Ovarian SPORE Projects

The Ovarian SPORE's major research themes center on pathogenesis (immunosuppression) and translational approaches to improve clinical outcome including novel treatments in Poly(ADP-ribose) polymerase (PARP) inhibition ± topotecan, flavopiridol-cisplatin, and the measles virus; as well as improved prediction of outcome in the immunosuppression project. Each project is co-directed by interdisciplinary investigative teams including basic scientists, population scientists, and clinician scientists with expertise in conducing translational research. The translational objectives of the four research projects in the Mayo Clinic Ovarian SPORE are highlighted below.

Project 1: Poisoning of PARP and topoisomerase I to treat ovarian cancer

Principal Investigators: Scott Kaufmann, M.D., Ph.D., and Harry Long, M.D.

Drs. Kaufmann and Long, working with other clinicians and researchers including Fergus Couch, Ph.D., and Guy Poirier, Ph.D., of Laval University, are investigating the ability of the PARP inhibitor ABT-888 to interact with topotecan, an active agent in ovarian cancer. This interaction appears to increase the effectiveness of topotecan. While ovarian cancers with decreased BRCA1 or BRCA2 function caused by mutations in these genes are known to be exceptionally sensitive to PARP inhibition, the effects of the combination of ABT-888 and topotecan are observed in cells with wild type BRCA1/2, as well.

This project will investigate the mechanism of the interaction between PARP inhibitors and topotecan, take this combination into the clinic with a Phase I-II trial in ovarian cancer, and examine clinical trial participants' samples for markers of response to treatment. These studies will make extensive use of the Biospecimens and Patient Registry Core, and the Biostatistics Core.

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Project 2: Mechanisms of immunosuppression in ovarian cancer

Principal Investigators: Keith Knutson, Ph.D., and Ellen Goode, Ph.D.
Co-Principal Investigator: Lynn Hartmann, M.D.

In this population science project, Drs. Knutson, Goode and Hartmann, along with Karin Hedin, Ph.D., and Haidong Dong, Ph.D., are assessing inherited genetic variations in immune system genes. Although ovarian cancer is known to be an immunoreactive malignancy, it has eluded most immune-based strategies designed to treat the disease. The underlying hypothesis of this project is that immunosuppression contributes to the growth and development of ovarian cancer.

The researchers are using both population science approaches and basic immunologic studies to understand how different cells and proteins contribute to the immunosuppressive microenvironment independently and as part of a network. The initial stages of the project will use the Biospecimens and Patient Registry, Biostatistics, and Animal Models cores. Validation steps of the project will proceed with collaborators in the Ovarian Cancer Association Consortium, an international group of scientists dedicated to understanding the role that genetic polymorphisms play in ovarian cancer.

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Project 3: Optimizing measles virotherapy in the treatment of recurrent ovarian cancer

Principal Investigators: Evanthia Galanis, M.D., and Kah-Whye Peng, Ph.D.

This investigative team has performed the first clinical trial in humans testing the safety of intraperitoneal administration of the measles virus. After the virus enters ovarian cancer cells that express native measles virus receptors, expression of viral proteins causes the infected cell to fuse with neighboring cells to form multinucleated syncytia of 100-1,000 cells. The cells in the syncytia are not viable.

Drs. Galanis and Peng, along with co-investigator Dr. Long seek to improve this therapeutic strategy by incorporating a therapeutic transgene, delivering the virus intravenously, and by investigating whether cellular carriers or immunosuppressive agents can blunt anti-measles immune responses. The project relies on the Animal Models, Biostatistics, and Biospecimens and Patient Registry Cores of the Ovarian SPORE.

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Project 4: Flavopiridol reverses platinum resistance in ovarian cancer

Principal Investigators: Keith Bible, M.D., Ph.D., and Viji Shridhar, Ph.D.

Extensive studies by Drs. Bible and Shridhar, along with co-investigator Dr. Kaufmann, have shown that flavopiridol, a semi-synthetic small molecule that inhibits cyclin dependent kinases, enhances intracellular cisplatin accumulation, platinum-DNA adducts, and platinum sensitivity in ovarian cancer cell lines. Flavopiridol has also been shown to interact with DNA and inhibit signal transducer and activator of transcription 3 (STAT3)-mediated transcription of survival factors.

Based on promising preliminary data from a Phase II trial of flavopiridol and cisplatin in women with platinum-resistant ovarian cancer, this project is exploring the molecular mechanisms by which flavopiridol enhances cisplatin's effects and explore strategies to improve these results even further. The study relies upon the Biospecimens/Patient Registry, Animal Models, and Biostatistics cores.

Read more about Ovarian SPORE Project 4