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.