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21. personalised therapy Flashcards

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1
Q

why is there a push for more focused therapies?

A

unlike chemo and radiotherapy, these discriminate between healthy and diseased tissue

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2
Q

leukaemia is uncontrolled haematopoiesis, what variation can there be of this?

A

> chronic - slow killer
acute - fast killer
lymphoblastic or myelogenous

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3
Q

what cells do CLP give rise to? what cells do CMP give rise to?

A

give rise to cells which are to do with antibodies

>everything else in the blood

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4
Q

what happens when there is deregulation of either CLP or CMP?

A

these churn out lots of mutant cells and clog up the blood = leukaemia

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5
Q

how many people are affected by CML and how curable is it

A

about 500 new cases a year in UK

quite curable

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6
Q

what age do people get CML

A

late onset – patients with CML tend to be around 65/70 years old

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7
Q

how does the age of people with CML affect potential therapeutics?

A

full body radiation to kill all BMSC and then have a SC operation is major even for young people

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8
Q

in addition to age what else may hinder using SC operation for CML

A

finding donors is hard

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9
Q

how long does the chronic phase of CML last? and what does this result in?

A

4 or 5 years - only produce a few extra non red cells in circulation and so only symptom is fatigue

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10
Q

what happens after chronic phase of CML?

A

cell division is increased and the bone marrow fills up with abnormal progenitor cells - this is the accelerated phase which last 6 - 18 months

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11
Q

what follows the accelerated phase of CML?

A

the blast phase lasts 4 - 6 months - the bone marrow cells enter circulation and being diving in circulation. this leads to fatality

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12
Q

how can CML be detected?

A

using blood smears

>this shows ratio of red cells to non-red cells which should be 1000:1

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13
Q

what percentage of CML are homogenous?

A

80-95%

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14
Q

what causes CML?

A

translocation between chromosome 9 and 22

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15
Q

what gene is on chromosome 9?

A

abl

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16
Q

what gene is on chromosome 22?

A

BCR - unknown function

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17
Q

relatively how much of BCR and abl are in the fusion protein?

A

little bit of BCR and a lot of abl

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18
Q

describe abl

A

> tyrosine kinase

>located in nucleus

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19
Q

what happens when abl is fused to BCR?

A

the kinase is constitutively active and now localised in the cytoplasm (away from its normal substrates)
>acts as surrogated activated TKR - recruits proteins in signalling pathways e.g. switches on AKT and prevents apoptosis

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20
Q

what does BCR-abl influence?

A

proliferation, apoptosis, adhesion and motility

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21
Q

BCR-abl added into mice in the appropriate cell compartment and these mice get a CML like disease, what happens when this is removed?

A

they are cured

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22
Q

name a potential inhibitor for kinase BCR-abl

A

Gleevec

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23
Q

how does the abl tyrosine kinase differ from other kinases? and how many other kinases are like this?

A

it has an ATP binding site like a channel rather than a pocket
>there are only 4 or 5 other kinases like this

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24
Q

what was shown in phase 1 of gleevec drugs trial?

A

the drug was shown to inhibit abl in healthy patients without bad side effects
>established the dose
>saw how long it stays in body and determined can be given two times a day

