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Cancer > Targeted therapy > Flashcards

Targeted therapy Flashcards

1
Q

Which pathways depend on signalling by receptor tyrosine kinase and how are these pathways activated?

A 
MAPK pathway (proliferation)
PI3K pathway (cell growth, proliferation, angiogenesis and metabolism)

Activation process:

  • receptors bind to growth factors
  • causes dimerisation of the receptor
  • structural changes occur on the intracellular part
  • tyrosine kinase becomes phosphorylated
  • it reacts with adaptor proteins
  • adaptor proteins activate the pathways
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2
Q

Which part of the receptor tyrosine kinase do monoclonal antibodies and small molecule tyrosine kinase inhibitors target?

A

Monoclonal antibodies: target extracellular/growth factor receptor ligand binding domain

Small molecule tyrosine inhibitors: target intracellular/tyrosine kinase domain

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3
Q

In the extracellular domain (of tyrosine kinase receptor), which regions are responsible for ligand binding and which are responsible for dimerisation?

A

1+3 bind to ligan

2+4 responsible for dimerisation

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4
Q

Give an example of a monoclonal antibody that stops tyrosine kinase signalling and describe how it works.

A

Cetuximab

Prevents the binding of ligand to the receptor

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5
Q

What type of cancer is cetuximab used in?

A

Metastatic colorectal cancer

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6
Q

How do antibodies access tumour cells?

A
  • Tumour tissue has disorganised vasculature which is structurally weak
  • Smooth muscle cells are reduced
  • Links between endothelial cells are weakened
  • -> makes blood vessels leaky (large molecules have access to malignant tissue)
  • Tumour tissue generally does not have a lymphatic drainage system
  • macromolecules are retained and can accumulate in solid tumours
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7
Q

Describe the nomenclature of mAbs.

A

*last syllable is always -mab

Next to last syllable:

  1. -u- = human (100%)
  2. -zu- = humanised (95%)
  3. -xi- = chimeric (65%)
  4. -o- = mouse; -a- = rat; -e- = hamster; -i- = primate

Previous syllable:

  1. -tu(m)- = for tumour in general
  2. -ma(r)- = breast; -pro- = prostate; -co(l)- = colon
  3. -ci(r)- = circulatory
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8
Q

Give examples of mAbs which target the following growth factor receptors:

  1. EGFR
  2. HER2 (ErB2)
  3. HER2/HER3
  4. VEGFR
A
  1. cetuximab and panitumumab
  2. trastuzumab
  3. pertuzumab
  4. bevacizumab
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9
Q

How do monoclonal antibodies work?

A
  1. Killing tumour directly:
    - inhibit ligand binding
    - signalling blocked
    - apoptosis induced
    - possible delivery of cytotoxic payload
  2. Killing tumour cells via an immune-mediated mechanism:
    - induction of phagocytosis
    - complement dependent cytotoxicity (CDC)
    - antibody dependent cell cytotoxicity (ADCC)
  3. Vascular or stromal ablation
    - VEGF antagonism
    - Inhibit formation of new blood vessels
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10
Q

What % of women with HER2 +ve breast cancer will respond to Trastuzumab?

A

~20%

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11
Q

What is the recommended therapy for HER2 +ve metastatic or locally recurrent unresectable breast cancer?

A

Pertuzumab in combination with trastuzumab and docetaxel

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12
Q

What is the MOA of Trastuzumab?

A
  • binds to domain IV on HER2
  • suppresses ligand-dependent HER2 signalling
  • prevents HER2 extracellular domain shedding
  • identifies cells for antibody-dependent cell mediated cytotoxicity
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13
Q

What is the MOA of Pertuzumab?

A
  • binds to domain II on HER2
  • inhibits homo- and heterodimerisation
  • suppresses ligand dependent HER2 signalling
  • identifies cells for antibody-dependent cell mediated cytotoxicity
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14
Q

Why might women with HER2 +ve breast cancer be resistant to Trastuzumab treatment?

A

HER2 is ligand dependent and doesn’t need a growth factor in order to be activated

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15
Q

What is VEGF and what is its role?

A

Vascular Endothelial Growth Factor

  • required for formation of new blood vessels
  • one of the most unregulated antigens in cancer
  • protects endothelial cells from death via activation of PKC pathway and up regulation of anti-apoptotic proteins such as Bcl-2
  • activity is mediated by tyrosine kinase receptors (VEGFR1 and VEGFR2)
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16
Q

What drug can inhibit VEGF signalling?

A 
Bevacizumab (Avastin)
Inhibiting VEGF signalling:
1. block receptor binding 
2. inhibit tumour growth and metastasis 
3. deprive tumours of nutrient-providing blood vessels
17
Q

How does trastuzumab emptansine (Kadcyla) work?

A
  • drug gets into lysosome (receptor-mediated internalisation into cells)
  • there is cleavage
  • high concentration of an anti-mitotic drug inside cells
    (anti-microtubule DNA - no new DNA formation - no tumour growth)
  • DM-1 catabolite binds to tubulin to cause mitotic arrest and cell death
18
Q

What is the MOA of Tarceva (Erlotinib)?

A

Statically inhibits ATP binding by targeting the ATP binding site
- terminal phosphate is unable to phosphorylate tyrosine

19
Q

What type of cancer is Tarceva/Erlotinib used for and what growth factor does it target?

A

Advanced stage NSCLC

Targets EGFR

20
Q

What do small molecule tyrosine kinase inhibitors target?

A

target oncogene products such as:

  1. Bcr-Abl (chronic myeloid leukaemia)
  2. EGFR (NSCLC)
21
Q

Describe the nomenclature of small molecule tyrosine kinase inhibitors.

A
  • ib = inhibitory

- tinib = tyrosine kinase inhibitors

22
Q

What is an activation loop?

A

Exon where ATP binds

23
Q

Which mutations (and in which axons) are associated with drug resistance to erlotinib?

A

Exon 19: D761IY (>1%)

Exon 20: T790M (50%)

24
Q

How many generations of EGFR tyrosine kinase inhibitors are there? Give examples for each.

A

1st generation (reversible)

  • erlotinib
  • gefitinib
2nd generation (irreversible)
- afatinib
3rd generation (mutant-selective)
- osimertinib
25
Q

What are the side effects of these targeted therapies? (try to link them with specific growth factors)

A
  1. skin changes:
    - skin rashes (acneiform) –> EGFR
    - dry skin
    - itchy skin
    - hand foot syndrome –> VEGFR
    - changes in hair
    - dry or red eyes and red and tender eyelids
  2. High blood pressure –> VEGFR
  3. Slow wound healing and blood clotting –> EGFR
  4. Congestive heart failure –> HER2
26
Q

How can trastuzumab cause cardiotoxicity?

A

HER2 survival pathways:

  • increased cellular transcription factors
  • increased production of nitric oxide
  • inhibition of ROS

Trastuzumab:
It inhibits the HER2 survival pathway and also causes endothelial dysfunction (increased production of ROS, reduced nitric oxide production, impaired vasodilation, reduced myocardial blood flow)

  • both of these contribute to congestive heart failure:
    1. left ventricular ejection fraction is <50-55%
    2. apoptosis of cardiomyocytes
    3. increased myocardial workload
27
Q

What are the different activating mutations in tyrosine kinase domain of EGFR in lung cancer?

A
  1. Exon 18:
    - G719C
    - G719S
    - G719A
  2. Exon 19:
    - δE746-A750
  3. Exon 20:
    - V769-D770
  4. Exon 21:
    - L858R

Cancer (7 decks)

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