In its unaltered, or wild type, form Salmonella can cause food poisoning and septic shock. Yale scientists at the School of Medicine and their colleagues report, however, that a genetically engineered strain of the Salmonella bacteria has the potential to target cancerous tumors and, by multiplying within those tumors, to inhibit the cancer's growth.
The Yale discovery was reported in the Oct. 15 issue of the scientific journal Cancer Research and has been licensed to Vion Pharmaceuticals Inc. in New Haven.
Even when stripped of its disease-causing characteristics, the altered Salmonella bacteria can still target solid tumors in laboratory animals in a similar manner to its wild-type parent, according to John M. Pawelek, one of the inventors of the new cancer therapy.
"In fact," he says, "we can now significantly prolong the life of mice with melanoma by injecting them with our attenuated bacteria. Although as few as 10 wild type bacteria are sufficient to kill a mouse, we can inject 10 million cells of our attenuated strains and the mice show no symptoms of infection.
Slowing tumor growth, prolonging life. "After the Salmonella are introduced into the mouse blood stream, they seek out tumors, multiply there in great numbers, and --by mechanisms not fully understood -- dramatically slow the rate of tumor growth and prolong life," adds the scientist. "Furthermore, because the bacteria amplify within the tumor itself, anti-tumor genes that we introduce genetically into the bacteria are also amplified."
A cancer biologist who studies melanoma, Mr. Pawelek developed the radical new therapy with his School of Medicine colleagues David Bermudes, a parasitologist; and K. Brooks Low, a bacterial geneticist. Mr. Pawelek is a senior research scientist in dermatology and a lecturer in pharmacology; Mr. Bermudes is assistant professor (adjunct) of internal medicine; and Mr. Low is professor (adjunct) of research in therapeutic radiology.
The three have worked hand-in-hand with a team of scientists from Vion Pharmaceuticals, Inc., to prepare their invention for possible clinical trials in cancer patients.
The three scientists say they were motivated by the work of Professor Rakesh K. Jain and his colleagues at Harvard University who, through the application of engineering sciences to tumors, have shown that numerous physical barriers exist within tumors, prohibiting efficient delivery of anti-cancer agents.
"Tumors have an irregular blood supply, with blood vessels not reaching many regions," explains Mr. Pawelek. "They tend to be under positive pressure from the inside out. Jain's group and others have shown that these characteristics present barriers that inhibit viruses, antibodies and drugs from reaching the innermost portions of the tumors.
"In contrast, Salmonella, which can move by their own swimming motion, are less subject to physical constraints and can reach and then multiply within deeper areas," he notes. "When Salmonella particularly are armed with anti-cancer genes, they have the potential to kill tumor cells in areas not easily reached by other therapeutic agents."
"Most exciting is the potential use of our technology for human cancer therapy," the three scientists agreed. "We've made the Salmonella both safe and effective for laboratory animals, and now the challenge is to do the same for humans."