Funded Research
An ESUN Announcement
August 15, 2009: The Liddy Shriver Sarcoma Initiative is funding a 1-year $25,000 research study, "A Preclinical Mouse Model for Targeted Therapy in Uterine Leiomyosarcoma," that is being undertaken by principle investigator Sandra Orsulic, PhD, Associate Professor in the Women’s Cancer Research Institute at the Cedars-Sinai Medical Center and her co-investigator, Beth Kartan, MD, Director, Women’s Cancer Research Institute at the Cedars-Sinai Medical Center.
The funding for this grant is made possible, in part, by donations made by the family and friends in memory Suzanne Kurtz and Teal Harris, who lost their lives to leiomyosarcoma, and by generous donations made by the family and friends of Jim Hauser, who is fighting leiomyosarcoma. Here is a summary of Prof. Orsulic’s research proposal:
Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy that has a low survival rate. Currently, there is no effective treatment for ULMS. We have generated a mouse model of ULMS and demonstrated that the loss of BRCA1 function accelerates the progression of these tumors. Consistent with the hypothesis that BRCA1 plays a role in ULMS, we have shown that the BRCA1 protein is absent in 36% of human ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS. To this end, we will determine the mechanism of BRCA1 downregulation in human tumor samples and test the efficacy of BRCA-targeted therapy in a mouse model of ULMS.
In order to determine the mechanism of BRCA1 downregulation in human ULMS, samples without detectable BRCA1 expression and samples with BRCA1 expression will be analyzed for BRCA1 germline and somatic mutations, LOH, and promoter methylation. We expect that BRCA1 will be silenced by one of the above mechanisms in those ULMS samples that do not show detectable BRCA1 protein expression.
Our mouse models of BRCA1-wild type and BRCA1-deficient ULMS provide unique experimental systems for the evaluation of therapies that target the BRCA1 pathway. One novel treatment that takes advantage of the inability of BRCA1-deficient cells to repair DNA damage is the inhibitory effect of poly(ADP-ribose) polymerase-1 (PARP-1). We will test whether the recently developed water soluble, orally available, small molecule PARP-1 inhibitor, GPI 21016-C9, is effective in reducing tumor burden in BRCA1-wild type and BRCA1-deficient mice. We anticipate that GPI 21016-C9 will be more effective in reducing tumor burden in BRCA1-deficient ULMS than in BRCA1-wild type ULMS. Since PARP-1 inhibitors are highly selective in targeting tumor cells, this therapy is presumed to be relatively safe and with minimal side-effects.
Future Directions: The results of these studies could provide justification for a clinical trial for ULMS patients with a novel BRCA-targeted therapy based on PARP-1 inhibitors.
You can learn more about this study in the article "A Preclinical Mouse Model for Uterine Leiomyosarcoma," by Yevgeniya J.M. Ioffe, MD , Deyin Xing, MD, PhD, Paul-Joseph Aspuria, PhD , Beth Y. Karlan, MD, and Sandra Orsulic, PhD, which appears in the August 2009 issue of ESUN.
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