Targeted approaches to cancer Flashcards
List targeted approaches to cancer
- Monoclonal antibodies (Bevacizumab) or receptor tyrosine kinase inhibitors (sorafenib) - targeting (VEGF)
- Monclonal antibodies (trastuzumab) - Targeting HER2
- Hormones - Tamoxifen
- Immunotherapies - CAR-T
- Immunotherapy/Vaccines - Gardasil
Review VEGF signalling
Explain the mechanism for VEGF inhibition.
- Inhibition of VEGFA ligand
1. VEGF-Trap
2. Bevacizumab - Inhib of VEGF receptor (R2)
- Inhib of VEGFR2 downstream signalling
- ANti-VEGFR1 or R2 antibodies
(red boxes important)
What is Bevacizumab?
- Inhib of VEGFA - Avastin
- Binds to VEGFA, prev interaction with VEGF-R1 and R2
- First-line treatment for many cancers
- Often used with chemo alongside targeted treatments –> Leads to cocktail of treatments whcih bring about LOTS of side effects
- Inc ovarian failure
- Treatment can leave lasting negative effects that don’t stem from disease
(See PP)
What is Ramucirumab?
- Inhibitor of VEGF-R2 - Cyramza
- A fully human IgG1 monoclonal antibody against the extracellular domain of VEGFR2
- BInds to ligand binding site, prev activation of the receptor
- Used to cut off and starve tumour
- VEGF helps wounds heal - Blocking it and then removing a tumour will mean the patient won’t heal as well
- Issue - Inc circulating VEGF levels
- Only improves survival by a few months
See PP
What are small molecule inhibitors?
Inhibit VEGF-R2 - receptor kinase inhibitors
- Block the phosphorylation event at ATP binding sockets
- Is multi-targeted – Good at targeting receptors that replace VEGF
- Resistance develops and can knock out multiple abilities in the body to respond to changes
Sorafenib vs Axitinib
Sorafenib:
1. Multi-targeted
2. Used in advanced disease
3. Bad side effects, so used in late stage cancer where side effects are worth it
Axitinib:
1. 2nd generation inhibitors are more selective but still multi-targeted
What are the consequences of VEGF inhibition?
What are the cardiovascular effects of Anti-VEGF therapies?
- Hypertension - can precede heart failure
- Arterial Thrombotic events - Can lead to cardiac or cerebral ischaemia
- Haemorrhage - Bleeding in lungs+GIST tumours
- Ventricular Dysfunction and congestive Heart failure - Effects of incd peripheral vascular resistance
- Renal Adverse events - EC damage, loss of podocytes etc
- Wound complications
What is HER2?
- Human Epidural Growth Factor receptor 2.
- Transmembrane tyrosine kinase- Promotes cell growth and tumour development
- Overexpressed in approx 20% of invasive cancer phenotypes. Expression related to more aggressive disease.
What is Trastuzumab?
The first HER2-targeted therapy approved by FDA for treatment of HER2 positive breast cancer
- Induces remission in 15-20% of patients
- In combo with chemo it inc response rates and duration and survival
What are the risks and side effects of Trastuzumab?
Risk Factors:
* Prev exposure to antracycline drugs (associated with dose-dependent irreversible heart damage)
* Diabetes mellitus
* Prior coronary artery syndromes
* Hypertension
* Pre-existing congestive heart failure
Side effects:
* Associated with pain, GI disturbances and pulmonary symptoms
* Most sig limiting side effect remains cardiac toxicity
What is Tamoxifen?
An Oestrogen receptor antagonist.
- Overexpression of oestrogen in breast cancers
Side effects:
* Hot flushes and nausea/vomiting occur in 25% of patients
* Sweating, fatigue and mood swings
* Weight gain due to water retention
* Vaginal bleeding/dryness and change in mesturation
- Long-term use may inc incidence of endometrial cancer (also linked to secondary endometrial cancer in women)
What is CAR-T cell therapy?
(Chimeric antigen receptor T cell therapy)
- Involves collecting and using patients own immune cells to treat condition – Reprogramming cells to attack the cancer
- Successful treatment: reduction innremission rates of up to 80% for heamatologic cancer and non-hodgkin lymphomas
What are HPV vaccines?
(Gardasil)
- Used for cervical cancer
- HPV is a major causative agent of cervical cancer
