Transcript Dr Mike Messenger, Leeds University

Molecular Biomarkers & Targets
an overview
Michael Messenger
NIHR Diagnostic Evidence Co-Operative & Leeds
Cancer Research UK Centre
What is a biomarker?
“a characteristic that is objectively measured
and evaluated as an indicator of pathogenic
processes, or responses to a therapeutic
intervention.”
(adapted from National Institute for Health, USA)
• Molecular Biomarkers include:
– nucleic acids, proteins, lipids, polysaccharides and
metabolites.
• Cancer Biomarkers:
– associated with “The Hallmarks of Cancer”
Hallmarks of Cancer
Sustaining
proliferative
signalling
Evading growth
suppressors
Deregulating
cellular energetics
Avoiding
immune
destruction
Resisting
cell death
Enabling
replicative
immortality
Tumour –
promoting
inflammation
Genome
instability &
mutation
Inducing
angiogenesis
Activating
invasion &
metastasis
Hanahan and Weinberg
“Hallmarks of Cancer: The next
generation” Cell 2001
How are biomarkers used clinically?
Molecular Targets (cancer)
“an accessible molecular biomarker involved
in a key biological process”
• the ideal target should have the following
characteristics:
– expressed only on/in tumour cells & not expressed on
critical host/normal cells (Specific)
– expressed on all tumour cells (Sensitive)
– expressed in high numbers
– no mutant or variant forms should be present
– critical to cell survival
– not shed, lost or circulated.
Molecular Targets (cancer)
Clinical Need in Colorectal Cancer
• Ability to detect and
stage cancers intraoperatively
• Tumour-specific
delivery of cytotoxic
drugs or contrast
agents for enhanced
imaging
Contact: Prof David Jayne
[email protected]
Potential targets in Colorectal Cancer
Clinical Need in Neuro-Oncology
• Glioblastoma multiforme (GBM) is the major unmet need in
adult practice
• Tumour heterogeneity is a major challenge in defining useful
targeted agents
• Targeting early events in gliomagenesis and common
resistance mechanisms is appealing
Contact: Prof Susan Short and
Dr Heiko Wurdak
[email protected]
[email protected]
Potential targets in Neuro-Oncology
• Targeting Stem cell phenotype:
SOX2 has emerged as major driver in GBM stem cell
population
SOX2 inactivator
• Targeting early events in gliomagenesis:
IDH1mutation is initiating mutation in secondary GBM
Cytotoxic specific to IDHmut cells
• Targeting common resistance mechanisms:
MGMT repair enzyme expression limits effectiveness of
chemotherapy in 60% of casesContact: Prof Susan Short and Dr Heiko Wurdak
[email protected]
MGMT inhibitor
[email protected]
Clinical Need in Urological Cancers
• Renal Cancer
– No biomarkers in routine clinical use, tools for better
diagnosis and prognosis required
– Resistant to chemotherapy. Few treatment options
• Bladder Cancer
– No biomarkers in routine use
– Treatments have not changed for >20 years.
Contact: Dr Naveen Vasudev
[email protected]
Potential Targets in Urological Cancers
• Harnessing the immune system – PD1 / PDL-1 antibodies
- Promising activity in kidney and bladder cancer
Powles et al. Nature 2014
Complete remission in a patient with metastatic bladder cancer
• Renal cancer imaging – CAIX labelled antibodies
- eg Superparamagnetic iron oxide (SPIO) nanoparticles and mAb G250 conjugated as mMRI
probe Lu et al. Plos One 2014
Contact: Dr Naveen Vasudev
[email protected]
Clinical Need in Breast cancer
• Tamoxifen- the first targeted cancer therapy
• Need for precision medicine to match patients to
therapies
• Deliver drugs more specifically and reduce
toxicity
• General need for targeting
– MicroRNAs
– Tumour stroma
• Fibroblasts
• Immune infiltrates
Contact: Prof Val Spears and
Peter Hall
[email protected]
[email protected]
Potential Targets in Breast cancer
Specific gene targets
– FGFR2
• consistently identified as a breast cancer risk locus
– CDK4/6
– PI3K/AKT/mTOR
– PARP
– Src
– HDAC
All identified from pre-clinical studies examining the
Contact: Prof Val Spears
mechanisms driving resistance
[email protected]
Next Generation Target Discovery
Acknowledgements
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Peter Selby
David Jayne
Susan Short
Heiko Wurdak
Naveen Vasudev
Val Spears
Example: Herceptin