Combating Ovarian Cancer

January 1, 2015

Translational research supporting personalized medicine 

Innovations in Cancer - Winter 2015 - View Full PDF

Analisa DiFeo, PhD

Assistant Professor of General Medical Science – Oncology, Case Western Reserve University School of Medicine

The Gynecologic Oncology Translational Research Working Group (GOTRWG) at Case Comprehensive Cancer Center was created to ensure translation of laboratory discoveries into a better understanding of the molecular defects that underpin epithelial ovarian cancer (EOC).

We have assembled a dedicated multidisciplinary group that includes gynecologic oncologists, pathologists, basic scientists, translational research scientists, information scientists and clinical fellows. I work especially closely with Steven Waggoner, MD, Division Chief, Gynecologic Oncology, UH Seidman Cancer Center; and Associate Professor, Obstetrics and Gynecology, Case Western Reserve University School of Medicine.

An important aspect of the program is our extensive gynecologic tumor biobank, one of only a few in the United States, which supports patient care and translational research.

GYNECOLOGIC TUMOR BIOBANK

After a patient has given informed consent and the surgeons have removed an ovarian or uterine cancer, the tumor sample is rushed from the operating suite to our tissue bank. There, researchers divide the sample, freeze a portion and start both a primary cell culture line and, in a mouse model, a patient- derived xenograft (see "Mouse Avatars" sidebar). A serum sample from each participant is also stored.

In its nearly two years of existence, the biobank has collected more than 175 tumor samples.

FOSTERING PATIENT-FOCUSED RESEARCH 

To support patient care, GOTRWG researchers test each mouse xenograft (avatar) with the chemotherapy that the patient is receiving. If the tumors recur or do not respond, this is a red flag for the clinician that may indicate a patient whose tumor needs more careful monitoring. The avatar can then be tested with other FDA-approved drugs and drugs being developed as part of the translational research program. If that patient's tumor does recur, then the clinician has advance information about which other FDA- approved drugs worked in the avatar.

One caution is that the avatar may not always adequately predict the behavior of a patient's cancer. While the avatar will reflect the sample received in the biobank, that sample may not always represent the most aggressive part of a patient's tumor.

UNDERSTANDING OVARIAN CANCER

One of GOTRWG's key goals is to develop ways to diagnose ovarian cancer at an early stage. Currently, only 10 percent of these cancers are detected at stage I. In my laboratory, we identified a microRNA biomarker, miR-181a, and discovered that it is a molecular driver of EOC. Because we have access to the biobank tumor samples, we were able to determine that this microRNA is associated with tumor recurrence and that it is highly expressed in cancer stem cells isolated from the patients' tumors.

We showed that elevated levels of miR-181a are associated with chemotherapy resistance and disease progression. We also determined that miR-181a blocks the expression of the Smad7 gene, which shuts down the TGF-B signaling pathway, a potent inducer of metastases. We are now looking for small molecules that can block the interaction between miR-181a and Smad7, stop TGF-B activation and, hopefully, prevent the spread of ovarian cancer.

For more information about the Gynecologic Oncology Translational Research Working Group at Case Western Reserve University and its biobank program, contact me at analisa.difeo@case.edu.

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