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Personalised Medicine > PMED in Oncology > Flashcards

PMED in Oncology Flashcards

1
Q

cancer 101

A

mutated cell
(uncontrolled growth)

primary tumour
(invasion and dissemination via blood and lymphatics)
metastatic tumour

or

treatment - remission
recurrence

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2
Q

what are the molecular aspects of cancer

A

genetic alteration (mutation)

altered protein (mutant form, overexpression)

altered pathways (activated cell survaval, loss of apopototic signals

altered biology
(limitless replication, angiogenesis, tissue invasion)

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3
Q

cancer treatment options?

A 
surgery
radiotherapy
chemo
hormonal
targeted therapy
adjuvant therapy
palliative care
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4
Q

define overall survival

A

length of time that patients are

alive, from either diagnosis or commencing treatmen

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5
Q

define progression free survival

A

length of time that

patients have disease but it does not get worse

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6
Q

define disease free survival

A

length of time after completing

treatment without any signs or symptoms of cancer

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7
Q

define response rate

A

percentage of patients whose cancer

shrinks or disappears after treatment

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8
Q

traditional diagnosis steps

A

1) site
2) invasion
3) histology
4) differentiation

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9
Q

traditional primary characteristic of cancer

A

uncontrolled cell division

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10
Q

traditional primary cancer treatment

A

chemotherapy - which inhibits DNA replication, disrupts microtubule function

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11
Q

what does tamoxifen do?

A

used for the treatment of both early and advanced estrogen receptor (ER)-positive (ER+) breast cancer

acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited

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12
Q

modern primary characteristics

A

specific mutations drive cell division

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13
Q

modern primary treatment

A

targeted therapy

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14
Q

what is gleevec/imatinib?

A

chemotherapy medication used to treat cancer. Specifically, it is used for chronic myelogenous leukemia (CML)

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15
Q

what is the philadelphia chromosome assoc with and what is it?

A

CML

Specific genetic abnormality in chromosome 22 of leukemia cancer cells

This chromosome is defective and unusually short because of reciprocal translocation of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is “always on”, causing the cell to divide uncontrollably

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16
Q

what is HER2?

A

member of human epidermal growth factor receptor

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17
Q

role of HER2 in cancer?

A

Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.It is strongly associated with increased disease recurrence and a poor prognosis

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18
Q

what is heceptin/trasruzumab?

A

humanised monoclonal antibody against HER2.

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19
Q

how doesherceptin/trastuzumab work?

A

Dimerised
HER2 receptors
signal to cells
to proliferate

Herceptin flags cells for
immune-
mediated death
(antibody dependent cellular
cytotoxicity, ADCC

Herceptin blocks downstream
HER2 signalling,
inhibiting proliferation

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20
Q

what was the response to herceptin?

A

Progression free survival increased from 4.6 to 7.4 months
•
Longer response to treatment, from 6.1 to 9.1 months
•
Increased survival, from 20.3 to 25.1 months

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21
Q

name another anti-her2 therapeutic agent and how is it different

A

pertuzumab

targets a different part of the HER2 receptor.

Can use both pertuzumab and herceptin so they work synergistically.

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22
Q

what is trastuzumab(herceptin)emtansine?

A

herceptin that is conjugated to emtansine.

Trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor. can also bind to EC domain, draw in immune system to kill

whereas emtansine can get takin into cells and broken down emantine is liberated and destroys them by binding to tubulin - disrupting microtubule assembly.

get 3 mechanisms of action in one.

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23
Q

how is HER2 detected?

A

using IHC (immunohistochemistry) and FISH (fluorescence in situ hybridisation)

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24
Q

what is lapatinib

A

tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways.

Can use all 3 together.

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25
Q

what is anaplastic lymphoma kinase (ALK)?

A 
Cell surface receptor with intracellular TK domain
•
Wild type activation:
ligand binding, dimerization, 
autophosphorylation
•
Associated with:
cell
-
cycle progression, survival, proliferation, angiogenesis.
26
Q

What is EML4-ALK

A

Its a fusion oncogene

get inversion in chr 2 which brings together half of EML4 and half of ALK = fusion gene, constantly active

27
Q

What is EML4-ALK associated with?

A

found in non-small cell lung cancer

28
Q

what is PF-02341066

A

A drug used to treat non-small cell lung cancer that has spread to other parts of the body.

It is a cMet (tyrosine protein kinase Met) selective tyrosine kinase inhibitor.

Also an inhibitor of the ALK tyrosine kinase

29
Q

what does PF-02341066 do?

A

It is used in patients whose cancer has a mutated (changed) form of the anaplastic lymphoma kinase (ALK) gene or the ROS1 gene.

PF-02341066 blocks the proteins made by the mutated ALK genes. Blocking these proteins may stop the growth and spread of cancer cells.

PF-02341066 may also prevent the growth of new blood vessels that tumors need to grow. It is a type of tyrosine kinase inhibitor and a type of antiangiogenesis agent.
Also called crizotinib, MET tyrosine kinase inhibitor PF-02341066, and Xalkori

30
Q

what was the ALK therapy used called and what was its response?

A

crizotinib, 50%

31
Q

better to start with 1st or 2nd gen drug?

A

trials show, better to start with 2nd gen drug as they are more potent/effective

32
Q

how does drug resistance occur?

A

1) you’ve got a mutated cell, forming a tumour. However the tumour is not homogenous, not same clonal expansion of that original cell. There are different cells within that tumour each with their own mutations.
2) when you treat tumour with targeted therapy, you are killing most of the cells in that tumour, but there are some which will be resistant in someway which can go and form a second tumour.

