Abstract 6249: Probabilistic causal network models from real-world prostate cancer data identify potential synergistic combinations with CBP/P300 inhibitors

Abstract The current standard of care for metastatic castration resistant prostate cancer (mCRPC) includes androgen-receptor signaling inhibitors (ARSIs), chemotherapy, PARP inhibitors (PARPi), or PSMA-radioligand therapies. Although these novel therapies have yielded substantial benefits for patients, many fail to respond or quickly develop resistance. Previous work identified key regulatory programs driving AR-altered, ARSI-resistant, late-stage prostate cancer, and further identified and validated that treatment with the CBP/p300 inhibitor pocenbrodib inhibits cancer cell growth both in vitro and in vivo. Here, we focus on identifying targeted therapies where combination with pocenbrodib could improve clinical response in late-stage prostate cancer. Previous analyses identified that treatment of prostate cancer cell lines with pocenbrodib downregulates a group of genes, termed a subnetwork, capturing G2M, E2F, and DNA repair mechanisms, suggesting that combination with a therapy that induces DNA damage or inhibits DNA repair could be additive or synergistic. Cell cycle profiling following treatment of cell lines with pocenbrodib confirmed induction of G2M cell cycle arrest. Next, we systematically ranked current targeted therapies based on publicly available RNA-seq signatures and signatures derived from RWD (e.g. BRCA2 alterations) to identify therapies that target our subnetwork of genes enriched for G2M, E2F, and DNA repair mechanisms. Given that both PSMA-radioligand therapies and PARP inhibitors induce DNA damage or inhibit DNA repair, we hypothesize that these drugs in combination with pocenbrodib would lead to additive or synergistic effects by enhancing the PARPi and PSMA-radioligand efficacy via their known mechanisms of action. To validate these hypotheses, we treated a panel of 5 genetically-diverse prostate cancer PDX-derived organoids with pocenbrodib, the PARPi olaparib, and in combination. The combination of pocenbrodib with olaparib led to additive or synergistic effects in 3 out of the 5 organoids, consistent with those showing some level of response to olaparib as a single agent. To evaluate the potential for combination benefit with PSMA-radioligand therapy, an in vivo efficacy study was performed using the PSMA+ 22Rv1 prostate cancer xenograft model. Addition of a low dose of pocenbrodib to a single dose of Lu177-PSMA617 (60 MBq) led to better tumor growth inhibition control than either single agent on its own. Mechanistic analyses from RNAseq are ongoing. Together, our integrated omics and experimental analyses support the hypothesis that combination of pocenbrodib with DNA damage-inducing or -inhibiting targeted therapies may provide further therapeutic benefit to prostate cancer patients than single agent therapies alone. Citation Format: Veronica Calvo, Bonnie Dougherty, Ananya Dutta, Duo Xu, Qi Pan, Andrew Armstrong, Jens Renstrup, Jason Somarelli, Eric Schadt. Probabilistic causal network models from real-world prostate cancer data identify potential synergistic combinations with CBP/P300 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6249.