Molecular therapy of prostate carcinoma

Abstract

Molecular imaging and therapy is based on a radiolabeled molecule that binds to a unique feature of a cell. Prostate Specific Membrane Antigen [PSMA] is a complex antigen with an extra-cellular, transmembrane and intra-cellular component that is uniquely expressed on prostate tissue and has a greater degree of expression on prostate carcinoma. The degree of PSMA expression increases with the degree of aggressiveness of the prostate carcinoma. A murine monoclonal antibody [termed J591] has been developed that binds to the extra-cellular epitope of PSMA with a high degree of affinity and specificity. It has been “humanized” and radiolabeled with the radionuclides Indium-111 [useful for imaging], Yttrium-90 [a radiometal that emits a beta particle which is potentially useful for targeted radionuclide therapy], and Lutetium-177 [which also emits a beta particle that is useful for targeted therapy as well as a gamma photon that can be imaged]. Over several years, physicians and scientists in nuclear medicine, urology and medical oncology have evaluated radiolabeled forms of hJ591 for therapy. In general, serum PSA has been used as evidence of recurrent and progressive disease in men with proven prostate carcinoma. The Maximum Tolerated Dose [MTD] for a single administration has been identified as 2.6 GBq (70 mCi)/m2. At this dose, PSA responses have been seen in many patients. The response is very dose-dependant with fewer responses observed at 2.25 GBq/m2. Accordingly, a dose fractionation protocol has been evaluated in which patients receive 2 doses, 2 weeks apart. The MTD for the fractionated protocol is 1.5 GBq/ m2 for a total dose of 3.0 GBq/ m2. Initial studies were performed in patients with advanced metastatic disease. More recently, additional protocols 1) to evaluate the potential efficacy of this therapy in patients with initial evidence of biochemical failure (i.e. rising PSA after initial therapy) and 2) to evaluate the incremental value of radiolabeled J591 as a supplement to Docetaxel chemotherapy.