Alternativley you afre creating a selection pressure (drug) which kills of most cells, leaving a few behind which can survive.

33
Q

what are the mechanisms of tumour resistance?

A

1) survival of the fittest
2) sometimes the tumour will develop a secondary mutation which give rise to resistance.
3) ALK amplification
4) activating alternative signalling/pathways
5) upregulation of frug efflux pump p-glycoprotein (MDR1)

34
Q

how can secondary mutation give rise to resistance (ALK-TKI)?

A

the resistance can hinder the drug binding to the TK, alter kinase conformation, affects binding affinity for ATP of the TK

35
Q

explain ALK amplification

A

amplification of fusion genes in subset of genes and when tumour reoccurs youi see cells all contain that ALK

36
Q

explain upregulation of efflux pump

A

upregulation of a pump which can pump the drug out of the cancer cell

37
Q

what is the classic gene involved in upreg of drug efflux pump and what does it code for?

A

Multi-drug resistance 1 gene (MDR1) codes for p-glycoprotein

38
Q

what drug is used against efflux pump?

A

can give verapamil (alongside crizotinib) - which inhibits p-glycoprotein

39
Q

what does EGFR stand for?

A

epidermal growth factor receptor

40
Q

structure of EGFR?

A

extracellular domain, transmembrane domain, intracellular tyrosine kinase domain

41
Q

EGFR role in cancer?

A

common mutations in the IC TK domain, which activate the TK domain which then activated downstream signalling pathways which then gives cancerous phenotype

42
Q

drug against EGFR?

A

EGFR TKI such as gefitinib

43
Q

what drug is used in melanoma and how does it work?

A

vemurafenib - targets the v600e mutation in BRAF.

second gen: trametinib

44
Q

advantages of targeted therapies

A

Exceptional responses in some patients

Increased survival

Well tolerated compared to cytotoxic chemotherapy

45
Q

problems w targeted therapies?

A 
1)Most patients lack the molecular changes treatable 
with current molecular therapies e.g 
V600E BRAF ≈ 50% (melanoma)
HER2 overexpression <30% (breast)
HER2 overexpression <20% (gastric)
EML4ALK translocation <6% (NSCLC)

2) Clinical trials: must recruit many patients to identify
sufficient with the molecular change e.g oGA
Trial of
Herceptin in gastric cancer:
recruited ~4000 patients
<600 treated

46
Q

what is basket/bucket trial?

A

one drug, many tumour types eg ALK inhibitor

47
Q

what is umbrella trial?

A

one tumour type, treat with lots of drugs ie. lung `cancer

48
Q

what is NCI-MATCH?

A

National Cancer Institute - Molecular Analysis for Therapy Choice. Trying to find 6000 patients with solid tumours, lymphoma and myelome. DNA seq of 142 key genes.

Depending on which mutations are present of those genes, the patient will go into on of 24 arms of clinical trials.

49
Q

more problems with targeted therapies?

A

1) Most patients lack targets
2) Clinical trial recruitment and design
3) Evolution of resistance

4)Relatively short survival gains
-
Ceritinib
, no improvement 
wrt
chemotherapy
-
Herceptin, 5 month gain (25 month total)
-
Pertuzumab
, 16 month gain (56 month total)
5)Expensive
-
Pertuzumab
, £16,765
-
Nivolumab
(melanoma), £5,700/month
50
Q

what is early stage breast cancer?

A

breast cancer which has not spread

51
Q

how you treat early stage breast cancer?

A

surgery (lumpectomy, mastectomy)
adjuvant therapy: radiotherapy, chemotherapy, hormone therapy (ER+ve tamoxifen)

need to predict recurrence in patients with LN -ve, ER+ve breast cancer

52
Q

how to predict patients whos cancer will recur

A

measuring gene expresion using microarrays

53
Q

give name of microarray that predicts recurrence in breast cancer

A

oncotype Dx

54
Q

what did NICE(2013) conclude the best predictor?

A

oncotype Dx

55
Q

how does oncotype Dx work?

A

uses 21 genes

uses qRT-PCR

56
Q

what was the impact of the oncotype Dx

A

Decreased chemotherapy use

Increased confidence in decision making

Cost effective in the UK

57
Q

what to do with intermediate patients?

A

trial assigning individualized options for treatment (TAILORx)
findings (sparano et al 2015) foung 16% of patients were lo risk and entered arm A, recieving hormone therapy alone, 98% still alive after 5 years.

concluded patients with a low risk repxression profile can be spared chemo and their risk of recurrence within 5 years is less than 2%.

58
Q

traditional method of monitoring disease?

A

imaging using CT and PET

molecular markers: PSA, CA15-3

59
Q

what is metastasis?

A

when you have a primary tumour, some cells break away and invade the blood circ and lymphatic system. Circulate round going elsewhere to distant sites and form a tumour in new location.

60
Q

circulating tumour cells?

A

found in absence of signs of metastasis
found months/years after resection
cell count correlates with prognosis (miller et al 2010)

61
Q

cell free DNA (cfDNA)

A

some dna is found free floating in blood (short fragments). Unknown reason.

sequence primary tumour and normal cells, identify tumour specific genomic variants, blood sample, isolate DNA from plasma, PCR amplification, sequencing and quantitation of tumour-specific mutations indicated tumour burden.

62
Q

advantages of CTC and cFDNA?

A

More sensitive than imaging techniques

Less invasive than biopsy

Longitudinal sampling to monitor disease
progression and response to treatmen

Personalised Medicine (17 decks)

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