Session 4: Cancer Flashcards
What are the first 6 hallmarks of cancer and cancer and their therapeutic targets?
- Sustaining proliferative signalling.
- EGFR inhibitors - Evading growth suppressors
- cyclin-dependent kinase inhibitors - Activation invasion and metastasis
- HGF/c-MET inhibitors - Enabling replicative immortality
- telomerase inhibitors - inducing angiogenesis
-inhibitors of VEGF signalling - Resisting cell death
- proapoptotic BH3 mimetics
How do cells sustain proliferative signalling?
Normal physiology: cells respond to growth factors which bind to GF receptors.
This phosphorylates and activates Ras which phosphorylates and activates transcription factors in a signalling cascase, leading to cell division.
Two mechanisms:
- in some cancers, Ras mutation means no ligand is required for activation. Ras phosphorylates downstream signalling proteins regardless of ligan presence.
- Some cancers have amplified GF receptors and there are more signals produced, cell division and survival is increased, promoting malignant expansion of the cell.
How do tumour cells evade suppressors?
Normal physiology: DNA damage triggers p53 activation for DNA repair. If repair fails, cells may undergo arrest and apoptosis or become senescent.
Cancer can suppress p53, leading to mutation accumulation and tumour growth.
What are the additional hallmarks of cancer?
What are the additional hallmarks of cancer?
7. Avoid immune destruction - immune activating anti-CTLA4 mAb
8. Tumour-promoting inflammation - selective anti-inflammatory drugs
9. Genome instability - PARP inhibitors
10. Deregulating cellular energetics - aerobic glycolysis inhibitors
Give examples of how cancer cells can resist cell death
Cancerous cells can avoid apoptosis by:
-Downregulation of: MAPK activity, NF-kappaB, caspases 3, 8, 9, p53.
-Upregulation of Bcl-2, Bc-XL, TNFAIP8
These mechanisms increase cell cycle and drug resistance.
How do cancer cells exhibit replicative immortality?
Telomeres = chromosome ends
Normal physiology = telomeres are made by telomerase early in development, then telomerase activity is turned off. Telomeres shorten with each cell division, ultimately leading to senescence.
In some cancers, telomerase is constitutively active so more telomeres are added, leading to the survival of cells.
What is tumour angiogenesis?
Tumours secrete vascular endothelial growth factor, increasing blood vessel expression and movement to the tumour. Tumour has an increased blood supply, promoting survival.
How are invasion and metastasis activated?
Cancer development is a multistep process. Individual steps can occur in a different order.
E-cadherin promotion/ mutation leads to tissue invasion and metastasis.
What are the enabling characteristics of cancer?
- genome instability and mutation
- tumour promoting inflammation
What classes of anti-cancer therapy are there? Give examples.
- Classical chemotherapy: alkylation, anthracyclines, taxanes, anti-metabolites, nucleoside analogues, vinca alkaloids.
- Corticosteroids
- mAB: single specificity, bi-specific, toxin-conjugated, radio-label conjugated
- immunomodulation: thalidomide, lenalidomide, pomalidomide
- Angiogenesis inhibitors: bevacizumab
- BCL2 inhibitors: venetoclax
- Immunotherapy: checkpoint inhibitors
- Chimeric antigen receptor T cells.
What is the role of classical chemotherapy?
Target cellular proliferation
What class of drugs are vinca alkaloids and what is their role?
Classical chemotherapy, inhibit tubulars in mitotic processes.
What are the main side effects of classical chemotherapy?
Hair loss, mucosal SE e.g. diarrhoea and vomiting, bone marrow anaemia, low platelets = bleeding, recurrent infection
What is the role of corticosteroids?
Directly kill some leukaemia, reduce inflammation.
What is the role of mAb?
Target surface proteins on cancer cells. Can bring T cells to cancer cell to kill it. OR it can be tagged to a toxin or radioactive molecule for targeting.
