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
