Research ArticleDrug Development

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

Science Translational Medicine  27 Jun 2012:
Vol. 4, Issue 140, pp. 140ra86
DOI: 10.1126/scitranslmed.3003886

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An Old Approach Is New Again

In the 1995 film The Last Supper, a group of graduate students invite a diverse cast of characters for a series of Sunday dinners. After one guest threatens the lives of several of the students, subsequent dinners turn deadly. If the guest holds views that the group considers toxic to society, then the house wine is made poisonous and served only to the unwanted houseguest, who promptly dies. In a related scenario, Denmeade et al. use a prodrug to seek out and selectively poison unsavory guests that are toxic to the body—namely, cancer cells.

The new work describes the development of a thapsigargin (TG) prodrug that is activated in the vasculature of solid tumors by tumor endothelial cells. The carboxypeptidase prostate-specific membrane antigen (PSMA)—which is selectively expressed on the surface of prostate cancer cells, including metastatic ones, and tumor, but not normal, endothelial cells—cleaves and activates the prodrug extracellularly in the tumor microenvironment. The activated cytotoxic moiety then poisons neighboring cancer cells within sites of metastases by entering the cells and inhibiting the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump, which is essential to the function of all normal and tumor cell types. The authors showed that treatment with the prodrug caused significant tumor regression in two mouse xenograft models of human prostate cancer and one model of human breast cancer with relatively little toxicity—less than that of the maximally tolerated dose of the widely used cancer drug docetaxel.

Although the targeted prodrug concept is not new, the current approach has several features that make it superior to many previous ones. First, unlike most cytotoxic cancer drugs, TG is not cell cycle–dependent and thus can kill nondividing cancer cells. Furthermore, drug toxicity is expected to be low, because the PSMA substrate in the prodrug is cleaved primarily by prostate cancer cells and in the vicinity of tumor endothelial cells. In fact, the authors report that studies in cynomolgus monkeys showed minimal toxic effects except in the kidney, and even that renal toxicity was minimal to mild and reversible at the low drug dose.

As with all cancer drugs, the new findings will require clinical validation in ongoing studies. However, this unusual therapeutic approach has the potential to be an effective and selective ouster of unwanted invaders that threaten their hosts.