Lecture 14: Targeted therapies I Flashcards
Treatments for cancer
- From 1960s, drug treatments focused on
arresting cell growth (chemotherapy) - Targeted approach began with hormone
therapy - Molecular targeted therapy era started in
late 1990s
Radiotherapy
- 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
Types of
chemotherapy
- Alkylating agents
- Anti-metabolites
- Mitotic inhibitors
- Topoisomerase inhibitors
- Anti-tumour antibiotics
Targeted therapies in cancer
- 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
Targeted therapy mechanisms
- Receptor
activation - Signalling
transduction
Targeted therapy mechanisms
* Monoclonal antibodies:
- Bind to the receptor extracellular
domain - Inhibit pathway activation
- Receptor internalisation
- Antibody-dependent cellular
cytotoxicity
Targeted therapy mechanisms
* Small molecule TKIs:
- Bind to the receptor intracellular
domain - Inhibit pathway activation
Targeted therapy mechanisms
* Antibody-drug conjugates:
- Bind to the receptor extracellular
domain - Inhibit pathway activation
- Receptor internalisation
- Payload delivery
- Antibody-dependent cellular
cytotoxicity
Strengths and weaknesses of anti receptor antibodies vs. low molecular weight tyrosine kinase inhibitors as anti cancer agents
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
The role of HER family in cancer
- 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
HER family activation
- PI3K pathway
- MAPK pathway
Numerous strategies for
targeting the HER family
Monoclonal antibodies
* Antibody-drug conjugates
* Small molecule tyrosine
kinase inhibitors
Approved HER2-targeted TKIs
Lapatinib, Neratinib, Tucatinib
Lapatinib
− 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
Neratinib
- Pan-HER TKI
- Irreversible inhibitor
- Approved in earlystage (single agent)
and metastatic
(+capecitabine) HER2+
BC
Tucatinib
− HER2-specific inhibitor
− Reversible inhibitor
− FDA-approved in
combination with
trastuzumab +
capecitabine for metastatic
HER2+ BC
Clinical comparisons of the HER2-targeted
TKIs
Neratinib approval
in mHER2+ BC
Tucatinib approval
in mHER2+ BC
No direct comparison of tucatinib with other HER2-targeted TKIs
In vitro cross-comparison of HER2-targeted TKIs
- 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
Pre-clinical cross-comparison of HER2-targeted
TKIs
- 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
Cross-comparison in breast cancer
Breast cancer subtypes:
* 5 x HER2+
* 6 x TNBC
* 1 x ER+
HER-altered cancer cell lines
- 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
Improving neratinib response in HER2+ breast
cancer
- We have shown that neratinib is highly potent in HER2+ BC
- However, innate resistance and acquired resistance occurs
Dasatinib – potential partner for
Neratinib
Dasatinib – targeting Src
- 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
Neratinib plus dasatinib is effective against
HER2-
positive breast cancer cell lines
Neratinib and dasatinib are highly synergistic
at
low nanomolar concentrations
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
Neratinib plus dasatinib causes
apoptosis
Summary
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
