Cancer therapy and treatment

Question 1

What are the conventional cancer therapies?

Answer 1

• Surgery (remove or debulk local tumour)
• Radiotherapy (local and regional)
• Chemotherapy (systematic treatment for metastatic disease, combinations of drugs with different site of action needed for effective treatment)

Question 2

Why is hormone therapy effective in breast cancer?

Answer 2

Tamoxifen inhibits ER
Change in one abnormal condition triggers apoptosis
Tailored therapy to molecular changes in individual cancer

Question 3

What is radiation dependent on?

Answer 3

Expression of wild type p53
True of certain drugs that inhibit topoisomerases (camptothecin, etoposide)
Taxol= spindle poison, damage reported via p53

Question 4

How can chemotherapy lead to drug resistance?

Answer 4

Unstable cancer cells can evolve
mdr overexpression (membrane channel secretion protein) Secretes drugs outside the cancer cells

Question 5

What are the targets for therapy?

Answer 5

Growth factors and receptors/ signalling molecules/ cell cycle proteins/ pro-angiogenesis and pro-apoptotic molecules

Question 6

What are angiostatic agents?

Answer 6

Anti-angiogenesis, block vessel growth to keep tumour small
Kill normal cells so unlikely to require resistance, effective in mouse models, clinical trial dramatic results but some variation

Question 7

Examples of cancer drug success

Answer 7

Imatinib/ Glivec
Herceptin
Vemurafenib
Panitumumab/ Cetuximab

Question 8

What is Imatinib?

Answer 8

Small molecule inhibitor bcr/abl fusion protein in chronic myeloid leukaemia
90% patients enter remission but gene still detectable in bone marrow so will eventually come back
Intrinsic mutability of cells contain range of drug-resistant sub-clones before treatment is selected

Question 9

What is Herceptin?

Answer 9

Monoclonal antibody to HER-2/ neu receptor protein, (EGF family receptor) only effective in HER-2 overexpressing breast cancers

Question 10

What is Vemurafenib?

Answer 10

Small molecule drug inhibitor of the mutant BRAF in melanomas (RAS pathway)

Question 11

What is Panitumumab?

Answer 11

Monoclonal antibodies to the EGF receptor in colorectal cancer- only effective without K-ras mutation

Question 12

What is immunotherapy?

Answer 12

Stimulates patient immune system to recognise and destroy cancer cells

Question 13

What are the immune checkpoint inhibitors?

Answer 13

Ipilimumab targets CTLA-4 (inactivates)
Pembrolizumab targets PD-1, PD-L1 (T cells)- monoclonal antibodies block reaction to free T cells
Boosts the immune system repsonse against melanoma cells and other cancers (defective mismatch repair in colorectal cancers)

Question 14

How may cancer cells evade host defences?

Answer 14

Downregulation of MHC class 1 on tumour cells (doesn’t present antigens)= safe from CTL attack
Induction of CTL non-responsiveness to tumour Ag (PD-1)
Release of immunosuppressive factors from tumour- TGF beta

Question 15

What is synthetic lethality?

Answer 15

Using genomic instability for tumour selective drugs
BRCA 1/2
Have defective DNA d/s strand repair (homologous recombination)
Susceptible to drugs that block other major DNA repair pathway

Question 16

What drug is used in BRCA mutations?

Answer 16

Olaparib= PARP inhibitor (Poly ADP Ribose Polymerase)

Kills BRCA 1/2 cancers

Question 17

How does synthetic lethality work?

Answer 17

Two genes- mutation in either gene not lethal, bothy mutated= cell death
Disables base excision repair in s/s brake repair so causes cell death (knocks out compensating pathway)

Question 18

How does drug resistance occur?

Answer 18

• Overexpression of mdr (membrane channel secretion protein that exports drugs)
• mutation or amplification of the target protein or other proteins in the same signalling pathway
• Mutation in cell death pathway

Question 19

How are appropriate therapies selected?

Answer 19

Tumour profiling- Genomic (DNA copy number changes and Next Generation Sequencing/ NGS), transcriptomic and proteomic analysis, mRNA micro array
Inform about molecular abnormalities that may respond to tailored therapies
Changes in RNA expression

Question 20

What are the 2000Orignal Hallmarks of cancer?

Answer 20

• Self-sufficiency in growth signalling (cell cycle control)
• Evading apoptosis (death pathways)
• Limitless replicative potential (immortalisation)
• Insensitivity to anti-growth signals (signalling pathways)
• Sustained angiogenesis (cytokines)
• Tissue invasion and metastasis (adhesion, proteolysis and movement)

Question 21

What are the emerging hallmarks in the 2011 version?

Answer 21

• Deregulating cellular energetics increased Fluoro-deoxy glucose in PET scan
• Avoiding immune destruction (escape surveillance and checkpoints)

Question 22

What are the enablers in the 2011 version?

Answer 22

• Genomic instability and mutations

- Tumour-promoting inflammation