Research Yields Potential Target for Epithelial Ovarian Cancer Treatment

SAN DIEGO, CA (April 7, 2014)—Epithelial ovarian cancer is often referred to as a silent killer: Advanced-stage disease has a low survival rate, and in a vast majority of patients, the disease has already spread to other organs at the time of diagnosis because the symptoms are difficult to identify. Fox Chase Cancer Center researchers who are investigating the biological mechanisms behind metastatic epithelial ovarian cancer recently found that an enzyme called focal adhesive kinase (FAK) can play a critical—and previously unstudied—role in the growth and spread of the disease. The research will be presented on Monday, April 7 at the AACR Annual Meeting 2014.

FAK, which is also known as PTK2, helps cells adhere to each other and to other substances  It also mediates multiple normal processes that are often disrupted or corrupted in cancer cells, including cell growth, proliferation, survival, angiogenesis and migration. Previous research suggests FAK may play an important role in many types of cancer, including breast, cervical, brain and others, and the drug has been investigated as a diagnostic marker or even a therapeutic target in invasive or advanced breast cancer.

Research done by Fang Xiao, MD, PhD, Research Associate at Fox Chase, and Denise Connolly, PhD, Associate Professor at Fox Chase, led them to identify the importance of FAK in ovarian cancer, but the enzyme wasn’t part of their investigation at the beginning.

They initially set out to study a transcription factor called STAT3, known to be important in the proliferation and survival of cells. Previous studies suggest STAT3 also plays a role in the migration and invasion of tumor cells, and it has been observed in both primary tumors and human ovarian cancer cell lines. But STAT3 itself is not a promising candidate for targeted therapy, Connolly says, because, as a transcription factor, it lacks catalytic activity that could be blocked directly.

“At the beginning of our experiment we manipulated cells to see how STAT3 played a role in ovarian cancer,” says Xiao.

Suspecting they could find a related molecule to inhibit the protein’s actions in cancer cell lines, Xiao and Connolly conducted laboratory experiments to better understand the underlying biology. They began by trying to target STAT3 by inhibiting Src, a well-known non-receptor tyrosine kinase that plays a role in tumor cell migration and invasion. It also activates STAT3. The researchers found that when they blocked the activity of either STAT3 or Src, the migration of ovarian cancer cells diminished. When they blocked Src alone, they expected to see STAT3 activation drop off, too, but that’s not what happened.

“Surprisingly, it increased STAT3 activity,” says Xiao. That response suggested the STAT3 protein had some other way to become activated.

The researchers then studied proteins that interacted with STAT3 within focal adhesions, the molecular complexes where cells attached to the extra-cellular matrix. These experiments, which used drug interactions and a RNAi-mediated approach, demonstrated that STAT3’s activation both at focal adhesions and in the nucleus depended on FAK.

“We showed that FAK inhibition resulted in dramatic reduction or inhibition of STAT3,” which suggests targeting the enzyme could be a way to also inhibit the action of STAT3 in epithelial ovarian cancer.

“What's unique about Xiao’s study is that focal adhesion kinase so far hasn't been shown to activate STAT3 in solid tumors,” says Connolly, whose research focuses on understanding the biological underpinnings of epithelial ovarian cancer. “My laboratory in general is interested in any pathway that could contribute to ovarian cancer and progression, particularly pathways that could be exploited as therapeutic targets.”

Evidence from lab experiments suggests the kinase is a potential target for therapy.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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