Targeted Suppression of Microtubule Dynamics for Treatment of Metastatic Castration-Resistant Prostate Cancer

University Of Texas Hlth Sci Ctr Houston, Houston TX

Investigators

Abstract

PROJECT SUMMARY The goal of this proposal is to develop a targeted therapy for treatment of metastatic castration-resistant prostate cancer (mCRPC). There is currently no cure for this disease and available therapies leave significant room for improvement based on dismal survival rates. Prostate-specific membrane antigen (PSMA) is a clinically validated molecular target for diagnostic and therapeutic purposes based on its significant overexpression in PCa tissue compared to normal cells. Glutamate-ureido-based small molecules have exceptional affinity for PSMA and have been labeled with radionuclides to enable targeted tumor detection and therapy. The small molecule 177Lu- PSMA-617 (cytotoxic beta radiation emitter) recently gained FDA-approval for PSMA-targeted radioligand therapy (RLT) of mCRPC. However, despite its initial antitumor activity, disease progression following 177Lu- PSMA-617 RLT occurs in virtually all patients and led to the development of the more potent RLT agent 225Ac- PSMA-617, where the alpha-emitting radionuclide 225Ac provides stronger DNA damaging capabilities. Although recent clinical data with 225Ac-PSMA-617 showed favorable responses, disease progression was still observed. Furthermore, non-tumor binding of 225Ac-PSMA-617 causes considerable damage to the salivary glands and leads to life-long xerostomia in a large percentage of patients. Since PSMA expression often remains actionable as a tumor target following RLT, the development of a non-radioactive targeted therapy could extend the therapeutic benefits of PSMA targeting without the associated risk of organ irradiation. Given the absence of a validated PSMA-targeted drug conjugate, we used PSMA-617 as the foundation for a drug conjugate containing the microtubule inhibitor monomethyl auristatin E (MMAE) and a custom macrocyclic linker known as MMC (multimodality chelator) to enable direct radiolabeling for imaging and quantitative analyses. We provide strong preliminary evidence of PSMA-mediated uptake with the drug conjugate in cells and tumor models, while also revealing remarkably fast elimination from blood and normal organs, including the salivary glands. Based on mounting clinical evidence of MMAE-related resistance, we identified cryptophycin, a microtubule inhibitor with 1-2 fold higher potency than MMAE in castration-resistant prostate cancers cells, as the preferred payload for drug conjugate development. We seek to build on these findings and propose the following specific aims: (1) to synthesize a PSMA-drug conjugate for selective delivery of cryptophycin, (2) to visualize and quantify the in vivo targeting properties of PSMA-mediated cryptophycin delivery in tumor models, and (3) to demonstrate in vivo efficacy and safety. To accomplish our aims, we have formed a strong investigative team with complementary expertise in basic, translational, and clinical theranostics. Successful completion of our aims will demonstrate the feasibility of treating mCRPC with a PSMA-targeted drug conjugate and could address an emerging treatment gap for patients that may not be eligible for additional PSMA-targeted treatment.