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

Samuel R. Denmeade, Annastasiah M. Mhaka, D. Marc Rosen, W. Nathaniel Brennen, Susan Dalrymple, Ingrid Dach, Claus Olesen, Bora Gurel, Angelo M. DeMarzo, George Wilding, Michael A. Carducci, Craig A. Dionne, Jesper V. Møller, Poul Nissen, S. Brøgger Christensen, John T. Isaacs

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number140ra86
JournalScience translational medicine
Volume4
Issue number140
DOIs
StatePublished - Jun 27 2012

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Denmeade, S. R., Mhaka, A. M., Rosen, D. M., Brennen, W. N., Dalrymple, S., Dach, I., Olesen, C., Gurel, B., DeMarzo, A. M., Wilding, G., Carducci, M. A., Dionne, C. A., Møller, J. V., Nissen, P., Christensen, S. B., & Isaacs, J. T. (2012). Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Science translational medicine, 4(140), [140ra86]. https://doi.org/10.1126/scitranslmed.3003886