Drug targets in cancer Flashcards
3 stages of cell cycle check points
G1/S
G2/M
M
G1/S check point regulated by
retinoblastoma protein
G2/M checkpoint regulated by
p53 (transcription factor)
M checkpoint
ensures proper attachment of chromasomes to mitotic spindle. If no proper attachment then cell death
Different types of anti-cancer drugs
Chemotherapy
ENdocrine therapy
Molecular targeted therapy
Immunotherapy
Oncogene addiction
When an oncogene uses one signalling transduction pathway.
E.g. HER2 (Breast Ca), BRAF (melanoma) EGFR and ALK (non small cell LC), BCR-ABL (CML)
Synthetic lethality
loss of function of either 2 or more gene individually has limited effect, but loss of function in both genes leads to cell death
Cancer targets can be found by
Immunohistochemistry
Insitu hybridisation
Next generation sequencing
Re: Molecular targeting agents
what is on target effects?
- side effects that are mechanism based.
- can be used as clinical biomarkers.
- e.g. sunitib = HTN
- gefitinib = rash
Re: molecular targeting agents
What is off target effects
- side effect that are caused by inhibition of other targets
- immune reactions
- toxic metabolites
- expression in ormal tissues
- chemo side effect: mucositis etc
What down stream signalling pathway does Tyrosine Kinase use?
Ras -> Raf -> MEK -> ERK
and
P13K -> AKt -> mTOR
Examples of tyrosine kinase receptors
ERBB/HER family
Often gain of function mutation
e.g. ERBB1 = EGFR
ERBB2 = HER2
Monoclonal antibodies for EGFR and its side effect
Cetuximab and panitumumab
acneiform rash, diarrhoea
Examples of TKIs for EGFR
Erlotinib, gefitinib (1st generation), afatinib (2nd generation)
side effect: rash, diarrhoea, fatigue, transaminitis.
Treat skin toxicity with: sun protection, oral antibiotics, skin care
What is osimertinib?
3rd generation EGFR TKI effective against T790M mutation and sensitising mutation.
Side effect of osimertinib
less skin side effect than 1-2nd line TKIs.
Monoclonal antibodies against HER2 in breast ca
Trastuzumab and pertuzumab.
side effect: cardiotoxicity
Lapatinib
Dual EGFR/HER2 TKI
S/E: N/V/D, mucositis, fatigue
WHat is Trastuzumab-emtansine?
antibody drug conjugate for HER2+ mBC cancer.
S/E: well tolerated, thrombocytopenia/raised aminotransferase
Examples of VEGF receptor and multikinase inhibitor
"-inib" Sorafenib Sunitinib Pazopanib Axitinib Cabozantinib Lenvatinib Vandetanib
Side effect of multikinase inhibitors
VEGF related: HTN, proteinuria, thromboembolism, RPLES
GI, skin, transaminitis/thyroid dysfunction.
How do you target Cyclin D/CDK/Rb in the cell cycle as part of cancer treatment?
(CDK4/6 + Cyclin D) phosphorylate and inactivate tumour suppressor Rb.
Inhibition of CD4/CD6 leads to reactivation of Rb and cell cycle arrest at G1.
What is ribociclib?
Selective CD4/6 inhibitor
Given orally w/ aromatase inhibitor.
S/E: neutropenia, LFT derangement, diarrhoea
Mechanism of action of PARP inhibitor
- PARP -> repair ss DNA break.
- ds DNA repair via homologous recombination (BRCA)
- if PARP is inhibited, then cells rely on homologous recombination to repair cells. If BRCA is mutated, they can’t fix dsDNA break so this leads to cell death.
Olaparib
PARP inhibitor
TO treat platinum sensitive relapse BRCA+ ovarian, fallopian tube, primary peritoneal cancer.
S/E: nausea, diarrhoea, fatigue
Mechanism of drug resistance in cancer
- Primary/intrinsic
- Secondary via:
tumour heterogeneity, activation of alternative pathway, alteration of drug target, reactivation of pathway
