Flashcards in 22. theraputic stratergies Deck (60)
what is oncogene addiction
when the cell relies on a dominant oncogene and they will die without this
give an example of an oncogene which as cancer is addicted to
what is mutated in 80% of lung cancer?
what do lots of haematopoietic cancers upregulate?
myc - this is a TF
you can carry out experiments were a cancer is expressing myc and then switch this expression off, what can be seen?
haematopoietic cancers went into senescence
>p16 levels rapidly rose (myc is supressing this in some way)
how does Myc function
heterodimer with Max
describe myc and max, are they good therapeutic targets?
>long alpha helices to interact with each other
>alpha helix to interact specifically with DNA.
- no, not much to target, although blocking protein-DNA and protein-protein interactions are being developed
in lung cancer, what mutation occurs in 10% of K-ras and how can this be targeted?
>mutants introduce a cysteine into an important part of the protein
>drug can irreversible covalently bind this cysteine and block these forms
- this adds selection pressure for resistance
in terms of oncogene addition what do we need to do for the future?
identify better oncogenes which tumour are addicted to target and combine these with existing therapies
what is synthetic lethality?
- both WT - no affect
- KO either separately - no affect
- KO both - death
Rb null cells are deregulated in proliferation. name a target of E2F that can be targeted and potentially with what?
topoisomerase II - this is upregulated in Rb null cells
what does topoisomerase II do?
unwinds DNA and prevents it becoming tangled - especially in replicating cells
what does etoposide do?
It binds topoisomerase II and holds it in its DNA cleaving complex this prevents break from reforming and results in double stranded DNA breaks
what happens when you treat Rb null cells with etoposide?
they have more double strand DNA breaks than they cannot repair - this results in apoptosis
what are more single stranded breaks seen in Rb null cells treated with etoposide?
these cells upregulate topoisomerase II
what is PARP?
poly(ADP ribose) polymerase
what does PARP do?
poly-ADP ribosylates proteins, it builds up huge chains of ADP ribose onto proteins
>has a role in transcription where it poly-ADP ribosylates histones and this allows histones to open up and allow TF to bind
>it predominantly binds to single strand breaks
in what cells is PARP synethically lethal?
cells defective in homologous recombination repair e.g. BRCA mutant
when there is a single strand break in DNA one of the first things that is recruited to this break is PARP. what then happens?
PARP recruits repair complex around itself and repairs the damage
if there is a ssDNA break in DNA and replication is occurring, when the machinery gets to this point what occurs? what type of cells cannot do this? and what do they do?
this looks like a double strand break and so homologous recombination pathway is triggered, replication continues
>BRCA mutants, they use PARP
what happens when you inhibit PARP in normal cells?
they use homologous recombination
what is the second proposed mechanism of how PARP inhibition in BRCA mutants causes synthetic lethality?
>PARP binds single strand break trapped to this strand in inhibited form
>normal cells use HR to move around blockage and continue replication
>these are ss breaks that BRCA mutants cant repair
why is using targeting by synthetic lethality good?
this target is only lethal in cells where the tumour suppresser is mutated
>normal tissue is resistant and so this gives you a bigger therapeutic window to achieve efficacy
what can synthetic lethality also be used in?
activated oncogenes - look for genes that when inhibited function in cells with oncogenes you get a death response
RNAi library was transfected into cells with activated k-ras, what gene was identified as synthetically lethal? when this genes is inhibited in WT Ras cells what happens? what also causes decreased in K-Ras cells?
>these cells do not die
give two examples of two things that are downstream of GATA2? how is this used therapeutically?
- proteasome complex
- Rho signalling
>GATA2 is a transcription factor and is not drugable. some of the things downstream of it are.
what two types of inhibitors can be used with K-ras cells?
- proteasomes inhibitor (bortezomid)
- Rho kinase inhibitor (Fasudil)
>either alone works well
>when used together and they target two braches of GATA2 pathway this works better
if we cannot target something in synthetic lethality what can we target?
name 3 ways to perform gene correction, and what may these be used for?
- zine finger nucleases
>edit the genome to remove key oncogenes or install key tumour suppresser