Anindya seminar 1 growth factors and cell cycle signalling in pathogenesis of cancerPresentation Transcript
Good afternoon..... Good afternoon....
GROWTH FACTORS AND CELL SIGNALLING IN THE PATHOGENESIS OF CANCER ---Dr ANINDYA MUKHERJEE 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 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
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
iii)somatic arrangements:-sporadic MTC
OVER EXPRESSION OF NORMAL FORMS:-
ERB1 over expressed in
i)>80% of Squamous cell carcinoma
iii)80% of head & neck carcinoma
ERB2 overexpressed in
i)25% of breast carcinomas
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
Most well studied is MYC protoncogene
E )MUTATION OF PROTOONCOGENES ENCODING CYCLINS AND CDKIs
CDKIs: i)CIP/WAP family:p21,p27,p57
*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 2 nd 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 -aminoglutethimide Second gen -Formestane,fadrozole,rogletimide Third gen -exemestane,anastrozole,letrozole,vorozole Advanced breast carcinoma Adrenal suppression and myleosuppression due to aminoglutethimide, others may cause hot flushes,arthralgias and fatigue