Lecture 21: Targeted cancer therapies

Question 1

Cancer is?

Answer 1

A disease of populations of cells that live, divide, invade and spread without reagard for normal limits

Question 2

Molecular basis of cancer?

Cellular basis of cancer?

Answer 2

Abnormalities of DNA caused by exogenous carcinogens, DNA replication errors or inherited

Cause by activation of proto-oncogenes and deactivation of tumour supressor genes

Cells have common phenotypic characteristics

• Evade apoptosis
• self-sufficiency in growth signals
• insensitivity to growth signals
• sustained angiogenesis
• limitless replicative potential
• tissue invasion and metastasis

Question 3

Chemotherapy targeting cycling cells?

Answer 3

• targets cells without discrimination between normal and cancer cells
• selective toxicity due to higher number of cycling cells in tumour
• Adverse effects due to inhibition of prolifertion of normal cells (alopecia, blood cytopaenias)

Question 4

2 examples of cycling cell targeted drugs

Answer 4

paclitaxel - antimicrotubule drug

(inhibits microtubules in the M-phase)

methotrexate - Antimetabolite drug

(inhibits DNA synthesis in the S-phase)

Question 5

Oncogenes?

Answer 5

Modified gense encoding abnormal proteins that increase probability of tumour formation (from proto-oncogenes by chromosomal translocation, mutation and amplification)

Question 6

Tumour supressor genes?

Answer 6

genes that if deleted or mutated, increase the probability of tumour formation. Normally promote apoptosis or repress cell cycle.

Question 7

Targeted cancer therapies?

Answer 7

1. Small molecualr drug
   - Block specific enzymes or growth factor receptors
   - eg. imatinib, gefitinib, sunitinib
2. monoclonal antibodies
   - bind to growth factors or their receptors
   - eg. trastuzumab, bevacizumab

Question 8

Chronic myeloid leukaemia?

drug action and ADE?

Answer 8

Philadelphia chromosome from translocation between 9-22

imatinib inhibits bcr-abl removing self-sufficiency of growth signals provided by this mutation.

Also used for GIST (gastrointestinal stromal tumours) that have a point mutation activating c-kit

Imatinib binds to the ATP binding site and stops tryosine kinase binding ability

GENERALLY WELL TOLERATED

Question 9

Breast Cancer?

Answer 9

Acquisition of self-sufficiency in growth signals by genetic amplification of HER-2 (human epidermal GF receptor-2)

Trastuzumab - is recombinant humanised monoclonal AB

• slectively targets extra-cellular domain of HER-2 blocking EGF
• side effects are mostly infusion reactions due to its administration.

Question 10

NSCLC?

Answer 10

Aquisition of self-sufficiency in growth signals by somatic mutations of Ras or EGFR leading to increased signal and increased proliferation.

Gefitinib is used for those showing EGFR mutations in the TK domain of the receptor

• Gefitinib binds to the ATP-binding site inhibiting EGFR tyrosine kinase activity

Adverse effect profile: Diarrhoea and skin rash

Question 11

Renal cell cancer?

Answer 11

associated with loss of von Hippel Lindau TSG (x2)

leads to high HIF-alpha not only in hypoxia but always allowing angiogensis to continually occur.

subitinib - small MW selective inhibitor og VEGF and PDGF receptors

ADE: hypertension haemorrhage, cardiac failure.