Targeted Radionuclide Therapy of Prostate Cancer

Abstract

Prostate cancer is an ideal target for the development of targeted radionuclide therapy because of the frequent occurrence of multi-focal disseminated disease when it recurs after treatment of disease initially thought to have been confined to the prostate gland or even at presentation in patients with advanced disease. This is particularly so because of the multi-focal nature of the metastases, thus precluding traditional surgery and radiation therapy and the lack of well-defined chemotherapeutics. Since prostate carcinoma has been demonstrated to express a relatively specific membrane surface marker, radiolabeled molecules with high binding affinity for prostate specific membrane antigen (PSMA) have been, and continue to be, evaluated as the basis for targeted radionuclide therapy to deliver sufficient doses of radiation to tumor deposits at diverse locations within normal tissues. Although no radiotherapeutic is available for routine clinical application at this time, there has been considerable progress in the past decade. The development of a radiolabeled anti-PSMA antibody for radioimmunotherapy of prostate cancer has identified and resolved several issues involved in the development of a clinical therapeutic: identification of a suitable antigen, development of an antibody of sufficient specificity and affinity; preparation on a nonimmunogenic version of the antibody; labeling chemistry, comparison, and selection of a radionuclide; design of clinical trials to evaluate safety and efficacy with incremental complexity and relevance to the particular natural history of the disease. J591 is an IgG monoclonal antibody that targets the extracellular domain of PSMA. Following preclinical and early phase clinical studies with radiolabeled J591 to demonstrate targeting of tumor cells and anti-tumor effects proportional to radiation dose, clinical studies in patients with biochemical evidence of relapse demonstrated decreasing levels of the serum biomarker PSA. Currently, ¹⁷⁷Lu-DOTA-J591 is being evaluated to optimize patient selection, alternate dosing schemes, combination chemo-radioimmunotherapy, and potential use as adjuvant therapy. Recently, an alternate approach has also been pursued based on the identification of molecules that serve as agonists or antagonists of PSMA as a transmembrane enzyme. ¹²³I and ^99mTc labeled heterodimers have demonstrated high affinity and specific binding to PSMA-expressing cells and tumor models. Subsequently, imaging studies in patients identified prostate carcinoma within the intact prostate gland as well as in metastatic sites. Based on these encouraging observations, an I-131 labeled version of one of these molecules has been administered to patients with metastatic prostate carcinoma. Impressive reduction of tumor size and serum PSA has been observed. Defining a successful protocol for the treatment of prostate carcinoma either as adjuvant therapy or for the treatment of advanced disease is a complex and challenging problem. Radioimmunotherapy utilizing radiolabeled monoclonal antibodies and/or targeted radionuclide therapy utilizing small molecules represent two different approaches to the challenge and are accompanied by different additional issues such as dosing schedule and nontarget organ dosimetry and exposure. The clinical use at the present time of any of these modalities alone or in combination with a chemotherapeutic requires additional evaluation and validation.

Research Support: Prostate Cancer Foundation, Department of Defense, National Institutes of Health, David H. Koch Foundation, Yablans Family Foundation.