Apoptosis therapy Flashcards
Why might c-myc be a good target for cancer therapeutics?
- myc induced apoptosis
- many tumours overexpress cmyc but also antiapoptotic proteins such as Bcl-2 + survival factors
- Bcl-2 KOcan drive apoptosis in c-myc overexpressing tumours
- stopping this blocking by c-myc
Why might a cancer with high Bcl-2 activity be more susceptible to apoptosis?
- cancer cells are primed to die
- mutations and stresses en route to malignancy upregulate BH3-only proteins
- proteins are ‘preloaded’ for apoptosis
- cell needs high Bcl-2 to keep these sequestered
- KO of Bcl-2 may allow BH3-only proteins to cause cancer cell death
What are the main targets in the intrinsic pathway?
- Bcl-2 antisense
- BH3 helices
- BH3 small molecule mimetics
- Bax trigger site activation
- XIAP antisense
- SMAC peptides and SMAC mimetics
What are the main targets in the death receptor pathway?
- TRAIL + combos or optimised
- TRAIL decoy receptor inhibtion
- mAbs for TRAIL receptors
How can Bcl-2 antisense be used to treat cancer?
- artificial antisense molecules (or can use siRNA)
- bind Bcl-2 mRNA and lead to its degradation
- also stimulates the immune system
- phosphates added to stabilise them but still quite unstable
What can be done to help with the instability of siRNA or antisense Bcl-2
- tested on glioma rat models
- put the RNA in a micelle with folate on the surface
- glioma cells overexpress folate receptors and internalise the the micelle and its contents
- micelle can also contain the drug TMZ which increases Bax and leads to apoptosis
- Bcl2 siRNA decreases Bcl-2 and TMZ increases Bax
What was the first attempt to mimic BH3-only proteins to treat cancer? What was the issue?
- BH3-only domains stabilised by hydrocarbon staples to create a BH3 helix
- effective in mouse models
- but large molecules with low bioavailability and harder to administer
How was this issue of BH3 mimics solved?
- BH3 mimetics - small molecule drugs
- function against specific Bcl-2 family members
- e.g venetoclax has high specificity for Bcl-2 and is used for CLL with 17p chromosomal deletions that afect p53
What have been the successes and failures of venetoclax?
- in combination with Mab, 86% response rate and complete remission in half
- in solid tumours resistance easily arises and cells begin to express MCL-1 which the drug can’t target
How can other drugs be used alongside BH3 mimetics?
- response is best when combined with an apoptotic stimulus
- mTOR inhibitors reduce MCL-1 expression and increase PUMA induction (apoptotic stimulus)
- the use of BH3 mimetic along with mTOR inhibitors enhances response in triple-negative breast cancer
- BH3 mimetic sensitises the cells to the apoptosis stimulation
What is the Bax trigger site?
- site when bound by specific BH3s leads to a conformational change in Bax leading to its insertion into the mitochondrial membrane and apoptosis
- BIM, tBID, PUMA
- can be mimicked by drugs or antibodies
What is the main cancer therapy target in the death receptor pathway of apoptosis?
- TRAIL
- doesn’t kill mice when injected (ras does)
- induces apoptosis more in cancer cells than normal cells
- many human tumour types overexpress TRAIL receptors possibly due to TRAIL signalling enhancing PI3K migration and invasion
- many immune cells produce TRAIL - NKs, DCs
How can the death receptor pathway actually lead to survival?
- instead of DISC, complex II is formed away from the membrane
- can activate pathways such as NFkB and MAPK that promote cell survival and differentiation
What are TRAIL decoy receptors?
- TRAIL R3 + R4
- overexpression in tumours can mop up TRIAL + decrease apoptosis
- blocking TRAIL-R3 in AML sensitizes cancer (stem) cells to TRAIL
- use of agnoistic TRAIL R2 antibody works better than TRAIL itself to induce apoptosis here
How does TRAIL-R4 work?
- has a truncated intracellular domain
- able to interact with TRAIL-R2 to impair caspase activation
- potentiates Akt activity independent of TRAIL by mechanisms not yet understood
