Abstract 3389: Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts

Abstract

Abstract Focal therapies for prostate cancer offer the possibility of less side effects than more aggressive interventions for organ-confined tumors. Vascular targeted photodynamic therapy (VTP) is being investigated in phase II and phase III clinical trials, and relies upon rapid, free radical-mediated destruction of tumor vasculature following photoactivation of a systemic prodrug. In a phase II trial, >80% of patients did not have detectable cancer in prostate biopsies taken 6 months after VTP treatment. Although these early results are encouraging, VTP efficacy could potentially be improved upon by combining with other therapies. Using the LNCaP-AR prostate cancer model system, we employed microarrays and Gene Set Enrichment Analysis (GSEA) to identify potential druggable pathways active in tumors exposed to VTP. Three to six hours post-VTP, androgen responsive gene sets were enriched, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using the AR pathway inhibitors degarelix (to achieve pharmacological castration) or enzalutamide (AR antagonist), alone or in combination with VTP. Degarelix was administered as a single 0.5-1 mg dose 3 days prior to initiation of VTP, while enzalutamide was given daily for two weeks total both before and after VTP. Serum measurements of prostate specific antigen (PSA) were used as a readout of AR activity. Compared to either AR pathway inhibitor or VTP used alone, degarelix or enzalutamide in combination with VTP significantly inhibited tumor growth. A sharp decline in serum PSA confirmed AR inhibition. Combined degarelix plus VTP treated tumors displayed intense TUNEL staining 7 days post-treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. In prostate cancer treated with VTP, compensatory acute upregulation of pro-survival AR signaling may occur. These findings may warrant investigation of combination with androgen deprivation therapy in future clinical trials utilizing VTP for prostate cancer. Citation Format: Kwanghee Kim, Philip A. Watson, Sylvia Jebiwott, Alexander J. Somma, Stephen P. La Rosa, Dipti Mehta, Katie S. Murray, Hans Lilja, David Ulmert, Avigdor Scherz, Jonathan Coleman. Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3389.