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Bench to bedside and beyond > 4. Personalised Cancer medicine > Flashcards

4. Personalised Cancer medicine Flashcards

1
Q

what does heterogeneous mean?

A

a tumour is made up of more the 1 cell type with different mutations.

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2
Q

why are heterogeneous tumours bad?

A

they present an obstacle to treatment

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3
Q

are all tumour heterogenous?

A

no but most are especially metastatic tumours

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4
Q

why is relapse much more likely in heterogeneous tumours?

A

because not all cells in the tumour are killed by the treatment and the remaining cells can repopulate the tumour

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5
Q

why do we need personalised medicine?

A

current cancer treatment doesn’t account for the individual tumour and are broad specturm medicines

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6
Q

what current broad spectrum cancer treatments do we use?

A

drugs that target mitosis like taxol
these still have a role but they don’t differentiate between normal and tumour cells very well.
tumour cells are more susceptible to these treatments due to fast replication

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7
Q

what can personalised treatment do?

A

it accounts for specific mutations and can target them
each patient can have tailored treatment for their tumour with less side effects

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8
Q

what is an example of personalised cancer treatment?

A

if a tumour has BCR-ABL mutation specific drugs can be used to target it

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9
Q

what is BCR-ABL mutation?

A

it is a fusion protein made by chromosomal translocation from chromosome 9 and chromosome 22
it phosphorylates things that are not normally

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10
Q

what can effect different tumour biomarkers?

A

genetic and epigenetic factors

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11
Q

what 2 cell types are all breast cancers derived from?

A
  1. luminal epithelial cells
  2. basal cells
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12
Q

what are the differences between luminal derived cancers and basal derived cancers?

A
  1. they responsed differently to signals
  2. they responsed differently to treatments
  3. basal cell cancers are normally receptor negative
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13
Q

what is basal luminal cell cancer?

A

a intermediate stage of cancer that tend to still have high levels of HER2 expression

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14
Q

what are 40% of luminal cancers?

A

Estrogen and progesterone receptor positive

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15
Q

what is triple negative breast cancer?

A

it makes up 15-20% of breast cancer
poor prognosis
Estrogen, progesterone and HER2 receptor negative
not as responsive to treatment

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16
Q

what does HER2 over expression lead to?

A

can be well treated with specific drugs

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17
Q

what happens in estrogen receptor positive breast cancer?

A
  1. estrogen stimulates receptors
  2. activation of transcription factors
  3. causes cell proliferation
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18
Q

how can we treat estrogen receptor positive breast cancer?

A
  1. tamoxifen blocks the binding of estrogen to the receptor
  2. prevents the cell proliferation signals
  3. used as a treatment to prevent cancer cell proliferation
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19
Q

what is the HER2 receptor?

A

a tyrosine kinase that activates a number of kinase pathways

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20
Q

what can the HER2 tyrosine kinase pathways influence in the cancer cell?

A
  1. adhesion
  2. differentiation
  3. cell growth
  4. migration
  5. apoptosis
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21
Q

how can we prevent HER2 signalling pathway stimulation?

A

using monoclonal antibodies like trastuzumab

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22
Q

what are the BRCA proteins involved in?

A

DNA repair

23
Q

what happens in DNA repair in normal cells?

A

there are lots of different DNA repair mechanisms and if one doesnt work then the other pathways can compensate

24
Q

what happens in BRCA1/2 DNA repair in tumour cells?

A
  1. either BRCA1 or BRCA2 pathways will be lost to start the cancer cell
  2. the cell is mutated enough that only 1 repair pathway left
  3. if we block the remaining repair pathway we can kill the cancer cells as the DNA becomes too damaged to replicate and survive
25
Q

what is very common in HER2+ tumours?

A

amplification rather then mutation
if the HER2 levels are high we can block the pathway

26
Q

what is BRAF?

A

an oncogene
mutation of BRAF is very common in skin cancer and other cancers

27
Q

what are the 4 subtypes of medulloblastoma?

A
  1. Wnt group
  2. SHH group
  3. Group 3
  4. Group 4
28
Q

what are Wnt group medullobastoma?

A

characterised by ß-catenin mutations
metastasis is rare
good prognosis

29
Q

what are SHH group medullobastoma?

A

sonic the hedgehog group
better survival in infants

30
Q

what are group 3 medullobastoma?

A

frequent metastases
MYC proto oncogene highly expressed

31
Q

what are group 4 medullobastoma?

A

cyclin dependant kinase 6 amplification
frequent metastases
Minimal MYC expression
high in infants

32
Q

why is knowing the type of glioblastoma important?

A

it determines how you treat the patient. this is especially important in children.

33
Q

what types of medulloblastoma need more aggressive treatment?

A

group 3 and 4 you would need early aggressive treatment
Wnt group wouldn’t need aggressive treatment

34
Q

what does MGMT hypermethylation do in glioblastoma?

A

gene silencing to prevent DNA repair mechanism

35
Q

what is unique about the MGMT assay?

A

it is one of the only DNA methylation based assays used in clinical settings

36
Q

why is MGMT hypermethylation good in cancer treatment?

A

the cancers respond better the DNA damaging treatment

37
Q

what is the drug most commonly used in MGMT hypermethylation therapy?

A

temozolomide - TMZ

38
Q

what does temozolomide do?

A

it adds methyl groups to guanine which interferes with the rapid replication of tumour DNA and cause DNA damage

39
Q

what does MGMT do?

A

it is part of our DNA repair mechanism

40
Q

what does silencing MGMT do?

A

prevents DNA repair mechanisms so can force the cancer cells to apoptose after damages from TMZ

41
Q

how is MGMT silenced?

A

using hyper methylation

42
Q

when is MGMT sensitive to temozolomide?

A

when MGMT is silenced
when MGMT is expressed at low levels

43
Q

what are the 3 types of neuroblastoma histology?

A
  1. Ganglioneruoma
  2. ganglioneuroblastoma
  3. neuroblastoma
44
Q

Ganglioneruoma

A

generally benign ganglionic cells
no need for aggressive treatment

45
Q

neuroblastoma

A

high stage
small undifferentiated cells
very aggressive
urgent strong treatment

46
Q

what are neuroblastomas?

A

sympathetic nervous system cancer

47
Q

what is MYCN?

A

a transcription factor
strong association with MYCN amplification and poor prognosis
very important in neuroblastoma

48
Q

what is an experimental drug that can interfere with MYCN transcription?

A

JQ1
BRD4 it will bind to acetylated histones and at the MYCN promoter and start transcription.
JQ1 binds BRD4 to prevent binding and prevent transcription

49
Q

how do we know what personalised medicine to use?

A

sampling technologies

50
Q

how do we determine tumour sensibility?

A

look for characteristics and features
- take a sample
- put in mice and try treatments
- make a biobank from the mice
- then recommend a suitable treatment

51
Q

what are less invasive diagnositic techniques?

A

biomarkers
liquid biopsies

52
Q

what are liquid biopsies?

A

saliva
cerebral spinal fluid
blood and urine to find circulating tumour DNA/cells

53
Q

what does these diagnostic tests look for?

A

gene fusion
methylation changes
Point mutations
circulating mRNA

54
Q

what is pharmacogenomics?

A

cancer genome sequencing that can inform choice of selective therapies

Bench to bedside and beyond (20 decks)

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