Sep. 3, 2008 Researchers at the Translational Genomics Research Institute (TGen) today announced a new approach to treating endometrial cancer patients that not only stops the growth of tumors, but kills the cancer cells.
In a potentially major breakthrough, TGen scientists and collaborators at Washington University School of Medicine in St. Louis discovered that introducing a particular inhibitor drug can turn "off'' receptors responsible for the growth of tumors in a significant number of patients with endometrial cancer.
And, they found that the inhibitor drug proved effective even in cancer tumors containing a commonly occurring mutant gene, PTEN, previously associated with resistance to drug treatment.
TGen's findings appear September 1 in a paper published as a priority report by Cancer Research, a Philadelphia-based peer-reviewed journal dedicated to original cancer research.
A clinical trial based on the TGen study will start within the next year.
Dr. Pamela Pollock, an associate investigator in TGen's Cancer and Cell Biology Division and the paper's senior author, led a team that used the latest genome-scanning technology to sequence 116 endometrioid endometrial tumor samples. This work was done in association with Dr. Paul Goodfellow, an expert in endometrial cancer and a professor in the departments of Surgery and of Obstetrics and Gynecology at Washington University.
Pollock and colleagues in May 2007 announced that they had discovered previously unrecognized alterations in the fibroblast growth factor receptor 2 (FGFR2) gene. The altered FGFR2 is present in the cancer cells of nearly 15 percent of women with endometrioid endometrial tumors. These kinds of tumors represent 80 percent of all endometrial cancers.
By introducing a commercially available inhibitor drug, PD173074, TGen researchers showed that they could stop the growth of tumors, and even kill cancer cells, in cases where the tumors contained the altered FGFR2 gene. The altered gene causes the receptors to get stuck in the "on'' position and signal the endometrial cells to grow out of control.
"These findings could accelerate the development of new treatments for endometrial cancer because there are already drugs in clinical trials that inhibit FGFR2 function,'' Pollock said.
Current treatment of endometrial cancer can involve surgical removal of the uterus, radiation and chemotherapy. While many women are successfully treated with these approaches, about 15 percent of those with endometrioid endometrial cancer have persistent or recurring tumors that are resistant to current drug therapies. Mutations in several genes previously have been identified in endometrial tumors, but they have not been suitable drug targets – until now.
"This targeted approach holds great promise for patients with uterine cancer (endometrioid endometrial) tumors that contain the FGFR2 mutation," said TGen physician-in-chief, Dr. Daniel Von Hoff, "and offers yet another powerful example of how genomic medicine is changing the way we look at and treat cancer."
Goodfellow agreed, "The discovery that endometrial cancer cells die when treated with an FGFR2 inhibitor - even when they carry other genetic abnormalities common in uterine cancers - suggests anti-FGFR2 therapies have great potential.''
The researchers' already established ties with the National Cancer Institute, which will assist with the clinical trials, should speed the development of new therapies, Goodfellow said. "Our collaborative group's strong ties with the NCI's Gynecologic Oncology Group will allow us to rapidly take our findings from the lab to patients.''
Endometrial cancer, which invades the inner wall of the uterus, is the most common gynecological cancer in the United States. This year more than 40,000 women will be diagnosed and nearly 7,500 women will die of the disease, according to the American Cancer Society (ACS).
Among women, only breast, lung and colon cancers strike with more frequency. And while endometrial cancer is slow to develop, and often is not detected until after age 60, nearly one in eight women who are diagnosed die within five years, according to the ACS.
Pollock plans to start clinical trials with an FGFR inhibitor in endometrial cancer patients within a year. The trials will be conducted in collaboration with Dr. Matthew Powell, a gynecologic oncologist and assistant professor of Obstetrics and Gynecology at Washington University School of Medicine.
Targeted drug therapy is a relatively new approach to cancer treatment that is based on identifying the abnormalities in cancer cells that cause them to grow uncontrollably. It involves treating tumors with drugs that specifically inhibit the activity of these genetic abnormalities.
This approach of targeted therapy allows oncologists to match the therapy to the specific genetic signature of each patient's tumor, a strategy that has been effective in multiple cancer types, including breast cancer, lung cancer and chronic myelogenous leukemia.
The study was funded, in part, by a two-year, $100,000 ($50,000 per year) grant from the Cary, N.C.-based, V Foundation for Cancer Research. The foundation is named in remembrance of famed North Carolina State basketball coach and award-winning broadcaster Jimmy Valvano, a cancer research advocate who died of Metastatic Adenocarcinoma in 1993.
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