Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Abstract

Simple Summary

Currently, there is no treatment that can cure patients with late stage metastatic prostate cancer. Prostate-specific membrane antigen is a type of protein overexpressed on the membrane surface of most prostate cancer cells. The preclinical and clinical experiences in the rapidly evolving field of targeted alpha-particle radiation therapy for metastatic prostate cancer overexpressing prostate-specific membrane antigen are reviewed. Targeted alpha therapy employs radionuclides emitting highly energetic alpha-particles (cytotoxic payload) chelated to small molecules or monoclonal antibodies designed to target prostate-specific membrane antigen. In this review, we summarize the availability of therapeutic alpha-emitting radionuclides (terbium-149, astatine-211, bismuth-212 (lead-212), bismuth-213, radium-223, actinium-225, thorium-227), and the development of small molecules and antibodies targeting prostate-specific membrane antigen. The limitations in studies using animal models of human prostate cancer to accurately predict efficacy and toxicity in patients are addressed. We have attempted to also critically discuss hurdles related to logistical and supply aspects between different alpha-emitting prostate-specific membrane antigen-targeting radiopharmaceuticals. Lastly, we discuss the potentials, limitations, and future perspectives of prostate-specific membrane antigen-targeted alpha therapy.

Abstract

Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β ⁻ therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.