P.COLOGY2: Pharmacological Targets for Cancer

Question 1

List the problems with anti-cancer drugs

Answer 1

• Selectivity + Specificity
• Off-target side effects
• Tumour cell heterogeneity
• Drug resistance
• Dose intensity

Question 2

What is the goal of cancer therapy?

Answer 2

• Preserve normal metabolism + cell function
• Shut down abnormal processes causing proliferation + growth

Question 3

Outline the approaches of Cancer Treatment

Answer 3

• Surgery
• Radiotherapy
• Chemotherapy
• Targeted therapy

Question 4

What drug targets VEGF signalling?

Answer 4

Bevacizumab

Question 5

What is the function of Bevacizumab?

Answer 5

• Monoclonal antibody
• Blocks angiogenesis by inhibiting VEGF-A
• Prevents activation of downstream signalling pathways
  
  • Cell migration, survival + proliferation
  • Kinase regulation
  • Vascular permeability
  • Cell proliferation
• Vascular regression - blocking VEGF cause tumour blood vessels to regress + lead to tumour shrinkage

Question 6

What drug targets HER2 signalling?

Answer 6

Trastuzumab

Question 7

What is the function of Trastuzumab?

Answer 7

• Inhibit signalling via receptor
• Inhibit cell cycle progression
• Decrease production of angiogenic factors
• Recruit natural killer cells to tumour
• When trastuzumab binds to HER2, can block tyrosine kinase SRC signalling, increase PTEN levels, which suppresses P13K/AKT signalling + decrease cell growth + survival

Question 8

Discuss trastuzumab resistance

Answer 8

Trastuzumab does not prevent HER3 dimerisation + overexpression of IGF-1R `(insulin-like growth factor 1 receptor) causing trastuzumab sensitive cells to be resistant to therapy

Question 9

What drug targets oestrogen signalling pathway?

Answer 9

Tamoxifen binds to estrogen receptor

• Does not change receptor shape
• tamoxifen receptor cannot bind to coactivators

Question 10

How does radiotherapy target cell cycle?

Answer 10

Radiotherapy damage DNA

1. External Bean Radiotherapy

• from outside the body using high energy ionising radiation
• used in up to 60% of treatments

2. Internal Brachytherapy

• radiotherapy from small radioactive seeds placed within the body

Both damage DNA

Surrounding normal tissues affected

Question 11

How does chemotherapy target cell cycle?

Answer 11

Chemotherapy interferes with cell cycle

• Inhibit cellular events that lead to cell division + replication
• Current chemotherapeutic cytotoxic agents target S/M phase of cell cycle
  
  • S = DNA replication
  • M = mitosis division of 2 daughter cells

Question 12

What are the 3 approaches to targeted therapy?

Answer 12

1. Inhibit interaction of a growth factor or hormone with its receptor (e.g. bevacizumab + VEGF)
2. Inhibit signalling via receptor (e.g. trastuzumab + HER2)
3. Target hormone signalling-pathways (e.g. tamoxifen + oestrogen receptor)

• Targets are more specific for cancer cells + important for tumour cell survival
• Therapies aimed @ cancer cells than all rapidly proliferating cells
  
  • increase effectiveness
  • decrease side effect
  • patient-specific

Question 13

Discuss surgical approach to cancer treatment

Answer 13

Invasive but best ‘cure’ for solid tumour

• Remove isolated metastatic masses
• Facilitate further treatment
• Used for prevention
• Debulking - removing bulk of tumour size before chemotherapy treatment starts