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MP421 > TARGETED CANCER THERAPY > Flashcards

TARGETED CANCER THERAPY Flashcards

1
Q

target therapy

A

drugs targeted at pathways, processes and physiology which are uniquely disrupted in cancer cells

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2
Q

chemotherapy vs targeted therapy

A

chemotherapy:
- drugs targeting dividing cells
- not very specific
- mostly intravenous, some oral
- cytotoxic

targeted therapy:
- drugs that inhibit a more specific target in cells
- many are oral agents
- mixture of cytotoxic and cytostatic

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3
Q

cytostatic

A

stopping the cancer cells from multiplying and growing

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4
Q

possible targets in cancer cells

A
  • can use targets that there are more of in cancer cells than normal cells
  • use targets that are mutated or different in cancer cells than normal cells
  • targets in both cancer and normal cells but normal cells regenerate or recover
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5
Q

targets in target therapy

A
  • receptors
  • genes
    angiogenesis or metastasis
  • microenvironment i.e. hypoxia
  • antigens expressed
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6
Q

personalised medicine

A

use molecular analysis to achieve optimum medical outcomes in the management of a patient’s disease or disease predisposition

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7
Q

advantages of personalised medicine

A
  • detect disease at earlier stage
  • enable selection of optimal therapy and reduce trial and error prescribing
  • reduces adverse effects
  • reduce time, cost and failure rates of clinical trials
  • reduce the overall cost of healthcare
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8
Q

disadvantages of personalised medicine

A
  • cost of tests and time
  • drugs themselves are expensive and not accessible to everyone
  • need good biomarkers to be able to stratify patients
  • need good biomarkers in the form of liquid biopsy to monitor response or development of resistance
  • resistance often develops
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9
Q

personalised medicine leads to

A
  • better matching patients to drugs instead of trial and error
  • customising drugs may eliminate life-threatening adverse effects
  • reduce cost of clinical trials
  • improved efficacy of drugs
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10
Q

cancer diagnostics for personalised medicine - what is the value of predisposition screen

A

identify patients for chemo-prevention

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11
Q

cancer diagnostics for personalised medicine - value of screen for presence of cancer

A

increase in patients - earlier recognition of disease

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12
Q

cancer diagnostics for personalised medicine - value of pharmacodynamic biomarkers

A

establish pharmacological dose

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13
Q

cancer diagnostics for personalised medicine - value of surrogate marker of clinical efficacy

A

early indication of proof of concept

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14
Q

application of the HER-2/neu receptor biomarker

A

select Herceptin (trastuzumab) for breast cancer

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15
Q

application of the BRCA1/2 biomarker

A

breast and ovarian cancer inherited risk, prophylactic tamoxifen and surgery

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16
Q

application of the transcriptional profile - 21 genes biomarker

A

avoid use of chemotherapy in breast CA patients with low risk of recurrence

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17
Q

receptors in breast cancer

A
  • breast cancer associated with amplification of the genes coding for a cell surface receptor HER-2/neu
  • these cells may have a 1000-fold increase in the number of these receptors on breast cancer cells
  • having lots of receptors is associated with rapid growth
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18
Q

how does Herceptin initiate an immune response

A
  1. HER2 molecules on the cancer cell surface pair up to send signals to encourage cells to multiply
    and for blood vessels
  2. cancer cells multiply and the tumours quickly grow
  3. blood vessels grown in to provide the tumour with nutrients
  4. herceptin can be used to block the signals, stopping cancer cells from multiplying
  5. immune cells bind to herceptin and attack cancer cells
  6. cancer cells do not multiply as quickly, slowing tumour growth
  7. blood vessels do not grow in, starving tumours of nutrients
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19
Q

chronic myeloid leukaemia

A
  • CML is the result of a reciprocal translocation between chromosome 9 and 22
  • the result is a fusion gene created by juxtapositioning on the ABL1 gene on xome 9 to part of the BCR gene on xome 22
  • the result of the translocation is the oncogenic BCR-ABL gene fusion
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20
Q

BCR-ABL gene

A
  • only present in CML
  • the ABL gene expresses a tyrosine kinase, the BCR-ABL transcript is also translated into a very active tyrosine kinase
  • ABL activates cell-cycle controlling proteins and enzymes, the result of the BCR-ABL fusion is to speed up cell division and inhibits DNA repair
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21
Q

imatinib (Gleevec)

A

inhibits BCR-ABL tyrosine kinase, the constitutive abnormal gene product of the Philadelphia chromosome in chronic myeloid leukaemia

indication: Ph+ CML, Ph+ SLL, GIST

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22
Q

imatinib moa

A

slots into ATP binding site so ATP cannot - no substrate present so target protein cannot be phosphorylated - switched on

