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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Samuel R Denmeade, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • Annastasiah M Mhaka, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • D Marc Rosen, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • W Nathaniel Brennen, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • Susan Dalrymple, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • Ingrid Dach, Denmark
  • Claus Olesen
  • Bora Gurel, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • Angelo M Demarzo, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • George Wilding, University of Wisconsin, Madison, United States
  • Michael A Carducci, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
  • Craig A Dionne, GenSpera Inc., San Antonio, United States
  • Jesper V Møller
  • Poul Nissen
  • Søren Brøgger Christensen, Institut for Lægemiddeldesign og Farmakologi, Denmark
  • John T Isaacs, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, United States
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.
Original languageEnglish
JournalScience Translational Medicine
Volume4
Issue140
Pages (from-to)140ra86
ISSN1946-6234
DOIs
Publication statusPublished - 27 Jun 2012

See relations at Aarhus University Citationformats

ID: 48091777