Health Research, Inc.
Grant: $335,208 - National Institutes of Health - Jun. 5, 2009
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Award Description: Summary description of the project that matches the Award: Our data indicate that the human prostate-derived Ets transcription factor (PDEF) plays an essential role in tumor suppression via downregulation of the expression of antiapoptotic protein survivin. Ectopic expression of PDEF in PDEF-negative breast cancer cells inhibits survivin expression as well as its promoter activity. In contrast, knockdown of PDEF in PDEF-positive breast cancer cells upregulates survivin expression along with increased cell proliferation in vitro, and increases xenograft tumor take rate and tumor growth in vivo. Importantly, patients with survivin-/PDEF+ tumor show better survival and less relapse than patients with survivin+/PDEF- tumor. Abnormal inhibition of apoptosis is known to be one of the critical steps for oncogenesis and malignant progression. Although the underlying mechanisms are not fully understood, evidence indicates that survivin plays an important role in the initiation, progression, metastasis and recurrence of cancer. Accordingly, many natural dietary components, including resveratrol, silibinin, sulindac, retinoid, selenium and vitamin D compounds that have cancer-preventive and therapeutic effects, downregulate survivin expression. PDEF appears to have an opposing role to survivin and likely via downregulation of survivin expression. It has been shown that PDEF inhibits cancer cell migration, invasion and growth. Based on these observations, we hypothesize that application of survivin and PDEF as interconnected biomarkers and targets to stratify patents with survivin+/PDEF- tumor and patients with survivin-/PDEF+ tumor may facilitate prostate cancer prognosis and personalized medicine. Two specific aims are proposed to test this hypothesis. In Aim 1, we will use a large cohort of prostate cancer tissues to determine survivin and PDEF expression status. Then we will analyze the association of survivin and PDEF expression status with patient survival, cancer metastasis and tumor relapse by appropriate statistical methods. In Aim 2, we will determine the methylation status in the PDEF gene in prostate cancer tissues. Then we will analyze the association of PDEF methylation status with the expression of PDEF and survivin. These studies may provide novel approaches for cancer prognosis and personalized medicine, by stratifying patients with survivin+/PDEF- tumor and patients with survivin-/PDEF+ tumor.
Project Description: First of all, the funds from this ARRA award enable our lab to keep two investigators to have a full-time research job. This award also supports a part of other 3 senior investigators? salary in 30%, 5% and 1%, respectively, and a statistician for about 5% of her salary through Consortium/Contractual agreement. In this quarter (6/8/09 -9/30/09), we did the following work that is related to the Award. Evaluate required Antibodies: After a careful evaluation of all the potential methods for determination of the expression of survivin and PDEF in a large cohort of human prostate cancer tissues, we selected immunohistochemistry (IHC) as a major method, because it is the most time and cost-effective approach. However, the key to obtain reliable data using this technology is the qualification of the antibodies. Therefore, we focused on testing on the available antibodies for survivin and PDEF for IHC application. Now, one of the antibodies for testing survivin is standing out and ready for the application while the other one antibody for survivin and the other two antibodies for PDEF are still in testing. Collect tissue DNAs for evaluating methods that can test methylation status of the PDEF gene: So far we have collected 27 prostate cancer tissue DNAs for methylation testing. We plan to collect up to 100 tissue DNAs for methylation testing of the PDEF gene in this project/award. Process prostate cancer tissue microarray (TMA)-relevant issues: We plan to use >700 prostate cancer tissue to test survivin and PDEF expression. Therefore, it is unrealistic to use regular IHC to test survivin and PDEF expression in such a large cohort. Instead, application of TMA appears to be the most time and cost-effective way to determine the expression of survivin and PDEF. Currently, we focus on obtaining enough TMA blocks for testing the 724 prostate cancer tissues. We have already identified the clinical and pathology coordinators.
Jobs Summary: The following job titles and job descriptions performed activities on this ARRA funded project . The mission of Roswell Park is to understand, prevent and cure cancer. The ARRA funding provided is to help realize this mission. HRI Scientist: Performs basic and applied research involving the formulation, conduct, analysis, interpretation and reporting of scientific investigations of phenomena or problems associated with the cause, cure, treatment, and prevention of cancer; conducts and may supervise phases of creative, original and independent scientific research studies in a specific field of assignment; defines problems and issues that enhances the development of scientific research programs; contributes significantly to a base of scientific knowledge; may teach in graduate education programs; generates peer-reviewed funding for Institute scientific research projects. Post-Doc Associate: Is a young researcher who has earned a doctorate and are beginning a scientific career. PBC Scientist: Performs basic and applied research involving the formulation, conduct, analysis, interpretation and reporting of scientific investigations of phenomena or problems associated with the cause, cure, treatment, and prevention of cancer; conducts and may supervise phases of creative, original and independent scientific research studies in a specific field of assignment; defines problems and issues that enhances the development of scientific research programs; contributes significantly to a base of scientific knowledge; may teach in graduate education programs; generates peer-reviewed funding for Institute scientific research projects. (Total jobs reported: 2)
Project Status: Less Than 50% Completed
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