PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

SIMPLE SUMMARY: One of the most frequently diagnosed cancer in men is adenocarcinoma of the prostate. Once the disease is metastatic, only very limited treatment options are available, resulting in a very short median survival time of 13 months; however, this reality is gradually changing due to the discovery of prostate-specific membrane antigen (PSMA), a protein that is present in cancerous prostate tissue. Researchers have developed pharmaceuticals specific for PSMA, ranging from antibodies (mAb) to low-molecular weight molecules coupled to beta minus and alpha-emitting radionuclides for their use in targeted radionuclide therapy (TRT). TRT offers the possibility of selectively removing cancer tissue via the emission of radiation or radioactive particles within the tumour. In this article, the major milestones in PSMA ligand research and the therapeutic developments are summarised, together with a future perspective on the enhancement of current therapeutic approaches. ABSTRACT: Prostate cancer (PC) is the second most common cancer among men, with 1.3 million yearly cases worldwide. Among those cancer-afflicted men, 30% will develop metastases and some will progress into metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis and median survival time that ranges from nine to 13 months. Nevertheless, the discovery of prostate specific membrane antigen (PSMA), a marker overexpressed in the majority of prostatic cancerous tissue, revolutionised PC care. Ever since, PSMA-targeted radionuclide therapy has gained remarkable international visibility in translational oncology. Furthermore, on first clinical application, it has shown significant influence on therapeutic management and patient care in metastatic and hormone-refractory prostate cancer, a disease that previously had remained immedicable. In this article, we provide a general overview of the main milestones in the development of ligands for PSMA-targeted radionuclide therapy, ranging from the firstly developed monoclonal antibodies to the current state-of-the-art low molecular weight entities conjugated with various radionuclides, as well as potential future efforts related to PSMA-targeted radionuclide therapy.