Project 1: Targeting Specific uPAR Protein Interactions in Colorectal Cancer
Membrane proteins are of particular interest in cancer because of their acknowledged potential therapeutic utility. Membrane proteins represent 30% of the genome and constitute approximately 70% of all human protein-based drug targets. We have pioneered new methods thatimprove membrane proteome coverage and have used these to identify membrane protein interactions that change during colon cancer progression and that are associated with cancer metastasis. This project translates these discoveries into new biomarkers for patient survival and new more specific less toxic colorectal cancer drug targets.
- Particular epithelial (cancer) cell-specific membrane protein interactions during colorectal cancer favour metastasis.
- These interactions can be measured as a prognostic colorectal cancer biomarker.
- These cancer cell surface protein interactions can be targeted therapeutically.
- Determine if the uPAR-ανβ6 interaction is a biomarker that predicts stage-specific CRC recurrence, adjuvant chemotherapy effectiveness or candidacy for interactome antagonist therapy, and
- Identify peptide, antibody and small molecule antagonists of uPAR-ανβ6 and evaluate their ability to abrogate CRC proliferation, aberrant signaling, invasion and metastasis.
This study immediately translates past work to the clinic.
We have found that the lack of uPAR expression allows clinicians to identify a cohort of uPARE- Stage B patients where surgery alone is curative. As a corollary, we also propose that CRC uPARE+ (potentially as part of a uPAR-ανβ6 cancer cell-specific protein interactome we discovered) predicts Stage B/C patients who do poorly after surgical resection. This project will evaluate the predicative capacity of the protein interaction as a cancer biomarker. Equally, that past data provides a compelling case for the need for judicious development of new anti-metastasis CRC treatments that specifically target the causes of cancer metastasis. Some patients only require surgery (Stage B uPARE-) whilst others (Stage B uPARE+) may respond better after aggressive adjuvant chemotherapy and/or novel targeted therapies. Given that the uPAR-ανβ6 cancer cell-specific protein interaction drives the cancer to a malignant state, we believe high-rewards will emerge from the development of targeted therapeutics (e.g., monoclonal antibodies (MAbs), interference peptides (iPEPs) and small molecules) against this target. The second part of this project undertakes a range of chemical, biochemical and cell biological studies developing strategies to antagonise the cancer cell surface uPAR-αvβ6 membrane protein interaction.
Professor Mark Baker