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Inhibitors of angiogenesis
26th April 2010
Angiogenesis in diseases
Lecture VII
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Physiological angiogenesis in adults is restricted
placenta uterus
Hair growthWound healing
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RheumathoidRheumathoidArthritisArthritis
TumorsTumorsAIDS AIDS
complicationscomplications
PsoriasisPsoriasis
InfertilityInfertility
SclerodermiaSclerodermia
CardiovascularCardiovasculardiseasesdiseases
UlcersUlcers
StrokeStroke
SightSight lossloss
angiogenesis
ExagerratedExagerrated
InsufficientInsufficient
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New capillary formation inresponse to wounding
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AJ Singer&RAF Clark, NEJM 1999
Angiogenesis and wound healing
VEGF is strongly induced after injuryKeratinocytes and macrophages are the major producers
12-24 hours
3-7 days
1-2 weeks
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Figure 13.14 The Biology of Cancer (© Garland Science 2007)
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Impaired wound healing in diabetes
Brem & Tomic-Canic, JCI 2007
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Inflammation is a component of the wound healing response
Coagulation
Inflammation
Migration/ProliferationAngiogenesis
EpithelializationContractionFibroplasia
Remodeling
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Tumors resemble wounded tissues that do not heal
Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
Dvorak HF N Engl J Med. 1986
Wound healing tumor progression
The ability of the tumor to grow requires continuous remodeling within the tissue, which is very similar to the process of wound healing.
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Inflammation promotes cancer:Old idea, renewed interest
• In 1863, Rudolf Virchow proposed that inflammation is one of the predisposing factors of tumor genesis.
• “Virchow’s hypothesis has almost been forgotten and ignored for more than a hundred years, but experienced a renaissance in the past 10 years”-Axel Schmidt, In Remembrance of Rudolf Virchow (1821-1902), 2006
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Inflammation and Cancer
• Cancer escapes immunosurveillance
• Many studies have found that not only does the immune system fail to eliminate cancer, but that certain aspects of the immunesystem act to promote the formation and progression of tumors
• Cells known to be involved in inflammation have been linked to tumor promotion
• The role of innate immune cells (i.e. macrophages) in tumor promotion has received the most attention, but there is evidencethat cells of the adaptive immune system (i.e. B cells) are alsoinvolved
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Tumor growth is dependent on angiogenesis
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JudahJudah FolkmanFolkman
1933-2008
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Tumor Angiogenesis: A Balancing Act
Folkman J, Nature Drug Discovery 6:274, 2007
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Angiogenesis is dependent on the balance betweenpro- and anti-angiogenic mediators
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Figure 13.23 The Biology of Cancer (© Garland Science 2007)
Laser microdissection
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Mechanisms ofangiogenic switch
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Avascular tumor growth is the growth of tumors without blood vessels. These are less complex than vascular tumors. Avascular growth is a distinct phase in cancer development and is the stage before the tumor develops its own blood supply and continues to grow (vascular growth).
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The Angiogenic Switch is necessary...for Tumor Growth and Metastasis
Somatic mutation
Smallavascular
tumor
Tumor secretion of angiogenic factors
stimulates angiogenesis
Rapid tumor growth and metastasis
Carmeliet and Jain. Nature. 2000; 407:249;
Bergers and Benjamin. Nat Rev Cancer. 2003; 3:401.
Tumor is dormant
Neovascularization:• Allows rapid tumor
growth by providingoxygen, nutrients, and waste removal
• Facilitates metastasis
Angiogenic switch
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The balance hypothesis for the angiogenic switch
Hanahan & Folkman, 1996
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Angiogenic Angiogenic switchswitch initiatesinitiates vesselvessel growthgrowth inin tumorstumors
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• Removes waste from growing tumor
• Provides tumor cells with oxygen and nutrients to grow
• Inhibition of tumor angiogenesis is promising as a cancer treatment
Tumor angiogenesis
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Tumor Angiogenesis
Angiogenesis: formation of new blood vessels from preAngiogenesis: formation of new blood vessels from pre--existing vasculatureexisting vasculature
Tumor Cells
Endothelial Cells
Extracellular Matrix
Basement Membrane
VEGF
bFGF
PDGFR
Supporting cells
proteases
PDGF
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BloodBlood vesselsvesselsinin tumorstumors areare differentdifferentthanthan inin healthyhealthy tissuetissue
HealthyHealthytissuetissue Tumor Tumor
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Figure 13.34b The Biology of Cancer (© Garland Science 2007)
Blood vessels in tumors are differentthan in healthy tissue
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BloodBlood vesselsvesselsinin tumorstumors areare differentdifferentthanthan inin healthyhealthy tissuetissue
HealthyHealthytissuetissue
Tumor Tumor
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Figure 13.15a The Biology of Cancer (© Garland Science 2007)
Tumor vessels are leaky
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Tumors are hypoxic
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Hypoxic area in tumors(a) Blue color (Hoechst dye) – blood vessels in tumors
(b) Red color (nitroimidazol EF5) – hypoxic area in tumor.
