Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC

Summary/Abstract While prostate-specific membrane antigen-targeted radiopharmaceutical therapy (PSMA-RPT) improves the survival of metastatic castration-resistant prostate cancer (mCRPC) patients, response rates remain suboptimal, and relapses invariably occur in all patients. Improving therapeutic efficacy requires a better understanding of the genetic, molecular, and immunological determinants of tumor responses to PSMA RPT. To identify such determinants we (i) performed dosimetry studies to optimize 177Lu-PSMA-RPT activity in prostate cancer (PCa) models; (ii) conducted global phosphoproteomic analyses of tumors from PSMA-RPT- treated mice and revealed the upregulation of DNA damage response/repair and TP53 pathways; (iii) showed that wild type TP53 plays an important role in mediating responses to RPT in mice; and (iv) investigated the impact of PSMA-RPT on the tumor immune microenvironment and demonstrated that PSMA-RPT synergizes with pharmacological activators of the cyclic GMP–AMP synthase (cGAS)/Stimulator of Interferon genes (STING) pathway, a cytosolic DNA sensing machinery that links DNA damage with the induction of innate immune responses via type I interferon (IFN) signaling. Relatedly, data in the literature indicate that mutant TP53, which occurs frequently in mCRPC, interferes with the function of the cGAS/STING/IFN pathway thereby decreasing tumor immunogenicity. Collectively, these findings led us to hypothesize that (i) 177Lu- PSMA-RPT triggers tumor TP53 mutational status-dependent tumor and immune cell signaling alterations in mCRPC; (ii) profiling these alterations will identify new determinants of response to PSMA-RPT; and (iii) targeting these determinants will enhance responses to PSMA-RPT. We will test these hypotheses via three Specific Aims leveraging an integrated platform for systematic profiling of RPT-induced transcriptional, signaling, and immunological alterations. In Aim 1, we will identify RPT-induced signaling alterations in the tumor cell compartment of human PSMA-expressing PCa models and test the hypothesis that mutant TP53 impairs responses to PSMA-RPT. In Aim 2, we will employ murine PCa models with wild-type or mutated TP53 to investigate how tumor TP53 status impacts RPT responses and tumor immunogenicity in immunocompetent mice. We will test the hypothesis that mutant TP53 interferes with cGAS/STING/IFN signaling in RPT-treated tumors and reduces tumor immunogenicity. In Aim 3, we will develop novel combination therapies that enhance or restore the cGAS/STING/IFN pathway in the mCRPC immune tumor microenvironment and improve the magnitude and durability of RPT responses via increased tumor immunogenicity. Successful completion of these aims will identify new connections between mCRPC TP53 mutational status, cytosolic DNA sensing mechanisms, and tumor immunogenicity that can be leveraged to increase the efficacy of RPT against mCRPC through rationally designed and clinically applicable combination therapies.