Endocrine Abstracts

The World Cancer Research Fund International predicts the number of prostate cancer (PCa) cases will approach 1.7 million by 2030. Patient-specific staging drives the demand for sensitive and specific imaging of PCa including intraprostatic disease as well as local and distant metastases. Definitive therapy such as surgery or radiation is highly effective, but if the tumor escapes the gland, treatment options are limited. New imaging approaches that can more accurately assess the status of disease are needed and targeted radiotherapy could be a powerful treatment for refractory PCa (mCRPC). Prostate specific membrane antigen (PSMA) may be the ideal target for PCa due to its near universal expression on PCa cells and recent significant clinical success in translating radiolabeled small molecule PSMA inhibitors for imaging and therapy. Early work on the development of inhibitors of NAALADASE, a glutamate carboxypeptidase II enzyme, identified a number of small molecule inhibitors of this enzyme. Ultimately, the identification of the structural and functional homology between NAALADASE and PSMA opened the possibility of using small molecules for the targeted treatment and imaging of PCa. The first published demonstration of PET imaging of PCa with small-molecule PSMA inhibitor in animals was described in 2002 using 11C. The first major clinical step forward was realized in 2008 with the first human experience with 123I-MIP-1972 and 123I-MIP-1095. A ‘theranostic’ breakthrough followed in 2011 with the first clinical demonstration of successful endoradiotherapy of mCRPC using 131I-MIP-1095. That same year 68Ga-PSMA-11 was introduced for PET imaging which rapidly spread worldwide. New 18F based tracers such as 18F-DCFPyL and 18F-PSMA-1007 followed. The promising results of 131I-MIP-1095 in mCRPC patients stimulated development of 177Lu labeled compounds, such as DKFZ-617 and PSMA I&T. These DOTA containing analogs represent a novel class of PSMA-targeting theranostics allowing the use of 68Ga for PET imaging and 177Lu (beta) and 225Ac (alpha) for endoradiotherapy. The latter recently introduced into the clinic and thereby creating a new theranostics paradigm. The promise of theranostics is powerfully demonstrated in the application of small molecule PSMA inhibitors to PCa.