg lung andGIT (liver cancer) cancers often do not respond well tosuch type of treatment in addition to the marked sideeffects that have been observedTherefore additionalcancer thera is stron l recommendedThe latter

should be targeting therapy based on biochemical andbiological approachbull Novel promissing biological ndashbiochemical therapy for

cancer

bull 1-Bio-immunotherapybull 2-Anti-angiogenesis amp anti-metastasis inducerbiomolecules

bull 3-Apoptosis inducer therapy

bull 4-Gene therapy 5-differentiation inducer therapy











Nephrotoxicity









The Paradigm Shift









ndash Receptors


ndash Tumor pH























Insensitivity to

anti-growth signals

Self-sufficiency in

growth signals

Evading

apoptosis





Sustained

angiogenesis














vasculature

































Isot es



























treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





























Nephrotoxicity









The Paradigm Shift









ndash Receptors


ndash Tumor pH























Insensitivity to

anti-growth signals

Self-sufficiency in

growth signals

Evading

apoptosis





Sustained

angiogenesis














vasculature

































Isot es



























treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib



























The Paradigm Shift









ndash Receptors


ndash Tumor pH























Insensitivity to

anti-growth signals

Self-sufficiency in

growth signals

Evading

apoptosis





Sustained

angiogenesis














vasculature

































Isot es



























treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib























ndash Receptors


ndash Tumor pH























Insensitivity to

anti-growth signals

Self-sufficiency in

growth signals

Evading

apoptosis





Sustained

angiogenesis














vasculature

































Isot es



























treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib








































Insensitivity to

anti-growth signals

Self-sufficiency in

growth signals

Evading

apoptosis





Sustained

angiogenesis














vasculature

































Isot es



























treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib































vasculature

































Isot es



























treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib















































Isot es



























treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib







































treatment













20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib

























20011118-129



Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















Mabthera








HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















HER2
























Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib




































Tumor is dormant

Neovascularization

Angiogenic switch

Somaticmutation

Smallavascular

tumor










On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















On







Off





VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib






















VEGF pathway


VEGF pathway

SolubleVEGF

receptors


(bevacizumab)

VEGFR-2VEGFR-1

P

PP

PP

PP

P

Endothelial cell

Small-molecule

VEGFR inhibitors

(PTKZK)



(VEGF-Trap)




(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib






















(EGFR)(EGFR)








GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















GefitinibGefitinib


cancercancer



























for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib










































for GIST

7120071200 91019101









Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib



























Drug Target

FDA-approved

indications

Toxicities side

effects and


Bortezom

ib

(Velcade)

26S

proteaso

me

Multiple

myeloma

mantle cell

lymphoma

(a subtype of

Peripheral

neuropathy

myelosuppression

rash constipation

diarrhea edema

Signs and

symptoms of

peripheral

neuropathy CBC

non- o g n s

lymphoma)

nausea an

vomiting

Dasatinib

(Sprycel)

BCR-

ABL

SRCfamily

c-KIT

PDGFR

Chronic

myeloid

leukemiaacute

lymphocytic

leukemia

Rash diarrhea

pleural effusion


myelosuppression

QT interval

prolongation

CBC ECG liver

chemistries


retention




Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















Erlotinib

(Tarceva)

EGFR Non-small cell

lung cancer

pancreaticcancer

Acneiform rash

diarrhea loss of


conjunctivitis

elevated liver

chemistries

Liver chemistries

signs of


in patients with

dermatologic

toxicity

Gefitinib

(Iressa)

EGFR Non-small cell

lung cancer

Acneiform rash

diarrhea loss of


lung disease (rare)


Liver chemistries

signs of

inflammatory or

infectious sequelae


toxicity



Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















Imatinib

(Gleevec)

BCR-

ABLc-KIT

PDGFR

Acute

lymphocyticleukemia

chronic

myeloidleukemia

gastrointestin

Rash weight

gain edemapleural

effusion

cardiactoxicity

(depression of

CBC liver


and symptoms

of fluidretention

al stromaltumor

hypereosinop

hilicsyndrome

systemic

mastocytosis

LVEF)nausea and

vomiting


myelosuppres

sion



Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















Lapatinib

(Tykerb)

HER2

neu

EGFR

Breast cancer

with HER2neu

overexpression

Cardiac toxicity

(depression of

LVEF QT

prolongation)

acneiform rash

palmar-plantar

LVEF ECG

electrolyte

levels liver

chemistries

ia (hand-foot

syndrome)

diarrhea nausea

and vomiting

elevated liver

chemistries




Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















Sorafenib(Nexavar)

BRAFVEGFR

EGFRPDGFR

Renal cellcancer




Bloodpressure


e eva e amy ase



syn rome




note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















note


intravenously






[Coumadin])




carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib





















carcinoma

983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)

983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148

983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)

983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144

983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141

983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155





983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib






















983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091

983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155

983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110

983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115

983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115

983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122

983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150





















S f ib



Sorafenib







































S f ib



Sorafenib





















Sorafenib



















Targeted Therapy in Cancer

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