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25
what happens in phase 2?
people with CML are given Gleevec
26
following gleevec treatment, what percentage of people with CML had normal haematological smears?
>95% of patients have in the chronic phase of disease | >30% in blasts
27
what percentage of could chromosome abnormalities no longer be observed in and why is this?
60% of people in chronic phase | >cells which have abnormal chromosomes died i.e. cells were addicted to this oncogene
28
why was phase 3 skipped?
there was no other treatment to compare it with
29
what was seen after people appeared to be cured from CML after gleevec treatment?
patients relapsed >this only occurred in 10% when disease was caught early >when caught in blast occur in 80%
30
what are the relapses in CML due to?
33 different point mutations that means gleevec can no longer bind Abl
31
which might people require higher dose of gleevec?
patients may have amplified BCR-abl locus
32
what does Nilotinib do? and what did this lead to?
it inhibits 32 out of the 33 abl mutants >one mutant that it did not inhibit was selected for - another inhibitor has been developed for this with good results (DCC-2036)
33
what are single agent therapies are easy for tumour cells to... and what would improve this?
bypass >give multiple variants of the inhibitors at the same time and different drugs that target something else unlikely to produce variant cells that can overcome combination of therapies
34
what type of receptor can be amplified on breast cancer cells?
her2
35
name three things that a breast cancer cell can be + or - to
Her2 ER PR
36
name an antagonist of ER
tamoxifen
37
name the antibody against her2 and what is Iressa
Herceptin | >inhibitor against the kinase activity of Her2.
38
how do we determine what the breast cancer is + and - for?
immunostaining/sequencing
39
what might become possible in terms of sequencing?
sequence everyone’s tumours before treatment
40
how much has the cost of sequencing a human genome nearly come down to? and what might this mean?
$1000 | >may be cheaper to sequence a genome that treat with drugs for years
41
why characterise somatic mutations in human cancers?
- understand more about cancer - identify mutated genes for therapy - information about process of mutagenesis - help with early detection and prevention
42
what is the risk of breast cancer in the UK
1 in 8 women
43
how many breast cancer cases are hereditary?
5-10%
44
what can sequencing genomes of normal people be used for?
predictions - give you your relative risk of developing the disease
45
what is the candidate approach for genome sequencing?
sequence well known oncogenes
46
what did the candidate approach progress to? and what has this been superseded by?
large scale exon sequencing | >whole genome sequencing
47
what was identified when using the candidate approach in malignant melanomas?
>sequenced 20 genes in many different patients >found mutation in BRAF in 90% >only one mutant copy was needed - oncogene
48
what does activated BRAF activate?
MAP kinase pathway
49
how is the BRAF protein mutated and what does this mimic?
always mutated to negative residue and this mimics phosphorylation - moves the aviation loop and makes kinase constitutively active.
50
inhibitor was developed for BRAF, what is it called and what did it show?
PLX | >inhibits the mutant form a lot more than the wild type form.
51
name the dye that can fluorescently label viable cells
Calcein-AM - passes into cells and is cleaved to fluorescence green
52
what is propidium iodide stain?
get into cells with broken membranes (dead cells), can intercalate with DNA and fluoresce red.
53
what was seen when PLX was added to BRAF mutant cells and normal cells?
mutant cells died | WT cells did not
54
what was seen when people with metastatic melanomas were given PLX?
massive shrinkage of their metastasis
55
what different ways can BRAF mutant cancer cells become resistant to PLX?
there are many different mutation that can occur, this may be in BRAF, MEK, RAS - lots of possible mutations in the pathway to bypass therapy
56
what is clear cell carcinoma?
type of renal carcinoma that make up 75% of renal cancer (there are four types of renal cancer)
57
what is the COSMIC database?
a catalogue of all the somatic mutations in cancer
58
what is found in 46% of renal cancers? and how was this identified?
mutations in VHL (highly vascularised tumours) | >large scale exon sequencing, screened coding regions for copy number and expression
59
large exon sequencing identified VHL to be mutated in 60% of cells tested, what occurs in 82% of cases?
expression has upregulation of genes associated with cellular hypoxia
60
what did large exon sequencing also identify that had never been previously unknown to be involved in kidney cancer ?
5 genes - histone methylase/demethylases
61
if large exon sequencing does not pick up any mutations what does this suggest?
this suggests that the exon sequencing is not giving a complete picture which is why people have moved on to looking at whole genome sequencing
62
what has whole genome sequencing been used in ?
breast cancer - 20 driver genes identified
63
what are driver mutations?
mutations are statistically found more commonly than to just be found by chance
64
around how many driver mutations were seen per breast cancer? and what implication does this have on therapy?
5 >all of these will need to be targeted in order to get a good therapeutic response.- we are far away from being able to do this
65
what 2 things need to be considered when using targeted therapy?
- intratumoural heterogeneity | - mechanisms of metastatic spread
66
what as done to show intratumoural heterogeneity in renal cancer?
samples were taken from 8 locations in primary tumour and 2 distal locations - chest and close to kidney >looked at mutations in each sample >65% of mutations in a single biopsy were heterogeneous
67
what could be determined from looking at the 8 regions of solid tumour and the 2 metastatic renal cancer?
all metastatic cells cane from region 4 >this was done looking at common genes >this region picked up mutations that promoted metastasis
68
dose a single biopsy provide sufficient information for making treatment decisions?
probably not, but for this moment this is a good as it gets
69
using a combination of targeted therapies would be better than using one, why cant we do this at the moment?
we don't have enough drugs
70
what might prove more useful over genome sequencing?
more functional analysis and targeting phenotypes with therapeutics
71
what are genome England currently doing?
sequencing 100,000 individuals genomes. they are looking at different alleles in the population of different genes and how this may affect susceptibility to cancer

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