Quickening the pace from bench to bedside

Just eight months after scientists in a lab on Cedar Street devised a new approach for treating ovarian cancer, clinical trials began in June at Yale’s gynecologic oncology clinic a block away on Howard Avenue. The experimental protocol is among four clinical trials under way in the Discovery to Cure program—an informal collaboration that began in the late 1990s and took on its new name in June. The program is designed to speed progress in detecting and treating women’s reproductive cancers through an unusual alliance of basic researchers, clinical investigators and nurses. The clinicians report directly back to the laboratory scientists, who incorporate findings into planning for new research.

The latest study uses the anticancer drug phenoxodiol to sensitize ovarian cancer cells before chemotherapy. Phenoxodiol, developed in Australia for possible use as a treatment for cancer and cardiovascular disease and as an anti-inflammatory, was among about 200 compounds screened for their anticancer properties by Gil Mor, M.D., Ph.D., an associate professor of obstetrics, gynecology and reproductive sciences, and his team. Phenoxodiol attacks a problem common in cancer cells: normal cell death is blocked, allowing cells to proliferate and form tumors. The drug, which affects intracellular signaling, helps activate caspases, the enzymes that regulate cell death. Mor said the intravenous treatment renders the cancer cells up to 100 times more vulnerable to the chemotherapy drugs cisplatin and paclitaxel. This sensitization allows doctors to prescribe lower doses of chemotherapy, reducing the damage to healthy cells that can cause debilitating side effects.

“Our new approach was not to develop new cytotoxic drugs but to find something specific that will remove those blockers [to cell death] in the cancer cell without affecting normal cells,” said Mor.

Mor is encouraged by how quickly discoveries about molecular pathways are being tested in patient trials. “All these findings are immediately brought to the clinic,” he said. “This is quite unusual. Findings in the lab can take years to get to the clinic.”

Once his group developed its therapy, Mor said, it took about eight months to gain approval from the medical school’s institutional review board, the Human Investigation Committee, and then recruit 40 patient volunteers to take part in a combined Phase I/Phase II trial that tests both safety and effectiveness. Mor said the researchers save time because lab investigators have immediate access to tissue samples from cancer patients and a clinical population that allows them to launch a trial quickly. In one instance in 1999, he noted, a basic science lab without close ties to a clinic couldn’t get an ovarian cancer drug into clinical trials until 2003.

“The time cut is years,” said Mor’s clinical colleague, Thomas J. Rutherford, Ph.D., M.D., FW ’94, associate professor of obstetrics and gynecology. Rutherford said the researchers learn not only from each other but also from others on the team, including nurses, who have insights into man-aging clinical problems. “If you’re willing to talk and listen—and I’d say listening is most important—there’s a tremendous amount of information people will give you.”

The Discovery to Cure program sponsors research on four gynecological cancers: ovarian, cervical, uterine and breast.

Of these cancers, ovarian cancer poses a particularly daunting problem, because it is rarely discovered in its early stages. When diagnosed in the advanced stages, the five-year survival rate ranges from 20 to 40 percent. Mor and Rutherford are working to develop a blood test to detect the cancer early, collaborating with Peter E. Schwartz, M.D., HS ’70, the John Slade Ely Professor of Obstetrics and Gynecology.

Rutherford is optimistic. “We have identified what we think to be protein markers for early ovarian cancer,” he said. “If it proves to be true, it will be a good thing.”