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 Avoiding immune destruction Enabling replicative immortality Tumour – promoting inflammation Activating invasion & metastasis Inducing angiogenesis Genome instability & mutation Resisting cell death Deregulating cellular energetics 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 intra- operatively Tumour-specific delivery of cytotoxic drugs or contrast agents for enhanced imaging Contact: Prof David Jayne

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

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 cases MGMT inhibitor Contact: Prof Susan Short and Dr Heiko Wurdak

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

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

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

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 mechanisms driving resistance Contact: Prof Val Spears

Next Generation Target Discovery

Acknowledgements Peter Selby David Jayne Susan Short Heiko Wurdak Naveen Vasudev Val Spears

Example: Herceptin