Preclinical Development in Radiopharmaceutical Therapy for Prostate Cancer

Abstract

Prostate cancer is a leading cause of cancer death in men worldwide. Among the various treatment options, radiopharmaceutical therapy has shown notable success in metastatic, castration-resistant disease. Radiopharmaceutical therapy is a systemic approach that delivers cytotoxic radiation doses precisely to the malignant tumors and/or tumor microenvironment. Therapeutic radiopharmaceuticals are composed of a therapeutic radionuclide and a high-affinity, tumor-targeting carrier molecule. Therapeutic radionuclides used in preclinical prostate cancer studies are primarily α-, β^--, or Auger-electron-emitting radiometals or radiohalogens. Monoclonal antibodies, antibody-derived fragments, peptides, and small molecules are frequently used as tumor-targeting molecules. Over the years, several important membrane-associated proteases and receptors have been identified, validated, and subsequently used for preclinical radiotherapeutic development for prostate cancer. Prostate-specific membrane antigen (PSMA) is the most well-studied prostate cancer-associated protease in preclinical literature. PSMA-targeting radiotherapeutic agents are being investigated using high-affinity antibody- and small-molecule-based agents for safety and efficacy. Early generations of such agents were developed simply by replacing radionuclides of the imaging agents with therapeutic ones. Later, extensive structure-activity relationship studies were conducted to address the safety and efficacy issues obtained from initial patient data. Recent regulatory approval of the ¹⁷⁷Lu-labeled low-molecular-weight agent, ¹⁷⁷Lu-PSMA-617, is a significant accomplishment. Current preclinical experiments are focused on the structural modification of ¹⁷⁷Lu-PSMA-617 and relevant investigational agents to increase tumor targeting and reduce off-target binding and toxicity in healthy organs. While lutetium-177 (¹⁷⁷Lu) remains the most widely used radionuclide, radiolabeled analogs with iodine-131 (¹²⁸I), yttrium-90 (⁸⁹Y), copper-67 (⁶⁷Cu), and terbium-161 (¹⁶¹Tb) have been evaluated as potential alternatives in recent years. In addition, agents carrying the α-particle-emitting radiohalogen, astatine-211 (²¹¹At), or radiometals, actinium-225 (²²⁵Ac), lead-212 (²¹²Pb), radium-223 (²²³Ra), and thorium-227 (²²⁷Th), have been increasingly investigated in preclinical research. Besides PSMA-based radiotherapeutics, other prominent prostate cancer-related proteases, for example, human kallikrein peptidases (HK2 and HK3), have been explored using monoclonal-antibody-(mAb)-based targeting platforms. Several promising mAbs targeting receptors overexpressed on the different stages of prostate cancer have also been developed for radiopharmaceutical therapy, for example, Delta-like ligand 3 (DLL-3), CD46, and CUB domain-containing protein 1 (CDCP1). Progress is also being made using peptide-based targeting platforms for the gastrin-releasing peptide receptor (GRPR), a well-established membrane-associated receptor expressed in localized and metastatic prostate cancers. Furthermore, mechanism-driven combination therapies appear to be a burgeoning area in the context of preclinical prostate cancer radiotherapeutics. Here, we review the current developments related to the preclinical radiopharmaceutical therapy of prostate cancer. These are summarized in two major topics: (1) therapeutic radionuclides and (2) tumor-targeting approaches using monoclonal antibodies, small molecules, and peptides.