Novel Anticancer Drug Targets Vital Molecular Pump

A novel experimental anticancer drug targets a protein pump required by all human cells but only becomes active when exposed to the microenvironment found inside a solid tumor.

Investigators at Johns Hopkins University (Baltimore, MD, USA) created the new drug from the combination of a synthetic analog of thapsigargin (obtained from the weed Thapsia garganica) and a peptide that specifically targets the protein carboxypeptidase prostate-specific membrane antigen (PSMA) that is produced by tumor endothelial cells. Thapsigargin is a potent inhibitor of the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. The hybrid molecule, which is referred to as G202, only becomes active when the PSMA peptide binds to cells within a tumor.

Results published in the June 27, 2012, issue of the journal Science Translational Medicine revealed that G202 could be administered to mice and specifically inhibit tumor growth with only minor toxicity toward normal cells. A three-day course of the drug reduced the size of human prostate tumor xenografts grown in mice by an average of 50% within 30 days. In a direct comparison, G202 outperformed the chemotherapy drug docetaxel, reducing seven of nine human prostate tumors in mice by more than 50% in 21 days. Docetaxel reduced one of eight human prostate tumors in mice by more than 50% in the same time period.

“Our goal was to try to re-engineer this very toxic natural plant product into a drug we might use to treat human cancer,” said first author Dr. Samuel Denmeade, professor of oncology, urology, pharmacology, and molecular sciences at Johns Hopkins University. “We achieved this by creating a format that requires modification by cells to release the active drug.”

As G202 is targeted to the SERCA pump, a metabolic system that all cells require, the investigators anticipate that it will be difficult for tumor cells to become resistant to the drug, because cancer cells cannot halt production of this protein.

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