Drug targets in cancer

Question 1

3 stages of cell cycle check points

Answer 1

G1/S
G2/M
M

Question 2

G1/S check point regulated by

Answer 2

retinoblastoma protein

Question 3

G2/M checkpoint regulated by

Answer 3

p53 (transcription factor)

Question 4

M checkpoint

Answer 4

ensures proper attachment of chromasomes to mitotic spindle. If no proper attachment then cell death

Question 5

Different types of anti-cancer drugs

Answer 5

Chemotherapy
ENdocrine therapy
Molecular targeted therapy
Immunotherapy

Question 6

Oncogene addiction

Answer 6

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)

Question 7

Synthetic lethality

Answer 7

loss of function of either 2 or more gene individually has limited effect, but loss of function in both genes leads to cell death

Question 8

Cancer targets can be found by

Answer 8

Immunohistochemistry
Insitu hybridisation
Next generation sequencing

Question 9

Re: Molecular targeting agents

what is on target effects?

Answer 9

• side effects that are mechanism based.
• can be used as clinical biomarkers.
• e.g. sunitib = HTN
• gefitinib = rash

Question 10

Re: molecular targeting agents

What is off target effects

Answer 10

• side effect that are caused by inhibition of other targets
• immune reactions
• toxic metabolites
• expression in ormal tissues
• chemo side effect: mucositis etc

Question 11

What down stream signalling pathway does Tyrosine Kinase use?

Answer 11

Ras -> Raf -> MEK -> ERK

and

P13K -> AKt -> mTOR

Question 12

Examples of tyrosine kinase receptors

Answer 12

ERBB/HER family
Often gain of function mutation

e.g. ERBB1 = EGFR
ERBB2 = HER2

Question 13

Monoclonal antibodies for EGFR and its side effect

Answer 13

Cetuximab and panitumumab

acneiform rash, diarrhoea

Question 14

Examples of TKIs for EGFR

Answer 14

Erlotinib, gefitinib (1st generation), afatinib (2nd generation)

side effect: rash, diarrhoea, fatigue, transaminitis.

Treat skin toxicity with: sun protection, oral antibiotics, skin care

Question 15

What is osimertinib?

Answer 15

3rd generation EGFR TKI effective against T790M mutation and sensitising mutation.

Question 16

Side effect of osimertinib

Answer 16

less skin side effect than 1-2nd line TKIs.

Question 17

Monoclonal antibodies against HER2 in breast ca

Answer 17

Trastuzumab and pertuzumab.

side effect: cardiotoxicity

Question 18

Lapatinib

Answer 18

Dual EGFR/HER2 TKI

S/E: N/V/D, mucositis, fatigue

Question 19

WHat is Trastuzumab-emtansine?

Answer 19

antibody drug conjugate for HER2+ mBC cancer.

S/E: well tolerated, thrombocytopenia/raised aminotransferase

Question 20

Examples of VEGF receptor and multikinase inhibitor

Answer 20

"-inib"
Sorafenib
Sunitinib
Pazopanib
Axitinib
Cabozantinib
Lenvatinib
Vandetanib

Question 21

Side effect of multikinase inhibitors

Answer 21

VEGF related: HTN, proteinuria, thromboembolism, RPLES

GI, skin, transaminitis/thyroid dysfunction.

Question 22

How do you target Cyclin D/CDK/Rb in the cell cycle as part of cancer treatment?

Answer 22

(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.

Question 23

What is ribociclib?

Answer 23

Selective CD4/6 inhibitor
Given orally w/ aromatase inhibitor.

S/E: neutropenia, LFT derangement, diarrhoea

Question 24

Mechanism of action of PARP inhibitor

Answer 24

• 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.

Question 25

Olaparib

Answer 25

PARP inhibitor

TO treat platinum sensitive relapse BRCA+ ovarian, fallopian tube, primary peritoneal cancer.

S/E: nausea, diarrhoea, fatigue

Question 26

Mechanism of drug resistance in cancer

Answer 26

• Primary/intrinsic
• Secondary via:
  tumour heterogeneity, activation of alternative pathway, alteration of drug target, reactivation of pathway