Abstract 1249: LP184, a novel alkylating agent, is efficacious in prostate cancer models with DNA damage repair defects

Abstract

Abstract Prostate cancer (CaP) remains the most commonly diagnosed malignancy and the second leading cause of cancer related deaths in men in the US. While the 5-year survival rate for patients with localized CaP is over 99%, it is only 30% for patients with distant metastases. Despite impressive advances in the treatment of metastatic CaP with more efficacious inhibitors along the androgen/androgen receptor axis, eventual development of incurable metastatic Castration Resistant Prostate Cancer (mCRPC) is inevitable, necessitating the development of newer therapeutic strategies. Comprehensive evaluations of CaP genomes from localized and metastatic CaP have revealed that subsets harboring mutations in certain DNA Damage Repair Genes (DDRGs) account for up to 30% of patients. LP184, a novel alkylating agent belonging to the acylfulvene (AF) class is currently in preclinical development, having demonstrated appreciable anticancer activity in multiple prostate tumor models. LP184 exhibits nanomolar potency (20 - 350 nM) against widely used CaP cell lines in 2D culture while having reduced cytotoxicity in a non-tumor prostate epithelial cell line. In CaP cell lines, LP184 turned out equipotent as standard chemotherapeutic Docetaxel, 100-2000 times more potent than another alkylating agent Cisplatin, and 100-9000 times more potent than PARP inhibitor, Olaparib. LP184 is also effective in 3 CaP organoid models 3D cultured from patient-derived xenografts. We hypothesize that LP184 exhibits potent inhibitory effects on CaP cells through a compromised DNA repair milieu of mCRPC due to damaging DDRG mutations in BRCA2, FANCI, ERCC3, ERCC6, FANCG, PALB2 and ATM represented by the in vitro CaP models tested. DNA damage resulting from AF treatment is known to be processed exclusively via transcription coupled nucleotide excision repair. Consistent with this, we observed enhanced LP-184 sensitivity in a cell line model with truncated ERCC3 relative to the otherwise syngeneic parental cell line. Based on Connectivity Map (CMAP) analysis of full transcriptome profiling data on LP184 treatment in selected CaP cell lines, we identified potential drug classes including PARP inhibitors, proteasome inhibitors, topoisomerase inhibitors and MTOR inhibitors that emerged in silico as synergistic with LP184. This approach utilized matching of genes differentially expressed upon LP184 exposure compared to 5000 other small molecules within CMAP. Advancement of LP184, potentially exploiting recurrent and actionable DDRG mutations, is anticipated to be translated into future clinical trials for mCRPC, a lethal CaP that is responsible for ~33,000 deaths/year in the US alone. Given that only a subset of patients responds to any single drug in this advanced CaP stage, LP184 stands out as a unique agent that may complement or synergize with drugs currently used in treatment of mCRPC and improve the outcomes for men with lethal CaP. Citation Format: Aditya Kulkarni, Partha Banerjee, Umesh Kathad, Kishor Bhatia, Panna Sharma. LP184, a novel alkylating agent, is efficacious in prostate cancer models with DNA damage repair defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1249.