Novel targeted combinatorial therapy for castration-resistant prostate cancer

About This Grant

CHK1 and WEE1 are critical G2/M checkpoint regulators and therapeutic targets in advanced castration-resistant prostate cancer (aCRPC), including CRPC-Adeno and NEPC. Frequent loss of tumor suppressor genes in these tumors impair G1/S control, creating dependence on the G2/M checkpoint. Targeting CHK1 and WEE1 exploits this vulnerability, but clinical success requires optimized combination strategies, effective delivery, and biomarker-guided patient selection. We propose a novel therapeutic strategy using hyaluronic acid (HA)-based nanocarriers (HASA) co-loaded with CHK1 inhibitor SRA737 (SRA) and WEE1 inhibitor AZD1775 (AZD) for targeted treatment of aCRPC. We demonstrated that the combined inhibition of CHK1 and WEE1 with SRA and AZD resulted in strong synergy in reducing the viability of aCRPC cells and tumor spheroids. In a transgenic NEPC mouse model, the combination of SRA and AZD effectively synergized in suppressing prostate tumor growth and metastasis, highlighting its potential for treating aCRPC. Mechanistically, WEE1 inhibition induced feedback activation of CHK1 and enhanced DNA damage drive their strong synergy in aCRPC cells, and lysine demethylase 5D (KDM5D), an epigenetic regulator frequently deleted in aCRPC, was identified as a novel regulator of SRA sensitivity. To further improve the safety and efficacy of SRA/AZD combination, we developed innovative hyaluronic acid (HA)-based nanocarriers (HASA) for effective codelivery of these drugs to prostate tumors. This delivery platform is highly effective in tumor targeting through the CD44-mediated transcytosis to cross endothelial barriers and accumulate in the tumor site. Our preliminary data confirmed effective loading of both drugs into the nanocarrier, slow kinetics of drug release, selective uptake by tumor cells, and potent efficacy in a syngeneic prostate tumor xenograft model. Thus, we hypothesize that CHK1 and WEE1 inhibitors synergize to disrupt the balance of mitotic control and enhance DNA damage, resulting in robust cell death in aCRPC. Optimized CHK1/WEE1 inhibitor combination based on HASA-mediated codelivery could potentially be leveraged as a safer and more efficacious therapeutic option for lethal prostate cancers. Our study aims to uncover mechanisms of sensitivity for SRA and SRA/AZD combination, and to evaluate the safety and in vivo efficacy of HASA nanocarriers loaded with these drugs in PC models. Two specific aims are proposed: Aim 1. Uncover the mechanisms underlying the varied sensitivity to SRA and its synergistic interaction with AZD in aCRPC cells and tumors. Aim 2. Develop HASA nanocarrier for effective co-delivery of SRA/AZD to improve therapeutic index.