JOHNS HOPKINS (US) — An experimental drug derived from a poisonous weed can travel harmlessly through the bloodstream until it detects cancer cells and kills them.
In laboratory studies, the researchers say, a three-day course of the drug G202 shrunk human prostate tumors grown in mice by an average of 50 percent within 30 days. It far outperformed docetaxel, a chemotherapy drug now used against prostate cancer, and was also highly effective against animal models of human breast cancer, kidney cancer, and bladder cancer.
The study by scientists at the Johns Hopkins Kimmel Cancer Center and from Denmark was published in the journal Science Translational Medicine.
G202 is derived from Thapsia garganica, a weed that grows in the Mediterranean region. The plant makes a product—dubbed thapsigargin—that since the time of ancient Greece has been known to be toxic to animals. In Arab caravans, the plant was known as the “death carrot” because it would kill camels that ate it, the researchers noted.
“Our goal was to try to re-engineer this very toxic natural plant product into a drug we might use to treat human cancer,” says lead study author Samuel Denmeade, professor of oncology, urology, and pharmacology and molecular sciences at Johns Hopkins. “We achieved this by creating a format that requires modification by cells to release the active drug.”
By disassembling thapsigargin and chemically modifying it, the researchers created a form that Denmeade likens to a hand grenade with the pin in. The drug can be injected and travel through the bloodstream without harming healthy blood vessels and tissues.
But when G202 finds cancer tumors, a protein released by the tumors (called prostate-specific membrane antigen), in effect “pulls the pin.” That releases cell-killing agents from the drug into the tumor and the blood vessels that feed it, as well as to other cells in the vicinity. Specifically, G202 blocks the function of another protein—the SERCA pump—that is necessary for cell survival, the researchers report.
“The exciting thing is that the cancer itself is activating its own demise,” says senior study author John Isaacs, professor of oncology, urology, and chemical and biomedical engineering at Johns Hopkins.
Based on their laboratory results, Johns Hopkins physicians have performed a phase I clinical trial to assess safety of the drug and have treated 29 patients with advanced cancer. In addition to Johns Hopkins, the University of Wisconsin, and the University of Texas-San Antonio are participating in the trial. A phase II trial to test the drug in patients with prostate cancer and liver cancer is planned.
Because G202 targets the SERCA pump, which all cells need to stay alive, researchers say it will be difficult for tumor cells to become resistant to the drug.
The study’s co-authors are from Johns Hopkins, the Danish National Research Foundation, Aarhus University, and the University of Copenhagen, and GenSpera Inc.
The work was supported by the Department of Defense Prostate Cancer Research Program, the Prostate Cancer Foundation and David Koch, the Danish Cancer Society, the Danish Research Council for Strategic Research, the Danish National Research Foundation, the Danish Medical Research Council, the Aarhus University Research Foundation, and National Cancer Institute.
Denmeade and Isaacs are consultants for GenSpera Inc. and have received equity and financial compensation. This relationship has been disclosed and is under the management of the Johns Hopkins University School of Medicine Conflict of Interest Committee.
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