Translational Radiopharmaceutical Sciences Laboratory – Prof. Margret Schottelius (CHUV) and Hélène Koch (UNIL/CHUV)
Improving the Efficacy of PSMA-Targeted Radioligand Therapy via Radiosensitization Strategies and Combination Treatments
This “allocated fund”, amounting to CHF 150’000, was awarded to Hélène Koch for two years in December 2025. Supported with the generous contribution of the LARDECO Foundation.
PSMA-targeted radioligand therapy (PSMA-RLT) has emerged as a cornerstone in the treatment of metastatic castration-resistant prostate cancer (mCRPC). While landmark clinical trials have demonstrated significant survival benefits, treatment resistance remains a major limitation. Up to 30% of patients show primary resistance, and the majority of initial responders relapse within months, reflecting the profound adaptability of prostate cancer cells and the activation of compensatory radioresistance pathways.
Preclinical and clinical studies have shown that inhibition of single resistance pathways can enhance the efficacy of PSMA-RLT, but complete and durable remissions have remained elusive. This project is designed to address this unmet need by systematically evaluating radiosensitization strategies that target complementary resistance mechanisms either individually or in combination. In a stepwise approach, we will employ xenograft models with robust endogenous PSMA expression, integrating survival studies with in-depth ex vivoanalyses to characterize treatment-induced changes in tumor biology. Radiosensitizers, chosen among already clinically approved drugs, will be administered in clinically relevant dosing schemes to assess their capacity to relieve hypoxia, disrupt repair signaling, and destabilize pro-survival pathways.
Synergistic regimens will be identified through iterative testing in vivo, and subsequently validated in an immunocompetent allograft model, providing critical insight into both tumor-intrinsic and microenvironmental contributions to resistance. The anticipated outcome is a set of rational, mechanism-informed radiosensitization regimens that markedly enhance the durability of tumor control by PSMA-RLT.
By integrating biological characterization, imaging biomarkers, and translational infrastructure, the project aims not only to improve treatment efficacy in prostate cancer but also to establish a generalizable framework for combination radiotheranostics. Clinically, this work is expected to extend survival and improve quality of life for patients with advanced prostate cancer, while reducing the need for late-line toxic therapies. The insights gained will provide the basis for early-phase clinical trials and may ultimately transform PSMA-RLT from a variably effective therapy into a precision-guided platform capable of overcoming radioresistance at its roots.