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.

Grant Number: 1K99CA304511-01
NIH Institute/Center: NIH
Principal Investigator: Anil Parsram Bidkar