Good afternoon.....

Good afternoon....

GROWTH FACTORS AND CELL S IGNALLING IN THE

PATHOGENES IS OF CANCER

--- Dr ANINDYAMUKHERJEE, PGT dept of radiation

oncology

MOLECULAR BASIS OF CANCER

...the crux of the molecular basis:Targets of DNA damage are four classes of regulatory genes :

Protooncogenes :promotes growth. Tumor suppressor genes:inhibits growth

Apoptotic genes DNA repair genes, and a new class of molec-

Ules known as microRNAs

Mutated protooncogenes(AD) Mutated tumor suppressor-

uncontol genes(AR/haploinsufficiency) led

prolif. Mutated DNA repair genes-sublethal damage failed to repair CANCER Mutated apoptotic genes

Essential alterations for malignant transformation

SELF SUFFICIENCY IN GROWTH SIGNALS

Mutation of protooncogenes encoding expression of growth factors,growth factor receptors,signal transducing protein,nuclear regulatory proteins and cell cycle regulators.

A) GROWTH FACTOR PROTOONCOGENES Mechanism:Paracrine dependency Autocrine self sufficiency

Few oncogenes,overview.....

B) GROWTH FACTOR RECEPTORS PROTOONCOGENES

• MECHANISM 1…. Constitutive

dimerization of transmembrane receptors and activation

without binding to growth factors

RET protooncogene with tyrosine kinase activity:-

i)point mutation in its extracellular

domain :MEN 2A(MTC+Pheo+PTHadenoma)

ii)point mutation in its cytoplasmic catalytic

domain:-MEN2B(MTC+pheo)

iii)somatic arrangements:-sporadic MTC

MECHANISM 2….• OVER EXPRESSION OF NORMAL FORMS:-

• EGFR FAMILY

ERB1 over expressed in

i)>80% of Squamous cell carcinoma

ii)>=50% glioblastoma

iii)80% of head & neck carcinoma

ERB2 overexpressed in

i)25% of breast carcinomas

ii)ovary,lung,stomach,salivary gland

adenocarcinomas

Domains of EGFR undergoing mutation...

MECHANISM 3….

Mutation and rearrangements:-

a)FLT3(coding FMS like tyrosine kinase 3)

amplified in myeloid leukaemias

b)PDGF receptor point mutation results in

gliomas, leukaemias

c)cKIT(with tyrosine kinase activity)

mutation results in GIST,leukaemias.

C) SIGNAL TRANSDUCING PROTEINS ENCODED BY PROTOONCOGENES

• 1) Most well studied-RAS family of GTP binding proteins

C2)Less commonly due to point mutations...

viz,JAK2 point mutation results in Polycythemia vera

C3) Alterations in nonreceptor tyrosine kinase

Mostly due to translocations..

D) MUTATION OF PROTOONCOGENES ENCODING NUCLEAR TRANSCRIPTION FACTORS

Viz, MYC,MYB,JUN,FOS,REL..

Most well studied is MYC protoncogene

E )MUTATION OF PROTOONCOGENES ENCODING CYCLINS AND CDKIs

CDKIs: i)CIP/WAP family:p21,p27,p57

ii)INK4 family:

P15,p16,p18,p19.*Most radiosensitive

phase:G2M>M

*Most radioresistant phase : late S

E) CONTD...INTERNAL CONTROLS OF CELL CYCLE OR 'CHECKPOINTS'G1-S checkpoint:checks for DNA damage which is repaired/initiates

apoptosis if unrepairable, before cell commits itself to S phase. P53 chiefly and RB gene regulates this checkpoint.

CELL CYCLE ARREST AT G1-S CHECKPOINT AND S PHASE DELAY,contd....

G2-M CHECKPOINT: Monitors the completion of DNA replication and checks whether the

cell can safely initiate mitosis and separate sister chromatids. Arrest of cell cycle at this

checkpoint involves both p53 -dependent and p53-independent mechanisms. Defects in G1-S and G2-M transition checkpoints are a major cause of genetic instability in cancer cells.

CELL CYCLE ARREST AT G2-M CHECKPOINT...contd..

