Liquid biopsy-based detection of resistance to targeted therapy in prostate cancer patients

• Applicants: Privatdozent Dr. Matthias Heck; Dr. Christof Winter
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine ; Reproductive Medicine, Urology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403177117

Androgen receptor signaling inhibitors (ARSi) have become available in the past years for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and have significantly improved their survival. Despite this improvement, initial or emerging resistance to ARSi poses a major challenge in the treatment of these patients. There is therefore an urgent medical need for early detection of treatment resistance. Liquid biopsies – blood samples containing circulating tumor cells (CTCs) and nucleic acids from the tumor – can provide information about such resistance. We and others have shown that liquid biopsies can be used to detect the messenger RNA (mRNA) of AR-V7, a splice variant of the androgen receptor (AR) that is insensitive to ARSi, in whole blood, and that high levels of AR-V7 mRNA in mCRPC patients are predictive to non-response to ARSi. Several liquid biopsy approaches involving different blood compartments such as CTCs, exosomes, and whole blood have been used so far to detect AR-V7. However, it is unclear which liquid biopsy approach or which combination of approaches is best to predict resistance under ARSi therapy in the clinical setting. In addition, current approaches explain only up to 50% of resistant cases, suggesting that there are important non-AR-V7-mediated causes of resistance.With the proposed project, we aim at determining the optimal liquid biopsy approach to detect AR-V7 and exploring novel ones for best possible prediction of resistance to ARSi, and to develop a computational pipeline which robustly and objectively makes this information available for clinical routine diagnostics. To this end, we will systematically explore all relevant blood compartments (whole blood, leukocyte-depleted blood, CTCs, plasma (exosomes), and platelets) in a prospective cohort of mCRPC patients, quantify AR-V7 mRNA levels in each compartment, and determine the diagnostic value of compartment-specific AR-V7 mRNA levels for predicting response to subsequent ARSi therapy. We will further explore the clinical relevance of AR-V7 protein subcellular localization in CTCs for prediction of ARSi resistance. In addition, we will explore novel other, AR-V7 independent mechanisms of resistance and their predictive value for proper treatment. These are based on the expression of ARv567es (the second most abundant AR splice variant), and on neuroendocrine differentiation of prostate cancer cells. As a result of this project, we will have identified the best possible approach for informed treatment selection for mCRPC patients. Furthermore, our results will shed light on how mRNA released from tumor cells of a mCRPC patient is distributed among blood compartments and which compartments are the most relevant ones, which might provide useful cancer-related information also for other cancer types. With the proposed project we will make a significant step towards precision medicine in the treatment of mCRPC patients.

• DFG Programme: Research Grants
• Co-Investigators: Privatdozent Dr. Roman Nawroth; Professorin Dr. Margitta Retz