The focus of the GCWG and the GCWG program laboratory is to support collaborative interactions within the GCWG, in part through the Breast and Gynecologic Malignancies Faculty. This laboratory structure also provides a scientific training base for WRNMMC gynecologic oncology fellows and collaborative opportunities with the GYN-COE laboratories. - Endometrial Cancer (EC): Continued efforts have been applied to understanding the proteomic and genetic basis 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. A newly standardized process for validating expression of the findings of genetic and proteomic analysis using tissue microarray (TMA) has been completed. A series of endpoints related to the NFKB pathway are under collaborative investigation in the GCWG with Dr. Annunziata of the MOB and including a WRNMMC gynonc fellow. - 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. The TMAs have been constructed incorporating informative cases to allow further examination of differential NFKB expression between African American and Caucasian women across papillary serous v. endometrioid cancers initially observed on gene arrays. Dr. Annunziata identified an NFKB signature in the gene array data that differs from her findings in ovarian cancer and myeloma, confirming further her description of tissue specific NFKB pathway actiation. She continues her collaboration within the GCWG to examine the NFKB protein levels by TMA. - 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/GYN-COE. - The role of progranulin as a predictor of progression-free survival in ovarian cancer. This was developed as a thesis project for a WRNMMC GynOnc fellow working in Dr. Kohn?s laboratory through the GCWG. PGRN, mutated in early onset frontotemporal dementia, functions as a gain-of-function protein when overexpressed in cancers and was reported by Dr. Kohn?s group as a survival protein in ovarian cancer;they also have shown that its binding partner, secretory leukocyte protease inhibitor, SLPI, is a survival protein in ovca. Serial plasma samples from the WCC pilot proteomics repository trial 00-C-0018 were examined and the PGRN concentration in initial blood sample ascertained at completion of chemotherapy was found to prognosticate early recurrence of disease. Examination of serum samples from the same dataset suggested a relative relationship of serum and plasma concentration;a prognostic value for early recurrence was observed in blind studies of serum samples obtained collaboratively from Duke University, Dr. L. Havrilesky. Two GCWG protocol concepts have been submitted to the GOG to advance this biomarker project: 1) pilot study of serum PGRN concentrations as predictive biomarkers for response to platinum therapy (Drs. Han/Kohn) to use pretreatment samples from GOG182;2) validation study of PGRN as a biomarker of early recurrence using samples from the control arm of GOG 212. ? Dissection of the role of PGRN as a survival factor in ovarian cancer: This study is the thesis focus of a WRNMMC GynOnc fellow. An arthritis model and knockout mouse study (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. BAG4, also known as silencer of death domain (SODD), binds to and maintains the monomerization status of TNFR1/2, thus prevention activation of the pro-apoptotic signal. Studies are now evaluating the interactive roles of BAG4 and PGRN through the GCWG umbrella and funding. Thus, these new studies may be important in elucidating a new targetable pathway.
Showing the most recent 10 out of 13 publications
