Breakthrough shows promise for treating endometrial cancer

Researchers have found a potential new approach to treating endometrial cancer — a drug that was shown to be effective even against human endometrial cancer cell lines that tend to be treatment resistant.

Scientists at Washington University School of Medicine in St. Louis and the Translational Genomics Research Institute (TGen), a non-profit research organization based in Phoenix, Ariz., discovered that introducing a particular inhibitor drug can turn off cell receptors that are responsible for tumor growth in a significant number of patients with endometrial cancer.

The inhibitor drug proved effective even in endometrial cancer cell lines containing a commonly occurring mutant gene, PTEN, previously associated with resistance to drug treatment.

The findings appear today in a paper published as a priority report by the journal Cancer Research. A clinical trial based on the study is planned for next year.

Pamela Pollock, Ph.D., 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. The work was done in association with Paul Goodfellow, Ph.D., an expert in endometrial cancer and co-director of the Hereditary Cancer Core at the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital.

In May 2007, the research team 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, a kind of tumor that represents 80 percent of all endometrial cancers.

By introducing a commercially available inhibitor drug, PD173074, the researchers showed that they could stop cell growth and induce cell death in endometrial cell lines that contained the altered FGFR2 gene. The altered gene causes cell receptors to get stuck in the “on” position and signal 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 says.

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 none have 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 and offers yet another powerful example of how genomic medicine is changing the way we look at and treat cancer,” says TGen physician-in-chief, Daniel Von Hoff, M.D.

Goodfellow agreed, saying that 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 have established ties with the National Cancer Institute, which will assist with the clinical trials. “Our collaborative group’s strong ties with the NCI’s Gynecologic Oncology Group will allow us to rapidly take the findings from the lab to patients,” says Goodfellow, also a professor of surgery and of obstetrics and gynecology at Washington University School of Medicine.

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 Matthew Powell, M.D., a gynecologic oncologist with the Siteman Cancer Center 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.

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.

Byron SA, Gartside MG, Wellens CL, Mallon MA, Keenan JB, Powell MA, Goodfellow PJ, Pollock PM. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Research 2008; 68:(17). September 1, 2008 .

Funding from the V Foundation for Cancer Research supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.

The Translational Genomics Research Institute (TGen) is a non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process.