The focus of the GCPRL is to support collaborative interactions between the WR-NMMC and the CCR gynecologic oncology investigators, in part through the Breast and Gynecologic Maliganancies Faculty. This laboratory structure also provides a scientific training base for WR-NMMC gynecologic oncology fellows and collaborative opportunties with the DOD/WHIRC laboratories. - Endometrial Cancer (EC): Continued efforts have been applied to understanding the protomic and genetics of endometrial cancers. Optimized procedures for analyzing small tissue specimens using laser capture microscopy techniques and mass spectrometry techniques have led to new publications describing the proteomics of EC. Consideration is now underway using newly standardized processes for validating expression of the findings of genetic and proteomic analysis using tissue microarray (TMA) and independent data sets. A series of endpoints related to the NFKB pathway are under collaborative investigation with Dr. Annunziata of the MOB/CCR. - Racial Disparities in EC: We have continued our focus of investigation of causes of racial disparities in outcome between African American and caucasian (C) women with EC. Data from the WRAMC group and others confirms that access to care, clinical trials, etc cannot explain the diversity in outcome, suggesting genetic/genomic and other effects. That there is increased frequency of uterine papillary serous histology EC in African American women and also increased PTEN mutations supports these tenets. TMAs have been constructed incorporating informative cases to allow further examination of this hyptheiss. Dr. Annunziata identified differential NFKB expression between African American and Caucasian women across papillary serous v. endometroiod cancers on gene arrays. She continues to collaborate within the GCPRL to examinine the NFKB protein levels on the TMAs - Obesity and EC: The relationship between obesity and EC is more significant than for any other cancer type and is leading identification of factors that may be applied to ovarian cancer. Elements of GCPRL collaborations continue to address these questions, lead by Dr. T. Conrads of USUHS/WHIRC. - The role of progranulin as a predictor of progression-free survival in ovarian cancer. This was developed as a thesis project for a WRAMC GynOnc fellow working in CCR through the GCPRL. PGRN, mutated in early onset frontotemporal dementia, functions as a gain-of-function protein when overexpressed was reported by our group as a survival protein in ovarian cancer. The MSS has also shown that its binding partner, secretory leukocyte protease inhibitor, SLPI, also is a survival protein in ovca. Pursuant to the hypothesis that either might predict or prognosticate ovca outcome, serial plasma samples from the WCC pilot proteomics repository trial 00-C-0018 were examined. The concentration of PGRN at the initial blood sample ascertained at completion of chemotherapy was found to prognosticate early recurrence of disease;plasma SLPI also was prognostic but was within the poorly defined range of normal. Change over time of PGRN concentrations did not provide clinical value. HE4 and clinical CA125 values were incorporated into the study. Their value was limited to change over time. Follow up validation of this is ongoing with ascertainment of serum samples for validation that serum PGRN will act the same way. Serum samples available within the GCPRL TDAA and also by MTA from Duke Univ. will be examined by the current GCPRL fellow to evaluate the reliability of serum PGRN and SLPI concentrations and as an initial validation study. PGRN is cleaved by neutrophil elastase into pro-inflamatory granulins that may or may not support the prognostication results, hence the revalidation of the initial findings. A protocol has been submitted to the GOG internal serum bank for samples for a powered validation study if the analyses show serum is a reliable PGRN test source. - Ongoing studies involving a WRAMC GynOnc fellow are examining a potential pathway through which PGRN may stimulate growth, invasion, and survival of ovca. A recent study using an arthritis model and knockout mice (Science 2011), demonstrated that PGRN is a high affinity ligand for the TNFR1/2 receptors, with higher affinity than TNFa in some cells. Balkwill et al have shown over 2 decades that TNFa is a potent growth and invasion factor for ovca and showed preliminary activity of TNFa inhibitory therapy. Thus, these new studies may be important in elucidating a new targetable pathway.
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