title: Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy.
abstract: 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.
authors: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. denmesa@jhmi.edu
authors: Samuel R
authors: SR
authors: Denmeade
authors: Annastasiah M
authors: AM
authors: Mhaka
authors: D Marc
authors: DM
authors: Rosen
authors: W Nathaniel
authors: WN
authors: Brennen
authors: Susan
authors: S
authors: Dalrymple
authors: Ingrid
authors: I
authors: Dach
authors: Claus
authors: C
authors: Olesen
authors: Bora
authors: B
authors: Gurel
authors: Angelo M
authors: AM
authors: Demarzo
authors: George
authors: G
authors: Wilding
authors: Michael A
authors: MA
authors: Carducci
authors: Craig A
authors: CA
authors: Dionne
authors: Jesper V
authors: JV
authors: Møller
authors: Poul
authors: P
authors: Nissen
authors: S Brøgger
authors: SB
authors: Christensen
authors: John T
authors: JT
authors: Isaacs
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism*; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*
chemical_list: D000954:Antigens, Surface; D011355:Prodrugs; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II