Oct. 20, 2004 HOUSTON - Two different agents that have little individual effect on lung cancer when tested in low doses in the lab and in animals have a synergistic impact when combined together, say researchers at The University of Texas M. D. Anderson Cancer. They say this new therapeutic recipe might show potential in disarming the nation's leading cancer killer.
The study, published in the October 20 issue of the Journal of the National Cancer Institute, tested an experimental targeted therapy, the farnesyltransferase inhibitor SCH66336, and an agent, the insulin-like growth factor binding protein-3 (IGFBP-3), and found that even at a combined low dose, tumor size was reduced by half in mice implanted with human lung tumors.
"Together these agents work on multiple pathways important to the survival of a cancer cell, and we look forward to possibly translating our promising findings into a clinical trial," says Ho-Young Lee, Ph.D., an assistant professor in the Department of Thoracic/Head & Neck Medical Oncology Research and lead author of the study.
"Combined, these two agents block two different pathways and appear to have tremendous potential to make an impact in the treatment of lung cancer patients. We are in the process of developing a clinical protocol, which we hope to move forward to patients in the near future," says Waun Ki Hong, M.D., head of the Division of Cancer Medicine and chairman of thoracic/head and neck medical oncology. Scientists from U.S. Food and Drug Administration and from Emory University also participated.
The drugs, when used together, inhibit cancer cell survival pathways in cancer while inducing cell death. IGFBP-3 has demonstrated some effectiveness in laboratory studies involving several different kinds of cancer types, but has not yet been tested in patients. SCH66336 (also known as lonafarnib) already has been tested in an advanced clinical trial treating patients with lung cancer, but results were disappointing - enrollment to the trial was halted earlier this year when SCH66336, used by itself, showed no benefit during an interim analysis of results.
The researchers chose to test IGFBP-3 because IGFBP-3 has the ability to regulate the amount of IGF, a growth factor that is associated with aggressive lung cancer. Like other growth proteins, IGFs can bind to their receptors on cancer cells, and send signals inside the cell to enhance cell growth and division, inhibit the ability of the cell to destroy itself (cell death), induce angiogenesis (construction of a nurturing blood supply), and spur the spread (metastasis) of cancer cells to other locations in the body.
Agents known as IGFBP-3 have the potential to block the effects of systemic IGF, says Lee. Not only do these inhibitors stop growth signals from reaching the cell, "these binding proteins also have the independent ability to enter cells and shut down the growth cycle and induce the cell to self destruct," says Lee.
While previous work at M. D. Anderson has shown that IGFBP-3 successfully stops the growth of head and neck cancers when tested in animal models, other research has demonstrated that the agent can lose its effectiveness over time because cancer cells become resistant to the therapy.
The drug SCH66336 inhibits activation of Ras, an oncogene known to be activated in one-third of human cancers, including lung cancers. Ras induces cell growth independent of growth factors, but some researchers have suspected that Ras can interfere with functioning of the IGFBP-3 inhibitors. "We think that Ras signaling is what makes lung cancer cells resistant to IGFBP-3 inhibitors," says Lee.
To test this theory, Lee and a team of researchers set up experiments in both laboratory lung cancer cells and in mice that had been implanted with human lung tumors. They found that mild doses of each treatment alone had no impact on the tumors, but then they looked at the effect of the combination. To deliver the IGFBP-3 inhibitor to the mice, the agent was hooked on to a viral vector, and injected directly -- and just once -- into the lung tumor. Then the mice were fed a single tablet of SCH66336 each day for 16 days. The researchers showed that the combined treatment reduced cancer burden in the animals, shrinking tumors to 45 percent the size of tumors seen in untreated animals, and that none of the treatments produced measurable side effects.
The researchers are continuing to study the combination of drugs to find a dosing schedule that might completely suppress tumor growth.
The study was funded by the National Institutes of Health, the American Cancer Society, M. D. Anderson Cancer Center, and the U.S. Department of Defense. Collaborators include, from M.D. Anderson: Kyung-Hee Chun, M.D., Yoon-Soo Chang, M.D., Khaled Hassan, M.D., Lin Ji, Ph.D., and Reuben Lotan, Ph.D.; from Emory University, Fadlo Khuri, M.D.; and from the FDA's National Center for Toxicological Research, Hojin Moon, Ph.D.
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