(c) Merged – hypoxic area close to the blood vessel
Giordano and Johnson 2001.
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Half-life of endogenous VEGF mRNA is about 65 minstability increases ~ 3 times in hypoxia
HypoxiaHypoxia –– one one ofof thethe strongeststrongestinducersinducers ofof VEGF VEGF expressionexpression
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Other diseases…
psoriasis
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PSORIASIS
- hyperplastic and inflammeddermal blood vessels- epidermal thickening(acanthosia) with aberrantkeratinocyte proliferation- inflammatory infiltrates
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Blood 2003
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A psoriasis-like diseaseproduced in Tie2 transgenic mice
Voskas D et al., Am J Pathol. 2005 Mar;166(3):843-55
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Voskas D et al., Am J Pathol. 2005 Mar;166(3):843-55
Repression of Tie2 transgene expression with doxycyclinereverses the abnormal skin phenotype seen in transgenic mice
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Treatment ofnumerous
diseases can be improvedby anti-
angiogenictherapy
Treatment ofnumerous
diseases can be improved by
pro-angiogenic therapy…
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Anti-angiogenic Therapy
A new form of cancer treatment using drugs called'angiogenesis inhibitors' that specifically stop new blood vessel growth and starve a tumor by cutting off its blood supply.
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Tumor increases andmetastases Tumor decreases
Tumor withouttreatment
Tumor treated withantiangiogenic therapy
The influence of angiogenesis inhibition on the tumor growth
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VEGF inhibition dramatically affects vessel development
Kerbel & Folkman. Nat Rev Cancer 2002;2:727–39Jain. Nat Med 2001;7:987–9
Before VEGFinhibition
After VEGFinhibition
VEGF is over-expressed in a variety of tumours
Normalvasculature
Matureand stable
Disorganisedand hyperpermeable
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Stages of angiogenesis
� increase in vessel permeability and thrombin deposition� loosening of pericyte contact� proteinase release from endothelial cells � digestion of basement membrane and extracellular matrix� migration and proliferation of endothelial cells � formation of vascular structures� fusion of new vessels� initiation of blood flow
- inhibition of endothelial cell proliferation- inhibition of the migration of endothelial cells
� formation of basement membrane
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Various strategies to inhibit VEGF signaling
Ferrara and Kerbel, Nature 2005
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Different stages of angiogenesis inhibition
Inhibition of latestages of angiogenesis
(angiostatin, endostatin)
Inhibition of matrixdegradation andendothelial cells
migration
Inhibition of VEGF activity
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What is the mechanisms of actionsof anti-angiogenic drugs?
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Inhibitors of angiogenesis
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Normalisation of blood vessels as themechanisms of action of anti-angiogenic agents
Jain, Science 2004
normal tumor anti-angiogenic
therapy
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Three general mechanisms of angiogenesisinhibitors currently approved by FDA
Sutent = sunitinib
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Endogenous inhibitors of angiogenesis
Proteins or fragments of proteins that are formed in thebody, which subsequently can inhibit the formation of blood
vessels by disrupting the angiogenic process
They are• present in the circulation• sequestered in the ECM surrounding cells
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Angioarrestin2-Methoxyestradiol (2-d)
Vasostatin (calreticulin fragment)Kringle 5 (plasminogen fragment)
VasculostatinInterleukin-12 (IL-12)
TumistatinInterferon inducible protein (IP-10)
Transforming growth factor-betaInterferon alpha/beta/gamma
Thrombospondin-1Human chorionic gonadotropin (hCG)
rtisol-S Heparin hexasaccharide fragment
TetrahydrocoHeparinases
RetinoidsGro-beta
Proliferin-related proteinFibronectin fragment
Prolactin 16kD fragment Endostatin (collagen XVIII fragment)
Platelet factor-4 (PF4) CD59 complement fragment
Plasminogen activator inhibitorCartilage-derived inhibitor (CDI)
Placental ribonuclease inhibitor Canstatin
Pigment epithelial-derived factor (PEDF) Anti-angiogenic antithrombin III (aaATIII)
Metalloproteinase inhibitors (TIMPs) Angiostatin (plasminogen fragment)
List of Angiogenesis Inhibitors in the Body
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Angiogenesis inhibitors
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Main groups of endogenous inhibitors:
• Matrix-derived endogenous inhibitors (endostatin, thrombospondins)
• Fragments of blood coagulation fragments (angiostatin)
• Molecules of the immune system with anti-angiogenic activities(interferons, interleukins)
• Other inhibitors (tissue inhibitors of MMPs – TIMP)
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Angiogenesis Inhibitors
• Other angiogenesis inhibitors have been found in nature - in green tea, soy products, fungi, mushrooms, Chinese cabbage, tree bark, shark tissues, snake venom, red wine, and many other substances.
