Abstract 4570: Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer

Abstract Introduction: Prostate cancer is the most prevalent cancer among men in the United States and is their second leading cause of cancer death. During initial screen, about 17-31% of patients are diagnosed with non-metastatic high-risk localized prostate cancer. These patients have an increased risk of treatment failure and oncological progression. The contemporary treatment paradigm of high risk localized prostate cancer is moving toward a multidisciplinary integrated approach of systemic and local therapy. In addition, incorporation of molecular biomarkers can also improve the risk stratification and treatment of prostate cancer. Among the biomarkers for prostate cancer, prostate specific membrane antigen (PSMA) has been proven to be an excellent target for diagnosis and treatment of prostate cancer. We have generated a PSMA-targeted photodynamic therapy (PDT) agent, PSMA-1-Pc413, and a PSMA-targeted chemotherapeutic agent, PSMA-1-MMAE. The objective of this study is to generate a new molecule that combines PDT and chemotherapy to achieve improved antitumor activity. Methods: Using a bifunctional PSMA ligand, a novel theranostic PSMA-targeting conjugate was synthesized, which integrated both the photosensitizer Pc413 and the microtubular inhibitor monomethyl auristatin E (MMAE) in one simple molecule, PSMA-1-MMAE-Pc413. This molecule was first tested for in vitro uptake and cytotoxicity studies using PSMA-positive PC3pip and PSMA-negative PC3flu cells. The conjugate was then tested for in vivo fluorescence imaging using mice bearing both PC3pip and PC3flu tumors. Finally, the antitumor activity of PSMA-1-MMAE-Pc413 was tested in mice with PC3pip tumors with and without light irradiation. Results: In in vitro uptake studies, the uptake of PSMA-1-MMAE-Pc413 in PC3pip tumor was about 3-fold higher than that in PC3flu cells. In in vitro cytotoxicity studies, when exposed to 5 J/cm2 of 672nm light, PSMA-1-MMAE-Pc413 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells (IC50=2. 77nM) when compared to PSMA-1-Pc413 with light irradiation (IC50=372nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50=12. 6nM). In in vivo imaging studies, PSMA-1-MMAE-Pc413 demonstrated selective uptake in PC3pip tumors. Further, antitumor activity studies showed that PSMA-1-MMAE-Pc413 with light irradiation significantly inhibited PC3pip tumor growth and prolonged survival time as compared to mice receiving equimolar amounts of PSMA-1-Pc413 with light irradiation or PSMA-1-MMAE-Pc413 without light irradiation. Conclusion: We have synthesized a new theranostic agent PSMA-1-MMAE-Pc413 that combines imaging, chemotherapy and PDT. The new molecule dramatically improves the treatment effect as compared to each single treatment alone. (The work is supported by NIH 1RO1CA255925-01A. ) Citation Format: Xinning Wang, Aditi Shirke, Sriprada Chavali, Lifang Zhang, Ethan Walker, Gopolakrishnan Ramamurthy, James Basilion. Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4570.