rational treatment of cancer

Question 1

give some of the main treatment strategies against cancer

Answer 1

• prevent proliferative signalling
• induce differentiation
• promote pro-apoptotic signalling
• discourage anti-apopototic signalling
• exploit checkpoint vunerability
• identify relevent population for a specific strategy

Question 2

what is meant by indolent and invasive tumours?

Answer 2

indolent - low invasive/metastatic potential

aggressive - high metastatic potential

Question 3

what is myeloma?

Answer 3

type of cancer that develops from plasma cells from bone marrow
- has a range of lymphomas associated with it

Question 4

what can be used to treat myeloma?

Answer 4

and IkB kinase inhibitor - as some forms are caused by constitutively active NF-kB activation

Question 5

what classes of lymphoma can benefit from IkB kinase inhibitor?

Answer 5

ABC or PMBL

- GCB does not benefit - is not involved with constit NF-kB activation

Question 6

why could it be useful using differentiation to exploit cancer cells?

Answer 6

• if cancer cells are pushed towards a differentiated fate , they are no longer in a proliferating stem cell phase

Question 7

what is the fusion that occurs in accute pro-myelotic leukaemia?

Answer 7

PML and RARa gene fusion

• due to gene translocation
• RARa fusion protein cannot be derepressed by RA (as cannot bind) - differentiation genes remain depressed
• this means proliferation and leukaemia occurs

Question 8

what are the soluations to the PML and RARa gene fusion?

Answer 8

• use all trans retinaic acid - form of RA that can bind the fusion protein and derepress it - differentiation can occur, so proliferation is reduced
• arsenic trioxide (ARO3) cna recruit ubiquitin ligase to destroy RARa fusion protein selectively

Question 9

give an example of a small molecule drug that enhances / restores the function of a tumour suppressor gene

Answer 9

PRIMA-1 restores P53 mutant function

- can see as FACs shows apoptosis occuring in cells

Question 10

what does nutlin-2 do?

Answer 10

Nutlin-2 binds to MDM2 and stops MDM2 from binding and targetting P53 for degradation
- Nutlin-2 stabilises P53 levels - can accumulate and promote apoptosis

Question 11

what does VR54 do?

Answer 11

VR54 can upregulate P27 levels (CKI), causes subsequent inhibition of Rb phosphorylation, this restores the restriction point

Question 12

what components of cancer devlopment afre undruggable?

Answer 12

TF oncogenes e.g. cmyc and fos

- because they have a DNA binding cleft - cannot selectively bind Cmyc and fos

Question 13

what does gleevec do?

Answer 13

bind catalytic site so abl protein kinse cannot become activated

Question 14

how can we minimise evolutionary pressure when treating cancer cells?

Answer 14

• switch quickly between drugs/treatments

- doesnt give cells enough time to develop resistance - and this reduces the evolutionary pressure to evolve

Question 15

How has EGF-R been targetted in cancer treatment?

Answer 15

EGF-R is overexpressed in a large variety of cancers
- cetuximab but this cannot be applid to cancers where the EC domain of EGF-R is deleted

• need to find a drug that binds the IC domain - targets mutants with no EC domain

Question 16

what are the major problems ahead in cancer treatment?

Answer 16

• resistance of cancers emerge
• when drug is applied are creating selection pressures
• need different straegies to treat cancers - as cancers develop from multiple mutations and are part of a hetergenious population
• need to identify relevent population for specific treatment strategies