Personalising treatment for men with advanced prostate cancer

Abstract

Despite advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), many have up-front resistance to these therapies, and all develop resistance over time. Novel strategies are urgently needed. The ideal is precision medicine – matching a biomarker to an effective treatment.

PARP inhibitors are the first personalised treatment based on a biomarker. However, this requires identification of men with germline homologous recombination repair mutations. Conventional genetics services cannot manage the volume of men with mCRPC who require testing. This thesis evaluates an alternative genetic counselling model, mainstreaming, where counselling is performed by the patient’s oncologist. Mainstream consent for genetic testing for men with mCRPC was acceptable to both patients and clinicians and was resource efficient. Widespread implementation will facilitate timely access to genetic testing for men with mCRPC.

Beyond genomics, there are limited targeted options, and novel strategies are needed. A promising area is lipid targeted therapies. Comprehensive lipidomic profiling has shown that elevated circulating ceramides are associated with shorter progression free and overall survival (OS) in mCRPC. Ceramide can be metabolised into sphingosine-1-phosphate (S1P), which promotes cancer growth, metastasis, and drug resistance. The use of sphingosine kinase inhibitors in vitro and ex vivo to block the production of S1P overcomes enzalutamide resistance. This represents a promising frontier. To date, this lipidomic profiling has only been performed retrospectively, and there are challenges with conversion to a prospective biomarker. This thesis describes the development of PCPro, a clinically accessible, regulatory compliant circulating lipid biomarker PCPro positive patients had significantly shorter OS compared to PCPro negative patients. This biomarker will allow us to identify men for prospective trials of therapeutic agents targeting lipid metabolism.