TY - JOUR
T1 - Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy
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.
PY - 2012/6/27
Y1 - 2012/6/27
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84863198078&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863198078&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3003886
DO - 10.1126/scitranslmed.3003886
M3 - Article
C2 - 22745436
AN - SCOPUS:84863198078
SN - 1946-6234
VL - 4
JO - Science translational medicine
JF - Science translational medicine
IS - 140
M1 - 140ra86
ER -