Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMAexpressing cells with picomolar potency and >700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.Prostate cancer is the most common malignancy and the second leading cause of cancer death in men in the United States (1). Localized prostate cancer typically is treated with surgery or radiation, and recurrent disease can be controlled temporarily with androgen ablation (2). However, almost all prostate carcinomas eventually become hormone refractory and then rapidly progress (3). Hormone-refractory or androgenindependent prostate cancer has proven to be largely resistant to conventional chemotherapy. With the exception of palliative care, the only approved chemotherapy is docetaxel in combination with prednisone, which offers a modest (2.4 months) survival benefit (4, 5). New molecularly targeted therapies are urgently needed.Monoclonal antibody (mAb) therapies have shown considerable use in the treatment of non-Hodgkin's lymphoma (6), B-cell chronic lymphocytic leukemia (7), colorectal carcinoma (8, 9), and breast cancer (10). In addition, mAbs have proven effective as vehicles to deliver therapeutic drugs or radionuclides in acute myeloid leukemia (11) and nonHodgkin's lymphoma (12, 13). Antibody-drug conjugates (ADC) combine the molecular targeting of mAbs with the chemotherapeutic properties of potent cytotoxins and hold great promise as molecularly targeted therapies of cancer.Prostate-specific membrane antigen (PSMA) is a very well characterized cell surface marker of prostate cancer (14 -17). PSMA is a homodimeric type II integral membrane glycoprotein whose expression is largely restricted to the prostate and is highly up-regulated in prostate carcinomas (17,18). Its expression increases with disease progression, becoming highest in metastatic, hormone-refractory disease (19). In addition, PSMA is abundantly expressed on the neovasculature of most other solid tumors but not on normal vasculature (20 -24). Importantly, PSMA is rapidly and constitutively internalized...

Purpose Exposing human tumor cells to sublethal doses of external beam radiation up-regulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific CTLs. This study explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T cell – mediated killing. Experimental Design Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153-ethylenediaminetetrame-thylenephosphonate (153Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time PCR analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to153Sm-EDTMP and incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to T cell – mediated killing. Results Tumor cells up-regulated the surface molecules Fas (100% of cell lines up-regulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), MHC class I (50%), and intercellular adhesion molecule-1 (40%) in response to 153Sm-EDTMP. Quantitative real-time PCR analysis revealed additional up-regulated tumor antigens. Exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen, and mucin-1. Conclusions Doses of 153Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that153Sm-EDTMP may work synergistically with immuno-therapy to increase the susceptibility of tumor cells to CTL killing.

This article reviews the major topics discussed at the meeting with the goal of promoting research that will validate and optimize the use of PSMA-targeted radionuclide therapies for the treatment of advanced prostate cancer.

Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility from clinical, scientific, and coverage policy standpoints. The NCCN Molecular Testing Work Group identified challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence.

No abstract