Molecular Targeted Therapy

Question 1

Name some examples of cancer targets for therapy

Answer 1

Tyrosine kinase (intracellular aspect of GFR), growth factor receptors, epigenetic modifications, hormone receptors and angiogenic receptors or modulators

Question 2

What targets are used in the treatment of breast cancer?

Answer 2

HER2 which can be targeted with Trastuzumab (Herceptin)

Question 3

What targets are used in the treatment of colorectal cancer?

Answer 3

EGFR is targeted with a combination of cetuximab with oxaliplatin-containing chemotherapy

Question 4

What targets are used in the treatment of lung cancer?

Answer 4

EGFR lung cancer (usually non-small cell lung cancer) is treated with Afatinib, erlotinib and gefitinib

Question 5

What targets are used in the treatment of melanoma?

Answer 5

BRAF (V600E) mutation can be treated with vemurafenib, dabrafenib and trametinib (but these are v v expensive)

Question 6

What specific mutation is associated with unresectable or metastatic melanoma?

Answer 6

BRAF - V600E mutation is most common

Question 7

What are the three forms of biological therapy?

Answer 7

Antibody inhibitors of growth receptor, antibody-drug conjugates (antibody targets drug directly to tumour cells) and TKIs of growth receptors (bind to intracellular portion of GFR to prevent growth signal from being produced)

Question 8

How do ‘naked’ antibodies work in the treatment of cancer?

Answer 8

Activate the immune system, target checkpoints such as programmed cell death (PCD-1) and inhibit the activity of the antigen to prevent proliferation

Question 9

What are the two aspects of an antibody?

Answer 9

The variable portion at the top (the V) is the Fab portion, the stem (I) is the Fc portion

Question 10

Name two monoclonal antibodies which act on EGFR receptors

Answer 10

cetuximab and panitumab

Question 11

Name two monoclonal antibodies which act on HER2 receptors

Answer 11

ranstuzumab and pertuzumab

Question 12

Name a monoclonal antibody which acts on the VEGF receptor

Answer 12

Bevacizumab (avastin)

Question 13

Outline the normal function of the VEGF receptor

Answer 13

Usually protects the endothelial cells from death in tumour cells by activating the PKC pathway and up-regulating anti-apoptotic proteins such as Bcl-2

Question 14

How do monoclonal antibodies access tumour cells?

Answer 14

Normal tissue has blood vessels with an intact endothelium, whereas tumour tissues have leaky blood vessels which allows the passage of macromolecules such as antibodies to pass across. In addition, tumour tissues rarely have lymphatic drainage so these antibodies can accumulate in solid tumours.

Question 15

Describe the mechanism of action of Trastuzumab (Herceptin)

Answer 15

• Prevents cleavage of the HER2 receptor, which prevents unregulated signalling pathways from being activated
• Inhibits dimerization between HER2 receptors to inactivate signalling pathways
• Facilitates antibody-dependent cell-mediated cytotoxicity by bivalently binding to the HER2 receptor and a natural killer cell which leads to the destruction of the tumour cell
• Facilitates endocytosis of the HER2 receptor so it is degraded and can’t stimulate proliferation any longer

Question 16

What is a potential side-effects of trastuzumab?

Answer 16

May cause the development of a rash and can lead to congestive heart failure (may cause decline in left ventricular cardiac function)

Question 17

What is the mechanism of action of erlotinib and gefitinib?

Answer 17

Inhibit ATP binding and are used in the treatment of advanced stage non-small cell lung cancer by acting on the EGFR receptor

Question 18

Which mutations are associated with drug-resistance to TKIs in the treatment of EGFR lung cancer?

Answer 18

T790M (exon 20) and D761Y (exon 19) mutations in the tyrosine kinase domain of EGFR lung cancer

Question 19

Binding of monoclonal antibodies to which growth factor receptor may lead to slow wound healing and clotting?

Answer 19

EGFR (endothelial growth factor receptor)