New Drug Causes Cancer Cells to Commit Suicide;
Early Results Promising
Wouldn’t it be wonderful if we could somehow trick cancer cells into killing themselves? Scientists Samuel Denmeade, M.D., The Carolyn and Bill Stutt Scholar, and John Isaacs, Ph.D., The R. Christian B. Evensen Scholar working with Danish researchers, have been working to develop and test an agent that can do just that. Technically, it’s not a drug but a “prodrug” – a compound that is biologically inactive when it goes into the body, but that turns into a drug once it’s metabolized.
A three-day course of G202 reduced
the size of human prostate tumors
grown in mice by an average of
50 percent within 30 days.
“This can best be described as a molecular grenade,” says Denmeade, “one that can only be detonated by prostate cancer cells” – because only these cells have the secret code required to pull the pin. That code is a protein called prostate-specific membrane antigen (PSMA), found in prostate cells. When the prodrug reaches a prostate tumor, “the prostate cancer cells themselves cause the prodrug to explode,” notes Isaacs.
The result is not only a direct hit on the target, but on some not-so-innocent bystanders, nearby cells that support the cancer. The results in mouse studies have been impressive: “Destruction of human prostate cancer tumors, with minimal side effects to normal tissues,” Denmeade says. The prodrug, called G202, has passed another hurdle, initial clinical safety studies, and is now being tested in a multicenter, Hopkins-led clinical trial to determine its effectiveness in men with advanced prostate cancer. So far, 29 men have been treated.
In an article recently published in the journal, Science Translational Medicine, Denmeade, Isaacs and colleagues reported that a three-day course of G202 reduced the size of human prostate tumors grown in mice by an average of 50 percent within 30 days. How does this stack up to standard chemotherapy? G202 did better, reducing seven of nine tumors by more than 50 percent in 212 days; in comparison, the chemotherapy drug docetaxel reduced only one out of eight human prostate tumors in mice by more than 50 percent in the same time period. Also exciting: The scientists found that G202 also works on other cancers, producing at least 50-percent regression in animal models of breast cancer, kidney cancer, and bladder cancer. Another trial is being planned to test the drug in patients with prostate cancer and liver cancer.
Longtime readers of this publication and its predecessor, Prostate Cancer Update, may remember that nearly two decades ago, on a family vacation in the Mediterranean region, Isaacs picked samples of a local weed called Thapsia garganica, because he believed it had potential as an anti-cancer drug. For centuries, a toxin made by this plant, thapsigargin, has been known to be poisonous to animals; in fact, it was known as the “death carrot,” because it would kill camels that ate it. It took many years, but Isaacs and Denmeade managed to disassemble thapsigargin and modify it to target PSMA. How does G202 kill cancer cells? It blocks a protein called the SERCA pump, which regulates a cell’s level of calcium. Because all cells need this protein to stay alive, Denmeade and Isaacs do not believe it’s possible for tumor cells to become resistant to the drug. That would be like the lungs becoming resistant to oxygen.
Denmeade and Isaacs do not believe
it’s possible for tumor cells to become
resistant to the drug. That would be
the lungs becoming resistant to oxygen.
Annastasiah Mhaka, Marc Rosen, Nathaniel Brennen, Susan Dalrymple, Bora Gurel, Angelo De Marzo, and Michael Carducci of Johns Hopkins; Ingrid Dach, Claus Olesen, Jesper Møller, and Poul Nissen of the Danish National Research Foundation and Aarhus University; Craig A. Dionne of GenSpera Inc.; and S. Brøgger Christensen of the University of Copenhagen.