Rational treatment of cancers Flashcards
What are the 4 rational cancer strategies:
- Induce differentiation
- Discourage proliferative signalling
- Promote apoptosis
- Exploit checkpoint vulnerability
- Identify the relevant population for specific strategy
Why is cancer incidence falling in large?
- Storing food better
2. Increased screening of cervical and colorectal cancers
Why has detection improved since the 70s?
Encouraging people to look for breast cancer
MRIs increasingly detect smaller growths
What are the types of tumours and which one do we want to target?
Indolent tumours
Aggressive tumours
Intermediate tumours - (potential to disseminate- but can be treated before dissemination and metastases form)
-we want to target aggressive and intermediate tumours
How do we establish if a tumour is aggressive or indolent?
Age size of tumour number of lymph nodes in the vicinity that have been affected histology pathological grade receptor status
What % of people with breast and prostate cancer shouldn’t be treated?
80%
What test helps identify who really needs treatment?
EXPRESSION ARRAY- analysis of gene expression in cancer patients
By using bioinformatics- distinguished 70 distinct ‘prognosis’
prognosis gene expression could then be used to stratify the breast cancer patients
see if these prognosis genes are upregulated or downregulated
by collating this data- it is clear that patients have different profiles
some have a ‘good signature’- low level of metastases - high chance of survival
use this data to make a spectrum- people with a good signature don’t need treatment
How can differentiation stop (one form of) acute promyelocytic leukaemia?
Switch off the transcriptional repressor with retinoic acid
proliferation pathway undertaken by the promyelocytes is switched off
blast cells can be induced to differentiate into neutrophils by treatment with all-trans retinoic acid
treatment with ATRA and concomitant chemotherapy often results in complete remissions
How does the pathway do awry in promyelocytic leukaemia?
Predictable chromosomal rearrangement- translocation involving chromosomes 15 and 17
RA receptor gene breaks off- translocates- fusion with PML gene
RA no longer recognised
What organelle is coded for by PML and how does it change in cancer?
PML bodies= nuclear organelle, usually sits in the nucleus
in leukaemia- RA is fused to the PML bodies
Which 2 compounds can treat acute promyelocytic leukaemia?
All-trans retinoic acid (RA derivative)
Arsenic trioxide
How does arsenic trioxide work?
ARO3 promotes ubiquitin ligase to specifically target the PML fusion protein- drives it to the proteasome
All-trans retinoic acid mechanism is essentially the same
How can we exploit checkpoint vulnerability in cancer cells?
In hepatoma cells- treat them with doxorubicin- DNA damaging drug that normally induces G2 arrest-
mitotic catastrophe= fragmented nuclei
cancer cells killed
Why is it difficult to target tumour suppressor genes in cancer cells?
LOH is a traditional phenotype in cancer cells- theyve lost both copies of the TSG- its not there
running out of enzymatic targets in terms of inhibiting things
we want a GOF in tumour suppressor genes, instead of inhibiting
Why can we exploit checkpoint vulnerability in cancer cells but not WT cells?
WT cells- induce DNA damage-checkpoint ensure that there is a cell cycle delay- waiting for repair/stress to be removed- if you block cells in s phase- all replication forks stop-
there is no delay/stop in cancer cells- they will attempt DNA replication, and will complete G2 even if there is no replicated DNA- this leads to mitotic catastrophe= CELL DEATH
What does PRIMA1 do?
Small molecule that covalently attaches to mutant p53 and induces a shape change-
has the ability of reintroducing apoptosis
How can we see that cells are going through apoptosis?
FACS analysis
sub G1 population= apoptotic cells
What is Nutlin2?
A protein-protein inhibitor
inhibits mdm2 from binding p53- and therefore prevents the destruction of p53 in the proteasome
Which CDKIs block the phosphorylation and inactivation of rb?
p21 and p27
What drug increases P27 levels? And when is it used?
In ovarian cancer
vr54 increases the expression of p27 in a concentration-dependent manner
What are the features of a druggable target?
Cavity vulnerable to low MW compound
inhibit the function of the cavity
disrupt catalytic activity- catalysis ususally amplifies a signal, so inhibiting catalysis can have a large impact on the pathway
Lots of points of contact for drugs
Examples of undruggable targets
Myc and fos
Examples of druggable targets
v-EGF-R and Abl
What does gleevec do?
Sits in the catalytic cleft of the Abl protein kinase
kinase cannot bind ATP
Why are kinases good targets?
Many protein kinases are oncogenes
they are usually upregulated/ mutated to be permanently switched on
Why are kinases bad targets?
Protein kinases have evolved from a common ancestor- ATP binding site similar across all PKs
-despite this there is enough variation in the ATP binding site for competitive inhibitors to be produced
Whats a molecule that is specific to EGF-R?
Tarceva - tyrosine kinase inhibitor
What is cetuximab and when is it not effective?
Humanised monoclonal antibody against EGF-R
binds to the top part of the receptor
it’s no good when the receptor has mutated and the extracellular domain is lost- ligand independent firing
-used to treat metastatic colorectal cancer and non-small cell lung cancer
Why is resistance an issue with clinical trials?
To make a clinical trial valid- need people from all the subsets of a cancer- including resistant and sensitive types- becomes more and more complex with fewer people available= statistical power reduces
What does BCR-ABL fusion result in?
An oncogene
some tumours are resistance to Gleevec- which inhibits Abl
there are some tumours which are less sensitive
What’s one way of getting round resistance?
Predict when resistance will arise
develop inhibitors that will be first and second generation inhibitors and anticipate mutations
Another way= multi-pronged approach
switch from one rational cancer strategy to another- avoid the selective pressure and approach the cancer is a new way
Why do cynics argue that we should not try and ‘treat’ aggressive forms of cancer?
They will become lethal no matter what therapy is used (truly effective treatments of most kinds of metastases are not available at present)
How has gene expression arrays and bioinformatics helped breast cancer diagnosis?
They have increased the accuracy of predicting the course of breast cancer progression to more than 90%
What’s the issue with B-cell lymphomas (myelomas)?
They have very variable outcomes- can survive 3 weeks or 10 years
tumours have a very similar appearance under the microscope
gene expression analysis has allowed us to distinguish between the types
-B-cell lymphomas (PMBL)
-B-cell like lymphomas (GCB)
-Activated B-cell like lymphomas (ABC)
Which B cell lymphomas can be targeted, why can the other type be targeted in this way?
ABCs and PMBLs exhibit constitutively high levels of NF-kb activity
this transcription factor drives proliferation and protects them from apoptosis
Can use an IKK inhibitor- acts upstream of the pathway- - kills the tumour cells
GCB show low levels of NF-kb activity and thus remain essentially unaffected by this treatment
