4.8 Article

Engineering a Prostate-Specific Membrane Antigen-Activated Tumor Endothelial Cell Prodrug for Cancer Therapy

Journal

SCIENCE TRANSLATIONAL MEDICINE
Volume 4, Issue 140, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3003886

Keywords

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Funding

  1. Department of Defense Prostate Cancer Research Program, the Prostate Cancer Foundation
  2. Danish Cancer Society
  3. Danish Research Council for Strategic Research
  4. Danish National Research Foundation
  5. Danish Medical Research Council
  6. Aarhus University Research Foundation
  7. National Cancer Institute Specialized Program of Research Excellence

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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.

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