• Still other angiogenesis inhibitors have been manufactured synthetically in the laboratory.
• Some FDA-approved medicines have also been "re-discovered" to have anti-angiogenic properties.
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Angiogenic Inhibitors
Currently, a number of clinical trials in progress arecombining anti-angiogenic therapy with cytotoxic chemotherapy or radiation, as a way to maximize the anti-tumor treatment in human cancer patients
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Anti-Angiogenic Drugs in Clinical Trial for CancerNeovastatNM-3NPe6OctreotideOltiprazPaclitaxelPanzem (2ME2)PenicillaminePI-88PSKPTK787/ZK222584RevimidRo317453SqualamineSU11248SU6668TemptostatinTetrathiomolThalidomideUCN-01VEGF Trap
ZD6126ZD647
Combretastatin A4PCP-547, 632CP-564, 959DexrazoxaneDidemnin BDMXAAEMD 121974EndostatinFlavopiridolGBC-100Genistein Concentrated PolysaccharideGreen Tea ExtractInterleukin-12INGN 201Interferon alfaIressaLY317615Mab huJ591-DOTA-90 Yttrium (90Y)Medi-522Metaret (suramin)Metastat (Col-3)
A6Alpha5Beta1 Integrin AntibodyABT-510ActimidAngiocolAngiostatinAngiozymeAplidineAptosynATN-161Avastin (bevacizumab)AVE8062ABenefinBMS275291CarboxymidotriazoleCC4047CC7085CDC801Celebrex (Celecoxib)CEP-7055CGP-41251/PKC412
Cilengitide
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Specific Angiogenic Inhibitors
• Angiostatin• Endostatin• Avastin (Bevacizumab)
• Pegaptinib
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Angiostatin• Angiostatin is a polypeptide of approximately 200 amino acids
• It is produced by the cleavage of plasminogen, a plasma protein that is important for dissolving blood clots
• Angiostatin binds to subunits of ATP synthase exposed atthesurface of the cell embedded in the plasma membrane
• It exist as multiple isoforms
• Considerable uncertainty on its mechanism of action, but it seems to involve the inhibition of endothelial cell migration, proliferation and induction of apoptosis
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Angiostatin
• Naturally occurring protein found in several animal species, including humans.
• Can be cleaved from plasminogen by different metalloproteinases (MMPs), elastase, prostata-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase.
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Endostatin• It was first discovered in 1995 in
Dr. Folkman’s lab• Phase I clinical studies began in
1999• A naturally-occurring 20-kDa C-
terminal fragment derived from type XVIII collagen.
• Interfere with the pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF)
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Endostatin treated Lewis Lung Carcinoma
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Inhibition of tumor growth by endostatin
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Dose-dependent tumor inhibition
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Bevacizumab – Avastin
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Angiogenesis inhibitors in clinical trials
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Avastin
• Avastin is a humanized monoclonal antibody (MAb) that targets vascular endothelial growth factor (VEGF)
• Causes regression of tumor vasculature
• Reduces intra-tumor pressure, thereby improving the delivery of cytotoxic agents to the tumor
• Also inhibits new tumor blood vessel formation, restricting tumor growth.
• The first anti-angiogenic agent with demonstrated anticancer benefit in phase III trials.
