Expression of prostate-specific membrane antigen (PSMA) in the neovasculature of nonprostate human tumors of epithelial and nonepithelial origin.

Abstract

e21131 Background: PSMA is a transmembrane glycoprotein present not only in prostate cancer epithelial cells but also in the neovasculature of many other solid tumors. This expression profile makes it an attractive target for tumor-specific delivery of chemotherapeutic agents to the neovasculature of non-prostate solid tumors. We generated an antibody-drug conjugate (ADC) comprised of a fully human anti-PSMA monoclonal antibody (mAb), conjugated to monomethylauristatin E, a potent cytotoxic agent. PSMA ADC is currently undergoing Phase I clinical testing in men with advanced prostate cancer. Previously, we reported high level PSMA expression in the neovasculature of carcinomas from kidney, colon, non-small cell lung, breast and liver. Here we extend our study to additional carcinomas as well as tumors of non-epithelial origin. Methods: Expression of PSMA protein was evaluated by immunohistochemical analysis of frozen tissues using biotinylated mAb that specifically recognizes the native dimeric form of PSMA. The semi-quantitative scheme of 0 to 3+ was used to indicate the amount of epitope based on the intensity of the color reaction. The strongest possible staining was scored 3+ while 2+ staining was considered moderate and 1+ was considered weak. Endothelial cells were detected by morphology and staining of selected slides with an anti-CD 34 mAb. Results: Moderate to strong (2+ to 3+) neovasculature staining was seen in over 80% of specimens from, bladder (10/10), ovarian (9/10) and pancreatic (8/10) carcinomas. Moderate to strong neovascular staining was seen in 40-80% of specimens from several non-carcinoma tumors, including glioblastoma (4/5), melanoma (7/10), non-Hodgkins lymphoma (6/10), osteosarcoma (3/7) and myeloma (2/5). Only weak (1+) staining was seen in angiosarcoma (2/3) and no staining was observed in the testicular cancers tested (0/5). Conclusions: Robust neovascular expression of PSMA dimer was observed across all eight non-prostatic carcinomas. Significant neovascular expression was also observed in several non-epithelial tumors. These findings may be relevant to the development of novel anti-neovascular therapies that target PSMA.