Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

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  • Samuel R Denmeade, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • Annastasiah M Mhaka, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • D Marc Rosen, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • W Nathaniel Brennen, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • Susan Dalrymple, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • Ingrid Dach, Danmark
  • Claus Olesen
  • Bora Gurel, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • Angelo M Demarzo, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • George Wilding, University of Wisconsin, Madison, USA
  • Michael A Carducci, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
  • Craig A Dionne, GenSpera Inc., San Antonio, USA
  • Jesper V Møller
  • Poul Nissen
  • Søren Brøgger Christensen, Institut for Lægemiddeldesign og Farmakologi, Danmark
  • John T Isaacs, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
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.
OriginalsprogEngelsk
TidsskriftScience Translational Medicine
Vol/bind4
Nummer140
Sider (fra-til)140ra86
ISSN1946-6234
DOI
StatusUdgivet - 27 jun. 2012

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