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Anti-VEGF antibody Bevacizumab (Avastin)
� Recombinant humanised monoclonal anti-VEGF antibody 93% human, 7% murine
� Recognises all major isoforms of human VEGF
� RhuMAb VEGF binding is restricted to human
� Bevacizumab binds VEGF, preventing interaction with its receptors and activation of downstream signalling pathways
� This ultimately leads to vascular regression, leaving the tumour dormant
Bevacizumb
– P– P
P–P–
VEGF
X
Growth
Proliferation
Migration
Survival
X
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Inhibition of experimental human tumor growthby anti-VEGF antibody (precursor of Avastin)
livers
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Avastinin clinical development: overview
Combined with IFL in previously untreated mCRC5mg/kg every 2 weeks
(n=813)Hurwitz H, et al. 2004
Dose-escalation trial in solid malignancies. Safety and
pharmacokinetics(n=25)
Gordon MS, et al. 2001
Phase I Phase II Phase III
5-FU = 5-fluorouracil; LV = leucovorin; mCRC = metastatic colorectal cancer; FOLFOX = 5-FU/LV + oxaliplatin; XELOX = Xeloda + oxaliplatin;IFN = interferon; CP = carboplatin/paclitaxel; CG = cisplatin/gemcitabine; RCC = renal cell cancer; MBC = metastatic breast cancer;IFL = irinotecan/5-fluorouracil/leucovorin; NSCLC = non-small cell lung cancer; PC = pancreatic cancer
Combined with Xeloda in previously treated MBC15mg/kg every 3 weeks
(n=462)Miller KD, et al. 2005
Combined with chemotherapy in metastatic
cancers3mg/kg every week
(n=12)Margolin K, et al. 2001
Combined with either FOLFOX4 or XELOX in previously untreated mCRC (n=1,920)
AVOREN: combined with IFN-α2a in metastatic RCC 10mg/kg every 2 weeks
(n=638)
AVANT: combined with FOLFOX4 or XELOX in stage II/III colon cancer
5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks(n=3,450)
AVAIL: combined with CG in previously untreated stage IIIb, IV or recurrent NSCLC 7.5 or 15mg/kg every
3 weeks (n=830)
Combined with CP in previously untreated NSCLC(n=99)
Johnson DH, et al. 2004
Monotherapy in previously treated RCC3 or 10mg/kg every 2 weeks
(n=116)Yang JC, et al. 2003
Combined with 5-FU/LV in previously untreated mCRC
5 or 10mg/kg every 2 weeks(n=104)
Kabbinavar F, et al. 2003
Monotherapy in previously treated MBC3, 10 or 20mg/kg every 2 weeks
(n=75)Cobleigh MA, et al. 2003
Combined with 5-FU/LV in previously untreated mCRC
5mg/kg every 2 weeks(n=209)
Kabbinavar F, et al. 2005
Combined with gemcitabine in unresectable PC10mg/kg every 2 weeksKindler HL, et al. 2004
Combined with TarcevaTM + gemcitabine in previously untreated PC
5mg/kg every 2 weeks(n=600)
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Avastin: promising phase II data in renal cancer
Pro
gres
sion
free
sur
vial
(%)
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35
Months from on-study date
Two-sided unadjusted p values:high-dose versus low-dose: p=0.0821
High dose versusplacebo: p<0.001
Low dose versusplacebo: p= 0.0115
High dose
Low dose
Placebo
� Global phase III study starting in H2 2003
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Bevacizumab-related events in CRC trials to date: overview
� hypertension (most common event)
�proteinuria
�arterial thrombosis
�effects on wound healing
�bleeding
Kabbinavar F, et al. J Clin Oncol 2003;21:60–5Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Giantonio BJ, et al.ASCO GI Symposium; 27–29 2005; Hollywood, Fl. Abstract 169a./www.asco.org. 2005.
Kabbinavar FF, et al. J Clin Oncol 2005..
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Phase II trial of Avastin in metastaticCRC (AVF0780g): adverse events
Number of patients (%)
5-FU/LV + Avastin
Adverse event 5-FU/LV (n=35) 5mg/kg (n=35) 10mg/kg (n=32)
Hypertension 1 (3) 4 (11) 9 (28)
Proteinuria 4 (11) 8 (23) 9 (28)
Epistaxis 4 (11) 16 (46) 17 (53)
Thrombosis 3 (9) 9 (26) 4 (13)
GI bleeding 0 2 (6) 5 (16)
Diarrhoea 29 (83) 32 (91) 24 (75)
Leucopenia 1 (3) 4 (11) 1 (3)
All eventsNot adjusted for treatment duration
Kabbinavar F, et al. J Clin Oncol 2003;21:60–5
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Increase in survival of patients with renal cellcancer treated with Avastin
Fever, hypertension, proteinuria – adverse effects
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The FDA approved Avastin in February 2004 for use in combination with intravenous 5-Fluorouracil (5-FU)-based chemotherapy as a treatment for patients with first-line metastatic cancer of the colon or rectum. In June 2006, the FDA approved Avastin for use in combination with intravenous 5-FU-based chemotherapy for patients with second-line metastatic cancer of the colon or rectum. In October 2006, the FDA approved Avastin in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.
