Dream Team Targets Key Driver for Breast, Ovarian, Endometrial Cancers
Stand Up to Cancer Funds Joint Effort by M. D. Anderson, Harvard, Memorial-Sloan-Kettering
M. D. Anderson News Release 05/27/09
A Dream Team of leading cancer researchers will accelerate development of drugs to attack a mutated molecular pathway that fuels endometrial, breast and ovarian cancers, funded by a three-year $15 million grant awarded today by Stand Up To Cancer.
The grant is one of five that bring top researchers from different institutions together to speed new cancer treatments to patients. Stand Up to Cancer, a program of the Entertainment Industry Foundation, is a novel charitable initiative that raised most of its funds during a telecast last September that aired simultaneously on ABC, NBC and CBS.
"The pathway involved here is the most common abnormally activated pathway in all of cancer," said Gordon Mills, M.D., Ph.D., professor and chair of M. D. Anderson's Department of Systems Biology and a co-leader on the project with two other scientists. "What we learn in women's cancers will apply to many other types."
Genetic aberrations in the network, known as the PI3K pathway, are found in half of all breast cancer patients, 60 percent of all cases of endometrial cancer and 20 percent of ovarian cancer patients. Other cancers that include a mutationally activated PI3K pathway include melanoma, colon and prostate cancers, brain tumors, and leukemia.
A variety of drugs under development target different aspects of the complex pathway, which Mills describes as a "target-rich environment."
"Our major goal is to determine which patients are most likely to benefit from these drugs, so that we get the right therapy to the right patient the first time," he said. "By the end of three years we are expected to have changed the way in which we manage patients. That's a very large challenge."
Dream Team collaborators with Mills are project leader Lewis C. Cantley, Ph.D., chief, division of signal transduction, Cancer Center at Beth Israel Deaconess Medical Center and professor of systems biology at Harvard Medical School, and co-leader Charles Sawyers, M.D., director, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center in New York. The Dream Team also includes research groups at Vanderbilt-Ingram Cancer Center, Vall d'Hebron Oncology Research Institute in Barcelona, and Herbert Irving Comprehensive Cancer Center at Columbia University.
The PI3K network normally promotes cell survival, growth and protein synthesis. When it is abnormally activated by genetic aberrations, it contributes to tumor progression, connects to other cancer-causing pathways and causes resistance to treatment.
The team will use its combined cell line studies, animal model research and data from drugs that have completed phase I clinical trials to identify potential biomarkers - specific genetic mutations in patients' tumors, for example - that will indicate whether a drug will work for specific groups of patients.
Clinical trials of the targeted drugs also will test the validity of candidate biomarkers. Mills, who also directs the Kleberg Center for Molecular Markers at M. D. Anderson, expects the first phase II clinical trial, for endometrial cancer, to open in about six months.
Mills leads the team's tumor cell line and screening core, which will analyze every tumor sample to detect cancer-related genetic mutations, study the effect of genetic aberrations on the PI3K pathway and on PI3K inhibitors used in clinical trials, and identify drug combinations to block the pathway and biomarkers related to those drugs.
Combinations will likely be needed both to stifle the PI3K pathway and to inhibit a second interacting pathway, the MAPK/RAS network. Early cell line and animal model evidence suggest both pathways must be blocked to effectively treat the three cancers.
Also on the Dream Team from M. D. Anderson are Donald Berry, Ph.D., head of the Division of Quantitative Biology; Cheryl Lyn Walker, Ph.D., professor in the Department of Carcinogenesis and the co-director of M. D. Anderson's Gynecology Specialized Program in Research Excellence; and Russell Broaddus, M.D., Ph.D. associate professor in the Department of Pathology.
Clinical trials will be based at M. D. Anderson. The endometrial trials will be led by Karen Lu, M.D., and Robert Coleman, M.D., both professors, with Bryan Hennessy, M.D., assistant professor, all of the Department of Gynecologic Medical Oncology. Funda Meric-Bernstam, M.D., associate professor in the Department of Surgical Oncology, will be coordinator of clinical trials as well as leader of the breast cancer trials, working with Ana Gonzalez-Angullo, M.D., associate professor of breast medical oncology.
Stand Up to Cancer received 237 Dream Team applications and awarded a total of $73.6 million to the five teams announced today at a news briefing in New York. 05/27/09