Last minute flashcards to learn/remember
Name some cancer therapies that work by affecting the G1 (R) checkpoint
- Cyclin dependent kinase inhibitors (pablociclib for advanced breast cancer)
- Antibodies to growth factor receptors e.g. herceptin to Erb2 for breast cancer
- Chemical inhibitors of GFR-TK’s e.g. Iressa to EGF-receptor for breast cancer, lung cancer
- Farnesyl transferase inhibitors to block ras
- Rb activation - highly selective CDK4/6 inhibitor, PD-0332991
What mechanisms lead to apoptosis
DNA fragmentation, protein cleavage, nuclear membrane loss and organelle breakdown (caused by caspases)
Explain how oncogenic Ras mutations lead to cancer
Receptor -> Ras (mutated) -> Raf1 -> MEK -> ERK -> Transcription factor -> Cyclin D
TNF-a neuroprotective (experiments)
TNF receptor KO mice - increase infarct (necrosis):
Bruce et al 1996
TNF decreases glutamate toxicity in vitro:
Cheng et al 1994
TNF-a neurotoxic (experiments)
TNF increase infarct volume - MCAO:
Barone 1997
TNF binding protein decrease infarct volume
Dawson 1996
Explain an experiment done to measure cytokine levels in traumatic head injury
Winter et al. (2004) cerebral microdialysis:
microdialisis probe take out extracellular fluid from around the injury
measure cytokines produced by the brain around the injury
determined concentration of IL-1, IL-6 and NGF
Outcome:
measurments standardised on the glasgow outcome scale -5pt scale depending on how well you recover post-injury
results:
IL-1 didn’t have any difference on outcome
NGF - also no significant difference
IL-6 - patients with high IL-6 was a predictor for a good outcome
this was surprising as IL-6 is pro-inflammatory
What are the 4 subtypes of the pan-cancer microenvironment, which one is associated with immunotherapy resistance
immune-enriched, fibrotic
immune enriched, non-fibrotic
fibrotic
depelted
immunotherapy resistance - fibrotic (Bagaev 2021)
What does IDO stand for
Idoleamine 2,3-dioxygenase
What happens when cytochrome c leaked from mitochondria
When cytochrome C is released, it binds to the protein APAF-1, inducing an open conformation with it’s CARD domain exposed. This binds to other card domains and creates a wheel, which Caspases 9 binds to, to create an apoptosome. From here the caspase cascade occurs, leading to cell death
Explain ABT-199 resistance
tumours with high levels of anti-apoptotic Mcl-1 are protected against ABT-199
Trials in process for metabolism alteration to treat cancer
2-deoxyglucose (2-DG) - Blocks glucose uptake by inhibiting HK2. In clinical trials
-Lactate dehydrogenase A inhibitors - Lead compounds work in mouse models, by inducing ROS – no drugs yet
-MCT4 inhibitors - block lactate export. Compounds in development
-Dichloroacetate - Blocks PDK1 resulting in pyruvate flux into the mitochondria, and thus ROS. Clinical trials
-Metformin; an anti-diabetic drug that inhibits complex I in the mitochondria and results in AMPK activation - Observation from diabetic patients have lead to clinical trials for cancer