DSBs and DSB Response regulating ATM gene.....

Essence of lethality-DSBs

DSBs repaired by homologus recombination and non homologus end joining(NHEJ)

ATM gene:master regulator of DSB response,mu-

tated in ataxia telengiectasia where

DNA damages aren't detected,hence

no G1-S or G2-M transition phases.

CELL CYCLE EFFECTS OF ANTICANCER DRUGS

PHASE CCS DRUGS CCNS DRUGS

G1-S ETOPOSIDE PLATINUM COMPOUNDS

S ANTIMETABOLITES ALKYLATING AGENTS

G2-M BLEOMYCIN,ETOPSIDE ANTHRACYCLINES,DACTI

NOMYCIN

M VINCA ALKALOIDS,TAXANES,IXA

BEPILONE,ESTRAMUSTIN

E

MITOMYCIN,CAMPTOTHE

CINS

MONOCLONAL ANTIBODIES...FEW EXAMPLES AND

INDICATIONS

MONOCLONAL ANTIBODY TARGET INDICATION

Rituximab,Ibritumonab CD 20 B cell NHL

Gemtuzumab,Ozogamicin CD 33 CD 33 positive AML

Ocrelizumab,oftamumab CD 20 SLE

Alemtuzumab CD 52 B cell CLL

Adalimumab,Infliximab TNF-alpha Rheumatoid arthritis

Trastuzumab Her2-neu Breast cancer

Donesumab RANK ligand Osteoporosis

Bevazicumab VEGF Colorectal cancer

Ranibizumab VEGF Neovascular macular degeneration

Cetuximab EGFR Head neck CA.colorectal CA

Panitimumab EGFR Colorectal carcinoma

TYROSINE KINASE INHIBITORS...

Imatinib,Dasatinib,Nilotinib - inhibits tyrosine activated due to abl-bcr fusion(t9:22,Ph chromosome),used in chronic phase of CML and GIST.

Geftinib ,Erlotinib - inhibits tyrosine kinase assoc. with EGFR,used in NSCLC.

Sorafenib,Sunitinib - inhibit multiple tyrosine kinases.Both can be used in RCC.Additionally

sorafenib for HCC and sunitinib for GIST.

Lapatinib- inhibits tyrosine kinase assoc. with EGFR and her2/neu receptors,used in Breast cancer.

Sites of action on EGFR receptor-an example of targeted therapy...

HORMONES AND RELATED AGENTS :

CLASS DRUGS USED IN SIDE EFFECTS

Glucocorticoids Prednisolone Combination Chemotherapy in leukaemia,lymphoma

Fluid retentn,HTn,diabetes,obesity,infections,etc

Estrogens Estrogen Prostrate cancer Antiandrogenic effects

Progestins MDPA,Megestrol 2nd line therapy for metastatic hormone dependent breast and endometrial cancer

Fluid retention,bloating,oedema

Antiandrogens Flutamide,bicalutamide

Prostatic cancer Hepatic dysfunction,gynaecomastia,hot flushes

GnRH agonists Goserelin,Nafarelin,Leuprolide

Advanced prostratic cancer

Transient flare up,hot flush,gynaecomastia,osteoporosis.

GnRH antagonists Cetorelix,Ganirelix,Abarelix

Advanced prostratic cancer

Same as that of agonists except no flare-up occurs

HORMONAL AGENTS Contd....

CLASS DRUGS USED IN SIDE EFFECTS

SERMs(Selective estrogen receptor modulators)

Tamoxifen,tormifene Early and metastatic breast carcinoma

Menopausal symptoms,thromboembolism,endometrial cancer,etc

Pure ER antagonist(Selective estogen receptor down regulators-SERDRs)

Fulvestrant Metastatic breast cancer

limited

Aromatase inhibitors(inhibits conversion of androstendione to estrone)

First gen-aminoglutethimideSecond gen-Formestane,fadrozole,rogletimideThird gen-exemestane,anastrozole,letrozole,vorozole

Advanced breast carcinoma

Adrenal suppression and myleosuppression due to aminoglutethimide, others may cause hot flushes,arthralgias and fatigue

....Thank you