Date post: | 07-Jul-2015 |
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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