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23
Q

how to detect the Philadelphia chromosome

A

fluorescent in situ hybridisation (FISH)

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24
Q

second generation BCR-ABL inhibitors

A

nilotinib
dasatinib

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25
Q

difference between nilotinib and imatinib

A

nilotinib has higher potency of BCR-ABL inhibition

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26
Q

difference between dasatinib and imatinib

A

dasatinib has fewer structural constraints to binding, targets more kinases

27
Q

drugs targeting the VEGF pathway

A

bevacizumab
aflibercept

28
Q

bevacizumab (Avastin)

A
  • angiogenesis inhibitor
  • drug that slows the growth of new blood vessels
  • recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A)
29
Q

VEGF-A

A

chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer

30
Q

side effects of Bevacizumab

A

high blood pressure
nausea
fatigue
risk of bleeding

31
Q

indication of Bevacizumab

A

colon cancer
lung cancer
renal cancer
ovarian cancer
glioblastoma

32
Q

normal cell growth

A
  • for a normal cell to divide it needs a signal from the body i.e. growth factor
  • this signal turns on growth transiently
  • cell growth then turns off
  • if another growth factor binds it divides again
33
Q

proteins involved in signalling pathways

A

oncoproteins

34
Q

how do signals coming in at the cell surface result in a change in the cell behaviour

A
  1. receptor gets the growth factor first
  2. it passes the growth factor around along the route through the cell cytoplasm
  3. the signal to grow then gets to the nucleus
  4. once in the nucleus it directs proteins to transcribe certain bits of DNA to make proteins it needs to respond to that signal
  5. once these proteins are made the cell then does the action requested
35
Q

how does each protein in signals changing cell behaviour get turned on

A

phosphorylation by enzymes called kinases
removal of phosphates by enzymes called phosphates

36
Q

what do tyrosine kinase pathways mediate

A

cell growth
division
differentiation
metabolic regulation

37
Q

tyrosine kinase

A
  • TK catalyse the transfer of a gamma phosphate from ATP to the hydroxyl group of tyrosine residues of protein substrates
  • tyrosine protein phosphorylation is rare relative to serine/threonine phosphorylation tightly regulated in quiescent cells but abundant in rapidly proliferating cell therapeutic differential
38
Q

TK can be hyperactive by:

A
  • increased expression of receptor TK and/or its ligand
  • mutation that alters autoregulation of the TK
  • Fusion with a partner protein that results in constitutive activation of the TK
39
Q

result of aberrant TK activation

A
  • may result in high cell survival and proliferation
  • drug resistance
  • in tumours, increased angiogenesis and invasiveness
40
Q

targeting receptor tyrosine kinase for cancer therapy

A

targeted via 3 routes
- extracellular
- intracellular
- nuclear (not successful)

41
Q

targeting extracellular: growth factors

A
  • polypeptide growth factors stimulate proliferation of normal cells
  • many are suspected to influence tumourigenesis
  • mutations of genes that encode growth factors can render them oncogenic
42
Q

c-sis proto-oncogenic, platelet-derived growth factor (PDGF)

A
  • high level of expression of human c-sis resulted in transformation of recipient cells, relevant in sarcomas and glioblastomas
  • similar results have been subsequently obtained for other growth factors, including transforming growth factor alpha, epidermal growth factor, and fibroblast growth factor
43
Q

targeting growth factor receptors - EGFR

A
  • mutant receptors > continuous mitogenic signals to the cell to grow
  • overexpression of the normal forms of GFRs is more common than mutations/deletions
  • relevant for the EGFR following amplification or overexpression of the EGFR gene, contributing to the establishment of an autocrine ligand loops (continues self activation)
44
Q

anti-EGFR drugs

A

cetuximab
Panitumumab

45
Q

cetuximab

A
  • monoclonal antibody directed against EGFR
  • IgG1 chimerized anti-EGFR mAb
  • binds to EGFR domain with high affinity, prevents ligand binding and activation
  • approved in metastatic colorectal cancer and squamous cell carcinoma of the head and neck
46
Q

panitumumab

A
  • fully human antibody specific to the epidermal growth factor receptor
  • most likely to work for cancers with a lot of EGFRs on their surfaces
  • before being used to treat bowel cancer, the cells need to be tested for mutations in KRAS or the drug won’t work
  • not recommended use in advanced bowel cancer
47
Q

side effects of panitumumab

A

severe rash
most likely starting on hands

48
Q

targeting intracellular: small molecule inhibitors of the EGFR TK domain (TKIs)

A

anilinoquinazolines
- Gefitinib (1st gen.)
- Erlotinib (1st gen.)
- Osimertinib (later gen.)
- Afatinib (later gen.)

