RT Journal Article SR Electronic T1 Engineering a Prostate-Specific Membrane Antigen–Activated Tumor Endothelial Cell Prodrug for Cancer Therapy JF Science Translational Medicine FD American Association for the Advancement of Science SP 140ra86 OP 140ra86 DO 10.1126/scitranslmed.3003886 VO 4 IS 140 A1 Denmeade, Samuel R. A1 Mhaka, Annastasiah M. A1 Rosen, D. Marc A1 Brennen, W. Nathaniel A1 Dalrymple, Susan A1 Dach, Ingrid A1 Olesen, Claus A1 Gurel, Bora A1 DeMarzo, Angelo M. A1 Wilding, George A1 Carducci, Michael A. A1 Dionne, Craig A. A1 Møller, Jesper V. A1 Nissen, Poul A1 Christensen, S. Brøgger A1 Isaacs, John T. YR 2012 UL http://stm.sciencemag.org/content/4/140/140ra86.abstract AB Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.