5.2 Cancer therapies: cytotoxics to targeted therapies

Question 1

What are the phases of drug assessment?

Answer 1

In vitro: shows activity in cell lines
Preclinical: animal models
Phase I: clinical assessment - dose finding
Phase II: Safety and efficacy assessment in various tumours
Phase III: comparing against best available treatment
Phase IV: post marketing safety surveillance

Question 2

How does chemotherapy work?

Answer 2

Effect cellular division which promotes apoptosis. There is no selection for tumour cells but normal cells are thought to be able to recover better.
Works best against dividing cells

Question 3

Which cancer is chemo used as curative?

Answer 3

Paediatric tumours, germ cell malignancies, leukaemia, lymphomas

Question 4

What are monoclonal antibodies?

Answer 4

Proteins synthesised to bind onto specific ligands, tumour cel proteins or receptors on the cell surface necessary for tumour growth and neutralize their action

Question 5

What are small molecule inhibitors?

Answer 5

Block the activity of a signalling pathway inside the cells to prevent tumour growth

Question 6

What is the target for rutiximab and what is it used for?

Answer 6

CD 20 in lymphoma

Question 7

What is transtuzumab, what is its trade name and what is it used for?

Answer 7

Her2 receptor - Herceptin in breast cancer and gastric cancer

Question 8

What is imatinib, what does it target and what is it used for?

Answer 8

Glivec, c-KIT and bcr-abl used in GIST and CML

small molecule transduction inhibitor

Question 9

What is the role of Her2?

Answer 9

The Her2 receptors play a key role in cell growth and survival. Over expression or mutation leads to increased proliferation of the cancer cells.

Promotes invasion, survival and angiogenesis of cancer cells

Question 10

How to you determine Her status?

Answer 10

Immunohistochemistry to look for the receptors

Question 11

What are the strategies for inhibiting Her2?

Answer 11

Transtuzumab (Herceptin): monoclonal antibody to block ligand binding or receptor dimerization

Lapatinib (Tykerb): small molecule kinase inhibitor

Question 12

What is the main toxicity of transtuzumab?

Answer 12

Reversible cardiotoxicity

Question 13

What is transtuzumab emtansine and when is it used?

Answer 13

T-DM1
monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent DM1. This enters the cell and causes damage this way. Used in transtuzumab resistant Her2+ breast cancer

Question 14

What is Lapatinib and when is it used?

Answer 14

Small molecule dual kinase inhibitor (EGFR or Her2) and is used in transtuzumab resistant advanced cancer in combination with Xeloda

Question 15

What is the theory behind targeting VEGFR?

Answer 15

Causes regression of tumour microvasculature and normalisation of surviving mature vasculature to improve access of chemo drugs and inhibits new vessel growth

Question 16

What is EGFR

Answer 16

EGFR is a regulator of cell cycle progression, repair and survival and is involved in tumour metastases

Question 17

What is Bevacizumab and what is it used for?

Answer 17

Monoclonal antibody to VEGF

Works in metastatic colorectal, NSCLC, Breat and renal cell cancer

Question 18

What is Cetuximab and what is it used for?

Answer 18

IgG monoclonal antibody against EGFR the blocks EGFR and inhibits proliferation, angiogenesis and metastases and stimulates apoptosis

Used for EGFR positive colorectal and head and neck

Question 19

What is the marker in colorectal patients to indicate cetuximab (anti EGFR) usage?

Answer 19

K-RAS and NRAS wild type will respond to anti EGFR therapy

Question 20

What is the main side effect of cetuximab?

Answer 20

Acneiform rash - severity of which indicate positive response

Question 21

What are the tyrosine kinase inhibitors drugs of EGFR and what are the side effects?

Answer 21

Gefitinib
Erlotinib
Afatinib

Side effects: rash and diarrhoea

Question 22

What is Ipilimumab and what is it used for?

Answer 22

Anti CTLA-4 monoclonal antibody which blocks T cell activation - used for melanoma

Question 23

What is Dabrafenib and what is it used for?

Answer 23

Inhibitor of BRAF which blocks the MAPK pathway used for melanoma