49
Q

research into Gefitinib

A
  • research of gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways these mutations tend to confer increased sensitivity to TKIs such as gefitinib and erlotinib
50
Q

Erlotinib

A
  • used to treat non-small cell lung cancer, pancreatic cancer and more
  • reversible tyrosine kinase inhibitor that acts on the EGFR
  • expensive
  • as with other ATP competitive small molecule tyrosine kinase patients rapidly develop resistance
  • erlotinib resistance typically occurs 8-12 months from the start of treatment
51
Q

what causes resistance to erlotinib

A

over 50% of resistance caused by mutation in the ATP binding pocket of the EGFR kinase domain

52
Q

Gefitinib

A
  • treatment of locally advanced or metastatic non-small cell lung cancer with activating mutations of EGFR
  • EGFR inhibitor which interrupts signalling through the EGFR, therefore only effective in cancers with mutated and overactive EGFR
  • adenocarcinoma most likely to have this mutation
53
Q

common EGFR analytical methodologies

A
  • EGFR protein expression by immunohistochemistry (IHC)
  • EGFR gene copy number by fluorescence in situ hybridisation (FISH)
  • EGFR mutation status by gene sequencing
54
Q

overcoming resistance

A
  • overcome by monitoring for maintenance of mutations in resistant disease
  • 2nd mutations in EGFR can cause resistance
  • combination therapy
55
Q

mitogen-activated protein (MAP) kinase pathway

A
  • role in regulation of cellular proliferation
  • signals go from the cell membrane to the nucleus
  • signal transduction proteins
56
Q

RAS oncogenes

A
  • RAS gene encoded a small mol. weight G-protein called p21RAS
  • RAS gene mutations are the single most common abnormality of dominant oncogenes in human tumours
  • these mutations result in encoding a form of p21RAS that is consistently active in the GTP-bound state and does not return to an inactive form like that of normal RAS when deactivated
57
Q

how is RAS activated and deactivated

A
  • receptor tyrosine kinases and G-protein-coupled receptors activate RAS, which then stimulates the Raf-MEK-MAPK pathway
  • GTPase-activating proteins (GAP) normally facilitate the inactivation of RAS
  • however in tumours, point mutations in RAS prevent the GAP-mediated inhibition of this pathway
58
Q

most common RAS mutation in tumours

A

most common oncogenic RAS mutation found in tumours is Gly12 to Asp(G12D), which prevents RAS inactivation, possibly by increasing the overall rigidity of the protein

59
Q

targeting RAS

A

CAN’T PRESCRIBE WITHOUT K-RAS MUTATION TESTS

  • any drugs upstream of RAS will not work as RAS is always switched on
  • developed downstream blockers of the RAS cascade - MEK inhibitors and Raf inhibitors
  • targeting the RAS pocket also targets other normal proteins making it a difficult target
  • new target on RAS: allosteric inhibitor changes the conformation of the protein, stopping RAS from being activated
60
Q

allosteric inhibitors of RAS

A

sotorasib
Adagrasib
- allosteric inhibition is the binding of a regulatory molecule to separate site turning the enzyme off by changing the shape of the enzyme’s active site
- allosteric inhibition only works on patients with G12C mutation

61
Q

after RAS comes RAF

A
  • many tumours have specific Braf mutations - i.e. 50% patients have mutations at codon 600 - called V600E mutation
  • specific drugs designed to target V600E mutation
  • resistance develops
  • given in combination
  • example: vemurafenib and dabrafenib in melanoma
62
Q

MEK inhibitors

A
  • chemical or drug that inhibits the mitogen-activated protein kinase enzymes MEK1 and/or MEK2
  • can be used to inhibit the MAPK/ERK pathway which is often overactive in some cancers
63
Q

Trametinib and Dabrafenib

A
  • trametinib approved to treat BRAF-mutated melanoma, highly selective allosteric inhibitor of MEK1/MEK2
  • trametinib and dabrafenib target 2 different tyrosine kinases in the RAS/RAF/MEK/ERK pathway
  • the combination inhibits growth of BRAF V600 mutation-positive melanoma cell lines more than either drug alone
64
Q

Can’t Plug Grandads Old Aged Ears Silly Auntie Veronique Tough

A

Cetuximab
Panitumumab
Gefitinib
Osimertinib
Afatinib
Erlotinib
Sotorasib
Adagrasib
Vemurafinib
Trametinib

MP421 (12 decks)

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