Therapeutic Classes of Drugs for the Treatment of Cancer; Targeted Therapies Flashcards
What are the four different targeted therapies availible? 15:35
1) Monoclonal Antibodies (target specific growth factor)
2) Receptor Tyrosine Kinase Inhibitors (TKIs)
3) Hormones (ER/AR; inhibit signalling processes downstream)
4) Immunotherapy/Vaccines (prevent a virus from causing a cancer e.g cervical cancer/HPV)
What does Bevacizumab do?
Bevacizumab (Avastin)
- Inhibition of VEFG (signalling peptide)
- Binds VEGF; preventing its interaction with VEGFR1 and 2 (VEGF is swimming in extracellular environment, is bound and ‘mopped up’ by bevacizumab
»> May play a role in ‘normalisation’ of vascular structures; making vessels more susceptible to chemotherapy.
What is bevacizumab indicated for?
Initially indicated for treatment of (late-stage) metastatic colorectal cancer (combined w/5-FU)
»> First FDA approved anti-VEGF drug to for above
Then approved for:
- Lung cancer
- Renal cancer
- Glioblastoma
On-going Phase III trials for gastric, prostate, ovarian and melanoma-type cancers.
Have there been any issues with bevacizumab (Avastin) usage?
- Set-back in 2010; use for Avastin in breast cancer WITHDRAWN
- Lack of efficacy
- Side effects
What intracellular processes are triggered as a result of VEGF binding?
- Production of NO and PGI2
- Proliferation
- Survival
- Migration
- Permeability
What are VEGF’s normal functions (what downstream processes occur as a result)?
- Angiogenesis
- Endothelial cell (EC) integrity
- Vascular tone
- EC-platelet homeostasis; prevention of blood cell adherence to EC
- Protection of glomerular podocyte-BM-EC filtration barrier (renoprotection)
What occurs due to the blockade of VEGF signalling (e.g. w/bevacizumab binding it up)?
- Compromised wound healing and tissue repair (usually regulates angiogenesis/EC integrity)
- Hypertension (usually regulates angiogenesis/vascular tone; produces NO > CVD risks e.g. MI/stroke/CHF)
- Arterial thromboembolic event (blood clot; usually regulates EC integrity/EC-platelet homeostasis, prevention of blood cell adherence to EC)
- Cardiac dysfunction (usually regulates vascular tone)
- Proteinuria/renotoxic effects (usually regulates EC integrity/role in renoprotection; protection of glomerular podocyte-BM-EC barrier)
What is the role of VEGF in angiogenesis?
1) Tip cell migrates towards angiogenic stimulus (VEGF)
2) Stalk cells (shaft of new vessel) follow resulting in lumen formation, bringing 2 adjacent blood vessels together
3) Pericyte recruitment
4) Vasculature develops in avascular region
How does bevacizumab aid chemotherapy action when concomitantly given?
1) W/o bevacizumab; VEGF is opposing chemotherapy, protecting the EC layer (even though its a tumour cell), preventing chemotherapy from ‘blasting through’
1 b) W/bevacizumab; extracellular VEGF has been bound, thus endothelial lining is susceptible to chemo; can blast through EC layer and damage tumour cells
2) Tumour is normal size; then reaches critical size where more blood vessels needed to sustain growth (nutrients/O2); thus upregulates VEGF = angiogenesis, resulting in a larger, more invasive tumour.
2 b) W/bevacizumab, VEGF action is blocked even if tumour has upregulated it (all bound up) thus tumour stays ‘normal’ size (no angiogenic stimulus; avascular)
= easier for surgical removal, w/o further complications of haemorrage/bleeding.
3) New angiogenic vessels are more leaky (tortuous etc.); thus tumour cells are more likely to gain entry and be dispersed around body in vasculature (metastasising)
3 b) No intrinsically leaky blood vessels (due to bevacizumab preventing angiogenesis; bound VEGF), thus vessels are more ‘normal’ intrinsic barrier intact, reducing tumour metastases.
What are the CV effects of Anti-VEGF (e.g. bevacizumab) therapy?
- Hypertension
- Arterial Thromboembolic Events
- Haemorrhage
- Ventricular Dysfunction and CHF
- Renal Adverse Events
- Wound Complications
What does Anti-VEGF therapy (e.g. bevacizumab) commonly result in hypertension S/E?
- Most common of VEGF/VEGFR inhibitors
- VEGFR2 generates NO and PGI2; induce vasodilation in resistance vessels
- Blockage of VEGF may lead to vasoconstriction
- Leads to reduction in LVEF (left ventricular ejection fraction); precedes onset of heart failure (CHF)
Why may Anti-VEGF therapy lead to Arterial Thromboembolic Events?
- Primarily mediated by platelets
- Important role of VEGF in EC-platelet homeostasis (more likely to have sticky endothelial surface w/o VEGF)
- Prevents adherence of blood cells to the vasculature
- Maintains EC survival in response to vascular injury
- Result is cardiac/cerebral ischaemia (clot moving to brain; strokes, MIs etc.)
Why is there an increased risk of Haemorrage with anti-VEGF therapy? At what site?
- EC-platelet homeostasis compromised w/o presence of VEGF
- Thus increased risk of bleeding; especially in lung and GIST (gastro-intestinal stromal) tumours
Why is there an increased risk of Ventricular Dysfunction and CHF w/anti-VEGF (bevacizumab) therapy?
- VEGF maintains cardiomyocyte survival in response to stress and injury
- Effects of increased peripheral vascular resistance (hypertension)
Why is there an increased risk of Renal Adverse Events w/anti-VEGF therapy?
- Interaction of podocytes w/VEGFR2 on glomerular ECs = critical to normal function and repair
- Deletion of VEGF in podocytes results in thrombotic microangiopathy, EC damage, loss of podocytes and proteinuria
