Signal Transduction Therapy

Question 1

What is signal transduction therapy?

Answer 1

• Design drugs which specifically target defective proteins in patients cancer cells
• Inhibit oncogene function
• Restore or make use of lack of tumour suppressors

Question 2

Hormone Therapy

Answer 2

• Useful in specific cancers that remain dependent on hormone for growth (e.g breast cancer)
• Treatment involves depriving the cancer of mitogenic hormone, by blocking hormone production, inhibit hormone receptor interaction with
  antagonist

Question 3

Acute promyelocytic leukaemia

Answer 3

PML/RARa fusion blocks production of polymorphonuclear cells, ends up with immature neutrophils making ‘useless cells’.

Retinoic acid treatments showed complete remission in around 5 years 85%

Question 4

Kinase Inhibitors

Answer 4

Mimic ATP plus binding substrate

Question 5

Gleevac

Answer 5

Targets Abl kinase to treat chronic myelogenous leukaemia

Created after 300 rounds of chemical modification screening

Question 6

Gleevac pathway

Answer 6

Question 7

Gleevac treatment

Answer 7

• Initial results highly promising with good clearance of disease
• Problems recently noted with drug resistant tumour appearing bearing mutations that specifically prevent
  inhibition of BCR-Abl kinase
  -Problems can be overcome by using a cocktail of inhibitors or combining with another type of treatment
  eg RNAi

Lack of complete specificity of Gleevec for the Abl kinase has meant that it has also found use as an inhibitor of the Kit receptor kinase oncogene in
gastrointestinal tumours (GIST)

Question 8

Targeting the EGF receptor

Answer 8

• Built EGF receptor inhibitors which have high selectivity

Question 9

Herceptin Monoclonal antibodies

Answer 9

• Designed to recognise extracellular domain of an activated receptor
• Inhibit activation of receptor and recruit new response to target cells
• Humanise mouse monoclonal antibodies
• After treatment, amount of HER2 receptors decreases, lowers level of phosphorylation of kinases
• Combination treatment of cancer cells with herceptin plus radiation dramatically enhances cell killing

Question 10

Ras inhibition

Answer 10

Central to a number of signalling pathways
- some new inhibitors being
tested that can either inhibit specific Ras allele or block Ras interactions with effectors

Ras difficult to drug as it is a small protein with only 1 pocket that binds to GTP/GDP. High GTP levels therefore high levels of inhibitors needed