PT  - JOURNAL ARTICLE
AU  - Denmeade, Samuel R.
AU  - Mhaka, Annastasiah M.
AU  - Rosen, D. Marc
AU  - Brennen, W. Nathaniel
AU  - Dalrymple, Susan
AU  - Dach, Ingrid
AU  - Olesen, Claus
AU  - Gurel, Bora
AU  - DeMarzo, Angelo M.
AU  - Wilding, George
AU  - Carducci, Michael A.
AU  - Dionne, Craig A.
AU  - Møller, Jesper V.
AU  - Nissen, Poul
AU  - Christensen, S. Brøgger
AU  - Isaacs, John T.
TI  - Engineering a Prostate-Specific Membrane Antigen–Activated Tumor Endothelial Cell Prodrug for Cancer Therapy
AID  - 10.1126/scitranslmed.3003886
DP  - 2012 Jun 27
TA  - Science Translational Medicine
PG  - 140ra86--140ra86
VI  - 4
IP  - 140
4099  - http://stm.sciencemag.org/content/4/140/140ra86.short
4100  - http://stm.sciencemag.org/content/4/140/140ra86.full
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.