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

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.

Keywords: prostate cancer; prostate-specific membrane antigen; targeted alpha therapy.

Figure 1

The simplified structure of prostate-specific membrane antigen (PSMA), its binding sites for PSMA ligands and antibodies (this figure is based on references [52,53,54]).

Figure 2

Simplified decay chains of ¹⁴⁹Tb, ²¹¹At, ²²⁵Ac, ²²⁷Th, ²²³Ra, and ²²⁴Ra radionuclides. α–alpha particle, β–beta particle, β⁻–electron, β⁺–positron, ε–electron capture. Information extracted from the National Nuclear Data Center database, Brookhaven National Laboratory [75].