Enhancing Prostate Cancer Treatment Outcomes with Combined Radioimmunotherapy and Antibody Drug Conjugates

Project summary: Metastatic castration-resistant prostate cancer (mCRPC) is an advanced, particularly aggressive, and treatment- resistant form of prostate cancer. Existing therapies, such as chemotherapy and radiation, frequently result in significant side effects and the development of resistance, undermining their long-term effectiveness. The tumor- targeting approach employs an antibody-drug conjugate (ADC) to deliver cytotoxic drugs directly to cancer cells via antibodies, minimizing damage to healthy tissue. Similarly, alpha particle therapy provides precise radiation targeting, reducing off-site delivery. However, these antibody-based treatments are also associated with adverse effects at therapeutic doses, often requiring dose reductions to subtherapeutic levels. In response to these challenges, our project proposes a novel tumor-targeted combination therapy designed to enhance efficacy and reduce toxicity. Utilizing the distinct modes of action of cytotoxic drugs (like monomethyl auristatin E, MMAE) and the radioactive isotope Actinium-225, which exhibit non-overlapping toxicities, we plan to co-deliver these agents directly to cancer cells. This approach aims to create a novel synergy that effectively combats cancer without the typical adverse effects. Aim 1 of this project focuses on developing a single CD46-targeting antibody dual-labeled with MMAE and Actinium-225, for synergistic therapeutic efficacy with reduced toxicity. This innovative combination will be rigorously tested against metastatic and drug-resistant tumors. Aim 2 involves constructing tumor models resistant to current treatments such as Enzalutamide and PSMA-targeted radioligand therapy to evaluate the efficacy of our dual-labeled agent. We anticipate this tumor-targeted strategy will successfully treat resistant tumor types at critical metastatic sites, including bone and lymph nodes. Aim 3 will expand our strategy to target two antigens overexpressed on tumor cells, using separate antibodies to deliver the cytotoxic drugs and Actinium-225. This method is anticipated to further enhance the precision and effectiveness of our therapy. Through this project, we employ a transformative approach in treating advanced mCRPC by combining the targeted drug delivery of ADCs with the precise radiation targeting of alpha particle therapy. By co-delivering cytotoxic drugs and Actinium-225, we aim to enhance treatment outcomes and overcome the limitations posed by conventional therapies, including their associated toxicities.