“We can put most patients that have ovarian cancer into complete remission. We can get more than 80% of patients to the point where they clinically have no measurable disease. That’s with standard chemotherapy and surgery. The problem is, these cancers come back.” Dr. Robert Edwards
Ovarian cancer is stealthy. In the early stages, it has few symptoms, and the ones that do occur are vague and easily overlooked. Routine pelvic exams, ultrasounds and blood tests are powerless to detect it, and Pap tests aren’t designed to find it. As a result, only about 20% of ovarian cancers are detected early, when treatment is most effective.
That’s a major reason why ovarian cancer accounts for more deaths than any other cancer of the female reproductive system, according to the American Cancer Society. In 2017, about 22,440 women will be newly diagnosed with ovarian cancer. About 14,080 of these women will die of the disease.
Dr. Robert Edwards, Chair of Obstetrics and Gynecology Reproductive Services at Magee-Womens Hospital of UPMC and primary investigator at Magee-Womens Research Institute, compares the disease’s rapid spread to shaking a snow globe. Cancer cells cascade over nearby organs and attach to them, setting the stage for aggressive treatment. “We can put most patients that have ovarian cancer into complete remission,” he says. “We can get more than 80% of patients to the point where they clinically have no measurable disease. That’s with standard chemotherapy and surgery. The problem is, these cancers come back.” Edwards says that most patients, once they develop ovarian cancer, spend over 50% of the rest of their lives in treatment. “Then they end up dying of the disease, but not before the therapies themselves cause a lot of morbidity and affect their quality of life.”
“Depending on the biology of the patient or the cancer itself, [the seeds left by the cancer reactivate] one to four years later. Now we’re looking at developing specific immune and targeted treatments that completely eliminate those seeds.” Dr. Robert Edwards
Magee is a leader in using chemotherapy infused directly into the abdomen to boost 5-year survival rates as high as 60% for even the most advanced ovarian cancers. But eventually the cancer adapts to chemotherapy. “What we can’t do right now is cure women,” says Edwards.
But a cure could be just over the horizon.
Dr. Edwards and his fellow researchers are working hard to find a more effective way to completely eliminate the possibility of ovarian cancer returning. “We think it has to do with the small seeds left behind after you prune the cancer back through chemotherapy,” he explains. “Depending on the biology of the patient or the cancer itself, they reactivate one to four years later. Now we’re looking at developing specific immune and targeted treatments that completely eliminate those seeds.” There are many conditions that may lead to ovarian cancer—genetics, family history, proliferative ovarian cysts, and uterine tubal precancerous conditions. However, one in particular that Dr. Edwards is studying is endometriosis. “Endometriosis is an extremely common and largely benign condition,” he states. “The majority of women who have endometriosis don’t develop ovarian cancer, but there’s a small percentage that do. We believe what promotes the progression into a cancer state is driven by the nature of the immune system’s inflammatory response and how the host responds to the inflammation.”
While we think of our immune systems as helping us fight disease, Dr. Edwards points out that it isn’t always the case. “Sometimes it actually promotes it,” he says. As the cancer cells develop, the surrounding stroma and inflammation may actually lead to cancer in some individuals. “Some cancers have an inflammatory response that’s a precondition in developing cancer,” Edwards said.
One prestigious grant. Two promising clinical trials.
Dr. Edwards oversees a renowned Specialized Programs of Research Excellence (SPORE) grant from the National Institutes of Health to develop methods to prevent, treat, and cure ovarian cancer with promising immunotherapies. Shared with Roswell Park Cancer Institute in Buffalo, NY, this elite award is one of only four in the country dedicated to ovarian cancer and immunotherapy.
The SPORE grant supports two on-going clinical trials examining combinations of immunotherapy and chemotherapy for advanced primary ovarian tumors and tumors that were treated but recurred.
One of the trials centers around an important advance in compounds called PARP inhibitors, short for poly ADP-ribose polymerase. PARPs are enzymes in the body that help repair DNA when it becomes damaged. Using PARP inhibitors can keep cancer cells from repairing their damaged DNA, causing them to die. “For a tumor to metastasize, it has to mutate,” states Edwards. “That makes them vulnerable to PARP inhibitors. They make the gene system go haywire and that makes the cancer cells die. It’s an exciting new type of therapy, and it is delivered through pills so patients don’t have to come in for infusions like chemotherapy. They’re very specific, so they don’t cause the same kind of side effects.”
Immune therapies are the second area of Dr. Edward’s research. “These therapies take advantage of the known infl ammation around the cancer,” begins Edwards. “They activate the immune system to turn it against the cancer that’s developed.” Highlighted on the cover of the Journal of Science as the advancement of the year in 2013, immune therapies have been well adopted for melanoma, lung and bladder cancer, but they’ve just recently been thoroughly evaluated in women’s cancers.
“There are new and exciting results coming out,” states Edwards. “Our group has been at the center of that for the last five years, including Dr. Anda Vlad, a researcher in our lab who has developed a mouse model to look at the best way to give these immunotherapies. We then give trials to humans based on the data from the mouse models, adapting the clinical trials for the best possible schedule and dose for patients. We’ve been working as a team on this for the last several years.”
Edwards and his team are pioneering how to use immune therapies in combination with other agents, like chemotherapies. “We’re infusing the chemotherapy and immunotherapy directly into the ovarian cancer,” he says. “That’s very novel.”
They’re also looking at combining these therapies with a family of drugs called checkpoint inhibitors. Edwards explains, “If the immune system gets too excited by either cancer or an infection, it can become so active that it causes disease itself. So the immune system, like other systems in the body, has checks and balances. When the cancer develops, the immune system is activated and can play a role in the development of the cancer. When inflammation goes on for too long, checkpoint molecules become dominant. They subdue the inflammatory response thinking it’s hurting the body. We found that by using checkpoint inhibitors in certain cancers, we can turn the checkpoint process off and get clearance of the cancers. It’s like turning a breaker switch back on.” While checkpoint inhibitors have been used for years, Magee- Womens Research Institute has one of the few labs that is looking at them specifically in combination with intraperitoneal therapy, where the therapy is given directly into the cancer.
A rare program at a rare institution
With ten faculty members, Magee has the fourth largest gynecologic oncology program in the country. Recognized for cutting-edge therapies and approaches, it is also known for having specialists who work at other hospitals under the Magee-Womens Hospital of UPMC name to increase the positive outcomes in women’s cancer throughout western and central Pennsylvania. “The Magee brand for women’s cancer is a brand of excellence throughout Pennsylvania,” states Edwards.
“We feel that without the contributions we’re making in ovarian cancer, it’s entirely possible that ovarian cancer would be bypassed by the advances seen in other cancers like melanoma and lung cancer,” he adds. “Since we have such a strong program with strong translational, preclinical data clearly demonstrating that these new agents have a role in these cancers, it allows us to attract new funding for our patients with gynecology cancer.”
Dr. Edwards, along with Dr. Anda Vlad and Dr. Xin Huang, are developing innovative models and methods to study how the immune system responds to ovarian cancer, show how tumors spread throughout the body, explain why some cancers resist chemotherapy, identify biomarkers for earlier diagnosis, and test new therapies that may become more effective, personalized treatments.
Most of all, they hope and are uniquely positioned to find a cure for ovarian cancer.