Targeted therapies Flashcards
What is chronic myeloid leukaemia?
a cancer of the bone marrow
What is the incidence of CML?
0.8% new cancers
What is the current 5 year survival rate of CML?
~60%
What was the 5 year survival rate of CML before 2003?
~30%
What affected the 5 year survival rate of CML?
through the understanding of the Philadelphia translocation that occurs in ~95% of CML patients
What is the Philadelphia translocation?
9:22 translocation creating the Philadelphia chromosome
Creates a fusion gene called BCR-ABL1
What is ABL?
kinase that drives cell proliferation
- usually switched off
What is a kinase?
atpase that splits atp, releasing energy to phosphorylate a protein to relay a signal
How does the Philadelphia chromosome affect ABLs function?
Splits above the regulatory region of ABL leaving it stuck in a switched on position due to the addition of the BCR
Describe the function of BCR
‘Always on’ signal produced
What is the significance of BCR-ABL?
BCR supplies ABL with the always on signal that allows able to trigger cell proliferation, which results in CML
How does imatinib work?
essentially mimics ATP by binding to the cleft on the kinase and preventing the ATP from binding and relaying the signal
= switched off the always on signal
Describe the treatment of CML with imatinib?
- once daily oral medication
- generally well tolerated
- still used as a first treatment
What is targeted therapy?
Drugs which target a specific process in an aberrant molecular pathway
= a drug that isn’t chemotherapy
What mechanism of cancer is able to be targeted?
For a mechanism to be ‘druggable’ it is easier to break a sequence that is working rather than to fix a broken sequence
Describe other mechanisms that can be targeted by a therapy
Angiogenesis within a tumour
Hormone stimulus
What is the significance of angiogenesis?
For a tissue to grow >2mm, it needs oxygen and nutrients from the blood supply, as oxygen and nutrients cant diffuse further than that
Cells that are starved of oxygen and nutrients sends out signals to trigger angiogenesis
What response signals occur when a cell is hypoxic?
cytokines which diffuse out of the hypoxic tissue into the blood vessel
The vessel detects the signal and will branch out to supply the area with blood
What is Von Hippel-Lindau syndrome?
an inherited condition associated with
- hemangiomas of the skin
- rare tumour of the cerebellum
- increased risk of a number of cancers, particularly kidney cancer
What molecular abberation can be found in most kidney cancers?
Disruption within the protein VHL
What does VHL do?
VHL works by binding to this protein called hypoxia inducible factor (HIF) to tag it for destruction
What does HIF do?
HIF is one of the factors that is involved in the hypoxia pathway. If the cell is starving, HIF goes up and results in transcription of these growth factors that result in the blood supply.
How is HIF regulated?
HIF is kept in check by VHL, which binds to HIF and tags it for destruction
What is the significance in damage to VHL?
it can’t bind to HIF, which can’t be destroyed. If levels of HIF go up, hypoxic signals go up, and you get very prolific blood supply
Which receptor is targeted in treatments that inhibit angiogenesis?
vascular epithelial growth factor receptor (VEGF)
- a tyrosine kinase that sits in the capillary cell membrane, which receives the signal from the blood vessel
How do drugs targeting VEGF work?
mimic ATP
- bind to the kinase and stop it from working
Describe the effect of testosterone on prostate cancer
testosterone is required for the growth and survival of normal prostate cells. When you get a cancer arising in the prostate, even when it spreads elsewhere the cancer still requires the signal to grown and survive
How is prostate cancer treated
castration
- previously surgical
- now pharmaceutical
How does pharmacological castration work?
- GnRH agonist (stimulates production of sex hormones resulting in down-regulation)
- GnRH antagonists (blocks production. immediate drop in testosterone)
- Estrogens (anterior pituitary switches off LH & FSH)
- Androgen receptor antagonists (testosterone can’t bind to prostate tumour)
Who is George Beatson
surgeon who discovered that if you take the ovaries out of pre-menopausal women with advanced breast cancer, sometimes the cancer went away
Who is George Beatson
surgeon who discovered that if you take the ovaries out of pre-menopausal women with advanced breast cancer, sometimes the cancer went away
Can targeted therapies be made against tumour supressor genes?
much harder to fix broken pathway in every cell
relatively few drugs available
How can cancers adapt to treatments?
Mutations:
- in the cleft where the drug binds, stopping the drug from binding
- splice variant meaning no receptor for drug and no need for binding to activate - already switched on
Adaptations:
- cancer learns to survive using different hormone signals or to drive the cell independently to the hormonal process
What is docetaxel and how does it work?
A chemotherapy drug that binds to microtubulues, stabilising microtubule assembly. Leads to decrease in free tubulin and results in inhibition of mitotic cell division between metaphase and anaphase
What are the advantages of newer targeted treatments?
- more selective for cancer cells
- less selective for normal cells
> therefore less side effects
> therefore higher dose can be given
> therefore potentially greater anti-cancer effects
What are the barriers to targeted therapy?
- Easier to break a pathway than fix a pathway
- drug resistance
What is personalised medicine?
targeting specific groups of patients using targeted therapies
Describe treatment of anaplastic lymphoma kinase activating mutation
- small cell lung cancer
- patients with mutation responded very well to ALK inhibitors
- mutation only in ~4% of patients with lung cancer
Why can certain cancer medications not be used on everyone?
Targeted therapy to a certain mutation.
If the mutation is present, it is almost guaranteed to work
If you haven’t got the mutation it is guaranteed not to work
What kinases can be targeted in lung cancer?
- anaplastic lymphoma kinase
- epidermal growth receptor kinase
mutations present in v. small amount of patients
What is a prognostic marker?
says this patient is going to do well or badly however you treat the patient
What is a predictive marker?
one that tells you whether or not you are going to benefit from a specific intervention
Give an example of a marker that is both prognostic and predictive
oestrogen receptor is prognostic:
- if it is positive, 5 year survival is good
- if negative, 5 year survival is poor irrespective of treatment
Oestrogen receptor is also predictive because if ER positive, you benefit from the drug tamoxifen
Why haven’t targeted therapies been found for all cancers?
most cancers need 5 mutations
CML is a single mutation disease
What problems do we have in detecting mutations to target?
heterogeneity
- if you take a tumour out and you chop it into pieces and carry out molecular genomics on each piece, different pieces will have subtly different mutations
how can the heterogeneity of different clones be mapped?
‘warm body’ post-mortem
What they found is that some mutations were present throughout (every tumour sample) and there were some that were only present in a subset of tumours
They then grouped the tumours according to the subset of mutations that they contained
- I.e. worked out a family tree of the tumours within a patient
Other than a biopsy how can a tumour sample be obtained?
Blood sample
- Quite often you are able to detect cancer cells circulating in the bloodstream
How does Enzalutamide work?
Enzalutamide is an AR signalling inhibitor that directly targets three stages of the AR signalling pathway
Androgen receptor antagonist
- steroid hormone receptor sits in the cytoplasm of the nucleus
- the hormone diffuses through the membrane, binds with the androgen receptor
- translocated to the nucleus
- directly binds DNA to cause cell division
The drug works by inhibiting the binding of the hormone to the receptor
Describe splice variants as a resistance mechanism
Gene is encoded in exons of DNA
non-coding DNA between = introns
RNA is spliced to remove the introns to make mRNA (just exons) which encode protein
That splicing process is sometimes variable
Whats happened in the androgen receptor is that the domain 5, the bit that binds androgen (if you have a translocation where you have lost domain 5), the protein is still made, but it doesn’t need the androgen
- it is active
