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cancer > 21. personalised therapy > Flashcards

21. personalised therapy Flashcards

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
Q

what happens in phase 2?

A

people with CML are given Gleevec

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26
Q

following gleevec treatment, what percentage of people with CML had normal haematological smears?

A

> 95% of patients have in the chronic phase of disease

>30% in blasts

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27
Q

what percentage of could chromosome abnormalities no longer be observed in and why is this?

A

60% of people in chronic phase

>cells which have abnormal chromosomes died i.e. cells were addicted to this oncogene

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28
Q

why was phase 3 skipped?

A

there was no other treatment to compare it with

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29
Q

what was seen after people appeared to be cured from CML after gleevec treatment?

A

patients relapsed
>this only occurred in 10% when disease was caught early
>when caught in blast occur in 80%

30
Q

what are the relapses in CML due to?

A

33 different point mutations that means gleevec can no longer bind Abl

31
Q

which might people require higher dose of gleevec?

A

patients may have amplified BCR-abl locus

32
Q

what does Nilotinib do? and what did this lead to?

A

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
Q

what are single agent therapies are easy for tumour cells to… and what would improve this?

A

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
Q

what type of receptor can be amplified on breast cancer cells?

A

her2

35
Q

name three things that a breast cancer cell can be + or - to

A

Her2
ER
PR

36
Q

name an antagonist of ER

A

tamoxifen

37
Q

name the antibody against her2 and what is Iressa

A

Herceptin

>inhibitor against the kinase activity of Her2.

38
Q

how do we determine what the breast cancer is + and - for?

A

immunostaining/sequencing

39
Q

what might become possible in terms of sequencing?

A

sequence everyone’s tumours before treatment

40
Q

how much has the cost of sequencing a human genome nearly come down to? and what might this mean?

A

$1000

>may be cheaper to sequence a genome that treat with drugs for years

41
Q

why characterise somatic mutations in human cancers?

A
  • understand more about cancer
  • identify mutated genes for therapy
  • information about process of mutagenesis - help with early detection and prevention
42
Q

what is the risk of breast cancer in the UK

A

1 in 8 women

43
Q

how many breast cancer cases are hereditary?

A

5-10%

44
Q

what can sequencing genomes of normal people be used for?

A

predictions - give you your relative risk of developing the disease

45
Q

what is the candidate approach for genome sequencing?

A

sequence well known oncogenes

46
Q

what did the candidate approach progress to? and what has this been superseded by?

A

large scale exon sequencing

>whole genome sequencing

47
Q

what was identified when using the candidate approach in malignant melanomas?

A

> sequenced 20 genes in many different patients
found mutation in BRAF in 90%
only one mutant copy was needed - oncogene

48
Q

what does activated BRAF activate?

A

MAP kinase pathway

49
Q

how is the BRAF protein mutated and what does this mimic?

A

always mutated to negative residue and this mimics phosphorylation - moves the aviation loop and makes kinase constitutively active.

50
Q

inhibitor was developed for BRAF, what is it called and what did it show?

A

PLX

>inhibits the mutant form a lot more than the wild type form.

51
Q

name the dye that can fluorescently label viable cells

A

Calcein-AM - passes into cells and is cleaved to fluorescence green

52
Q

what is propidium iodide stain?

A

get into cells with broken membranes (dead cells), can intercalate with DNA and fluoresce red.

53
Q

what was seen when PLX was added to BRAF mutant cells and normal cells?

A

mutant cells died

WT cells did not

54
Q

what was seen when people with metastatic melanomas were given PLX?

A

massive shrinkage of their metastasis

55
Q

what different ways can BRAF mutant cancer cells become resistant to PLX?

A

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
Q

what is clear cell carcinoma?

A

type of renal carcinoma that make up 75% of renal cancer (there are four types of renal cancer)

57
Q

what is the COSMIC database?

A

a catalogue of all the somatic mutations in cancer

58
Q

what is found in 46% of renal cancers? and how was this identified?

A

mutations in VHL (highly vascularised tumours)

>large scale exon sequencing, screened coding regions for copy number and expression

59
Q

large exon sequencing identified VHL to be mutated in 60% of cells tested, what occurs in 82% of cases?

A

expression has upregulation of genes associated with cellular hypoxia

60
Q

what did large exon sequencing also identify that had never been previously unknown to be involved in kidney cancer ?

A

5 genes - histone methylase/demethylases

61
Q

if large exon sequencing does not pick up any mutations what does this suggest?

A

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
Q

what has whole genome sequencing been used in ?

A

breast cancer - 20 driver genes identified

63
Q

what are driver mutations?

A

mutations are statistically found more commonly than to just be found by chance

64
Q

around how many driver mutations were seen per breast cancer? and what implication does this have on therapy?

A

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
Q

what 2 things need to be considered when using targeted therapy?

A
  • intratumoural heterogeneity

- mechanisms of metastatic spread

66
Q

what as done to show intratumoural heterogeneity in renal cancer?

A

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
Q

what could be determined from looking at the 8 regions of solid tumour and the 2 metastatic renal cancer?

A

all metastatic cells cane from region 4
>this was done looking at common genes
>this region picked up mutations that promoted metastasis

68
Q

dose a single biopsy provide sufficient information for making treatment decisions?

A

probably not, but for this moment this is a good as it gets

69
Q

using a combination of targeted therapies would be better than using one, why cant we do this at the moment?

A

we don’t have enough drugs

70
Q

what might prove more useful over genome sequencing?

A

more functional analysis and targeting phenotypes with therapeutics

71
Q

what are genome England currently doing?

A

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

cancer (24 decks)

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