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407 > Lecture 14: Targeted therapies I > Flashcards

Lecture 14: Targeted therapies I Flashcards

1
Q

Treatments for cancer

A
  • From 1960s, drug treatments focused on
    arresting cell growth (chemotherapy)
  • Targeted approach began with hormone
    therapy
  • Molecular targeted therapy era started in
    late 1990s
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2
Q

Radiotherapy

A
  • Pioneered by Marie Curie in 1900s
  • Exposure to ionizing radiation
  • Causes extensive cellular damage, formation of free radicals
  • 1 Gray causes damage to >1000 bases in DNA, ~100 SSBs and ~40 DSBs
  • Approaches:
  • External beam radiotherapy (XRT)
  • Internal radiotherapy (Brachytherapy/ seeded)
  • Radio-isotope therapy (eg Iodine -131 for thyroid cancer)
  • Drawbacks
  • Non-specificity
  • Requires carefully controlled administration
  • Unwanted Side effects
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3
Q

Types of
chemotherapy

A
  • Alkylating agents
  • Anti-metabolites
  • Mitotic inhibitors
  • Topoisomerase inhibitors
  • Anti-tumour antibiotics
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4
Q

Targeted therapies in cancer

A
  • Three key strategies for targeted therapies against cancer:
  • Monoclonal antibodies
  • Small molecule tyrosine kinase inhibitors
  • Antibody-drug conjugates (ADCs)
  • First successes in hematological cancers
  • Rituximab and imatinib
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5
Q

Targeted therapy mechanisms

A
  • Receptor
    activation
  • Signalling
    transduction
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6
Q

Targeted therapy mechanisms
* Monoclonal antibodies:

A
  • Bind to the receptor extracellular
    domain
  • Inhibit pathway activation
  • Receptor internalisation
  • Antibody-dependent cellular
    cytotoxicity
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7
Q

Targeted therapy mechanisms
* Small molecule TKIs:

A
  • Bind to the receptor intracellular
    domain
  • Inhibit pathway activation
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8
Q

Targeted therapy mechanisms
* Antibody-drug conjugates:

A
  • Bind to the receptor extracellular
    domain
  • Inhibit pathway activation
  • Receptor internalisation
  • Payload delivery
  • Antibody-dependent cellular
    cytotoxicity
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9
Q

Strengths and weaknesses of anti receptor antibodies vs. low molecular weight tyrosine kinase inhibitors as anti cancer agents

A

Small molecule: Target- tyrosine kinase domain, strong specificity, binding- most are rapidly reversible, oral daily, distribution in tissues more complete, toxicity- rash, diarrhaea, pulmonary, antibosy- dependent cellular toxixity- no

Antibody: Target- receptor ectodomain, stronger specificity, binding0 receptor internalised, only slowly regenerated, dosing- intravenous, weekly, distribution- less complete, toxicity- rash, allergy, antibody dependent cellular cytotoxicity - possibly

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10
Q

The role of HER family in cancer

A
  • Receptor tyrosine kinases
  • Over-expressed in numerous
    cancer types
  • EGFR most notably involved in
    lung, head and neck, colorectal
    cancers
  • HER2 is over-expressed in
    several cancer types but most
    notably in breast cancer
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11
Q

HER family activation

A
  • PI3K pathway
  • MAPK pathway
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12
Q

Numerous strategies for
targeting the HER family

A

Monoclonal antibodies
* Antibody-drug conjugates
* Small molecule tyrosine
kinase inhibitors

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13
Q

Approved HER2-targeted TKIs

A

Lapatinib, Neratinib, Tucatinib

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14
Q

Lapatinib

A

− Dual HER2/EGFR TKI
− Reversible inhibitor
− First HER2-targeted TKI
FDA-approved
− Approved in combination
with capecitabine in
HER2+ BC and with
letrozole in HER2+ HR+
BC

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15
Q

Neratinib

A
  • Pan-HER TKI
  • Irreversible inhibitor
  • Approved in earlystage (single agent)
    and metastatic
    (+capecitabine) HER2+
    BC
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16
Q

Tucatinib

A

− HER2-specific inhibitor
− Reversible inhibitor
− FDA-approved in
combination with
trastuzumab +
capecitabine for metastatic
HER2+ BC

17
Q

Clinical comparisons of the HER2-targeted
TKIs

A

Neratinib approval
in mHER2+ BC
Tucatinib approval
in mHER2+ BC

No direct comparison of tucatinib with other HER2-targeted TKIs

18
Q

In vitro cross-comparison of HER2-targeted TKIs

A
  • 115 cancer cell line
    panel
  • In vitro proliferation
    assay of HER2-
    targeted TKIs

− Genetic mutation data
obtained from
COSMIC and CCLE
− A list of 40 key genetic
alterations compiled
− Confirmation of
EGFR, HER2, and
HER3 mutation

− Gene expression
analysis using publicly
available data from
CCLE
− Correlation significance
was validated using
COSMIC RNASeq,
COSMIC CLP, and
Genentech mRNA
databases

19
Q

Pre-clinical cross-comparison of HER2-targeted
TKIs

A
  • Anti-proliferative effect of
    each TKI examined in 115-
    cell line panel
  • 25 different tumour tissue
    types
  • Neratinib most potent
    across cancer types
  • Subtype analysis:
    1. Breast cancer
    2. HER-family altered cancers
20
Q

Cross-comparison in breast cancer

A

Breast cancer subtypes:
* 5 x HER2+
* 6 x TNBC
* 1 x ER+

21
Q

HER-altered cancer cell lines

A
  • 22 HER-altered cell lines
    across cancer types
  • Only clinically-relevant
    mutations were included
  • Neratinib was the most
    potent in:
  • HER2-amplified
  • HER2-mutant
  • EGFR-mutant
22
Q

Improving neratinib response in HER2+ breast
cancer

A
  • We have shown that neratinib is highly potent in HER2+ BC
  • However, innate resistance and acquired resistance occurs
23
Q

Dasatinib – potential partner for

A

Neratinib

24
Q

Dasatinib – targeting Src

A
  • Dasatinib (Sprycel ®, BMS) is an orally active multi-kinase
    inhibitor.
  • Targets SFK, c-Abl, c-Kit, PDGFR, and ephrin-A
  • Most potently inhibits Src kinase (0.5 nM) and c-abl (<1 nM)
  • FDA-approved for the treatment of chronic myeloid
    leukaemia and Philadelphia-positive acute lymphocytic
    leukaemia
25
Q

Neratinib plus dasatinib is effective against

A

HER2-
positive breast cancer cell lines

26
Q

Neratinib and dasatinib are highly synergistic
at

A

low nanomolar concentrations

27
Q

Mechanism of action;
1. Printing samples
2. Incubation with first antibody
3. Incubation with 2nd antibody
4. Scanning NIR labelles slides
5. Data analysis and data visualisation

A
28
Q

Neratinib plus dasatinib causes

A

apoptosis

29
Q

Summary

A

Neratinib is the most potent HER2-targeted TKI in HER2-
positive breast cancer
* Dasatinib can enhance the effect of neratinib in pre-clinical
models
* Neratinib plus dasatinib causes greater growth inhibition,
apoptosis induction, cell migration inhibition, and growth
signalling suppression

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