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Flashcards in Targeted therapies Deck (49):
1

What is chronic myeloid leukaemia?

a cancer of the bone marrow

2

What is the incidence of CML?

0.8% new cancers

3

What is the current 5 year survival rate of CML?

~60%

4

What was the 5 year survival rate of CML before 2003?

~30%

5

What affected the 5 year survival rate of CML?

through the understanding of the Philadelphia translocation that occurs in ~95% of CML patients

6

What is the Philadelphia translocation?

9:22 translocation creating the Philadelphia chromosome

Creates a fusion gene called BCR-ABL1

7

What is ABL?

kinase that drives cell proliferation

- usually switched off

8

What is a kinase?

atpase that splits atp, releasing energy to phosphorylate a protein to relay a signal

9

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

10

Describe the function of BCR

'Always on' signal produced

11

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

12

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

13

Describe the treatment of CML with imatinib?

- once daily oral medication
- generally well tolerated
- still used as a first treatment

14

What is targeted therapy?

Drugs which target a specific process in an aberrant molecular pathway

= a drug that isn't chemotherapy

15

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

16

Describe other mechanisms that can be targeted by a therapy

Angiogenesis within a tumour

Hormone stimulus

17

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

18

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

19

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

20

What molecular abberation can be found in most kidney cancers?

Disruption within the protein VHL

21

What does VHL do?

VHL works by binding to this protein called hypoxia inducible factor (HIF) to tag it for destruction

22

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.

23

How is HIF regulated?

HIF is kept in check by VHL, which binds to HIF and tags it for destruction

24

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

25

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

26

How do drugs targeting VEGF work?

mimic ATP
- bind to the kinase and stop it from working

27

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

28

How is prostate cancer treated

castration
- previously surgical
- now pharmaceutical

29

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)

30

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

31

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

32

Can targeted therapies be made against tumour supressor genes?

much harder to fix broken pathway in every cell
relatively few drugs available

33

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

34

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

35

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

36

What are the barriers to targeted therapy?

- Easier to break a pathway than fix a pathway
- drug resistance

37

What is personalised medicine?

targeting specific groups of patients using targeted therapies

38

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

39

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

40

What kinases can be targeted in lung cancer?

- anaplastic lymphoma kinase
- epidermal growth receptor kinase

mutations present in v. small amount of patients

41

What is a prognostic marker?

says this patient is going to do well or badly however you treat the patient

42

What is a predictive marker?

one that tells you whether or not you are going to benefit from a specific intervention

43

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

44

Why haven't targeted therapies been found for all cancers?

most cancers need 5 mutations

CML is a single mutation disease

45

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

46

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

47

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

48

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

49

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