Avastin in clinics
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Diabetic retinopathy
healthy diabetic retinopathy
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What is AMD?
• Age-related macular degeneration (AMD) is defined as the loss of macular function from the degenerative changes of aging
• The macula is the most important part of the retina responsible for sharp, central vision
• AMD is divided specifically into two distinct types: the less severe or “dry” form, and the more severe and debilitating “wet” form
• The root causes of AMD are still unknown
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Age-related macular degeneration (AMD)
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Normal MaculaDry AMD:Drusenformation under the Macula
Wet AMD:Macula with abnormal blood vessels
Age-related maculardegeneration (AMD)
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ClinicalClinical trialstrials withwith LucentisLucentis ((RanibizumabRanibizumab), a ), a modifiedmodifiedversionversion ofof AvastinAvastin inin adultadult macularmacular degenerationdegeneration
antianti--VEGFVEGF antibodyantibodynot not onlyonly preventsprevents sightsightlossloss, but , but eveneven improvesimproves itit!!
Folkman, Nature Drug Disc Rev 2007
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Current Treatments for AMD…• Lucentis™ (ranibizumab) — The FDA approved
Lucentis in June 2006 for the treatment of wet AMD. – Lucentis (ranibizumab) is a humanized anti-VEGF antibody
fragment that inhibits VEGF activity by competitively binding with VEGF.
– A two-year study showed that 95 percentof people with wet AMD who received monthly injections of Lucentis experienced no significant loss in visual acuity. Genentech also reported moderate visual improvementin 24.8 percent of participants treated with a 0.3 mg dose of Lucentis and 33.8 percent of participants treated with a 0.5 mg dose.
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Pegaptanib –Macugen
Aptamer which binds VEGF-165
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Pegaptanib sodium
Pegaptanib sodium is a covalent conjugate of an oligonucleotide of twenty-eight nucleotides in length that terminates in a pentylamino linker, to which two 20-kilodalton monomethoxy polyethylene glycol (PEG) units are covalently attached via the two amino groups on a lysine residue.
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The chemical name for pegaptanib sodium is as follows: RNA, ((2'-deoxy-2'-fluoro)C-Gm-Gm-A-A-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2' -fluoro)C-Am-Gm-(2'-deoxy-2-
fluoro)U-Gm-Am-Am-(2'-deoxy-2' -fluoro)U-Gm-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2' -flu oro)U-Am-(2'-deoxy-2'-fluoro)C-Am-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2' -fluoro)C-Gm-(3'® 3')-dT), 5'-
ester with a ,a '-[4,12-dioxo-6-[[[5-(phosphoonoxy)pentyl]amino]carbonyl]-3,13-dioxa-5,11-diaza-1,15-pentadecanediyl]bis[w -methoxypoly(oxy-1,2-ethanediyl)], sodium salt.
The molecular formula for pegaptanib sodium isC294H342F13N107Na28O188P28 [C2H4O]n
(where n is approximately 900) and the molecular weight is approximately 50 kilodaltons.
Pegaptanib sodium
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Macugen was demonstrated to be effective inprevention of vision loss in two large clinical
trials in patients with AMD
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Tyrosine kinase inhibitors
Marty et al. 2008
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Neovasculature: Inhibiting ECM Breakdown
• MMPs (metalloproteinases) are proteolyticenzymes that cleave the basement membrane
• Three domains: pro-peptide, catalytic domain, haemopexin-like c-terminal domain
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MMP-Inhibiting Drugs
• Marimastat (left)– Binds to zinc ion– Very limited success due to toxicity factors and need for
cytotoxic combination
• Batimastat (right)– 1,4 bidentate hydroxamic acid ligand that binds very tightly
to the zinc ion in the catalytic (active) site
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Future Directions-VEGF-Trap
• Composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to a human Fc segment of IgG1 that binds VEGF
• Decreases free VEGF to bind to receptors and prevent vessel growth
• FDA approved for macular degeneration
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Receptor-pułapka (VEGF-trap)
Hallosh et al. 2002
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Take-home messages• Physiological angiogenesis in adults is restricted, however
disturbances of this process is a hallmark of many diseases
• Tumors resemble wounded tissues that do not heal – remodelling, inflammation, angiogenesis…
• One of the strategy to treat tumor/AMD… is the anti-angiogenictherapy
• Angiogenesis inhibitors specifically halt new blood vessel growth and starve a tumor by cutting off its blood supply
• Angiogenesis inhibitors prevent the VEGF from binding with the receptors on the surface of the endothelial cells
• Many anti-angiogenic factors are in the Phase II/III of clinical trails