Targeted cancer therapy

Question 1

Types of targeted therapy

Answer 1

Hormone therapy (HR positive breast cancers)
Signal transduction inhibitors (Bcr-Abl inhibitors)
Gene/protein expression modulators (nutlins)
Apoptosis inducers (nutlins)
Angiogenesis inhibitors (VEGF inhibitors)
Toxin delivery molecules
Immunotherapies

Question 2

Molecular subtypes of breast cancer

Answer 2

HER2 overexpressed in 15% of breast cancers

HR+/HER2- is 73%
HR-/HER2- 13%
HR+/HER2+ 10%
HR-/HER2+ 5%

Question 3

Her2 signalling

Answer 3

Homo/hetero dimer forms following ligand binding

Cytosolic domain phosphorylated, activating Ras/Raf signalling for proliferation

Question 4

Herceptin

Answer 4

Binds dimerisation domain and blocks downstream signalling
Blocks cleavage which leads to phosphorylation and signalling
Variable region recruits immune cells (cell mediated cytotoxicity)
Can induce HER2 endocytosis

Question 5

Vemurafenib

Answer 5

BRAF V600E inhibitor
Malignant melanoma tumours genotyped for V600E mutation

New mutation in MEK gene identified leading to resistance

Question 6

Targeted therapy resistance

Answer 6

Secondary mutation, amplification or activation of target
Bypass of oncogenic pathway
Activation of alternative pathway

Question 7

Nutlins

Answer 7

Mdm2 often upregulated in cancers
Nutlins inhibit Mdm2 binding to p53
Causes p53 re-expression and apoptosis induction

Question 8

Avastin

Answer 8

Monoclonal antibody that targets Vascular endothelial growth factors (VEGF)
Delays progression of lung and colon cancer