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. A series of endpoints related to the NFKB pathway are under collaborative investigation in the GCWG with Dr. Annunziata of the MOB. - Racial Disparities in EC: Dr. Annunziata has the lead on this project and has continued her investigation of the role of NFKB across African American and caucasian (C) women with EC, and across different EC histologies. That there is increased frequency of uterine papillary serous histology EC in African American women and also increased PTEN mutations supports these tenets. 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. - The role of progranulin as a predictor of progression-free survival in ovarian cancer. This was developed as a thesis project for WRNMMC GynOnc fellows 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. 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 are suggestive of a relative relationship between serum and plasma PRGN concentrations. Subsequently, PGRN concentrations were measured in two blinded sets of serum samples obtained collaboratively from Duke University, Dr. L. Havrilesky and Karmanos Cancer Center, Dr. M. Tainsky. Preliminary results indicate that the serum measures are not as robust as plasma in their relationship to patient progression but still trend in that direction. This may be confounded by preanalytical variables in the samples received, in that at least one sample set was from previously frozen and thawed samples. In addition, a pilot study of serum from newly diagnosed patients was undertaken. No clear predictive relationship of PGRN concentration and response to therapy was observed in this pilot sample set. As above, this sample set has looser preanalytical criteria than those used previously by this group. Dissection of the role of PGRN as a survival factor in ovarian cancer: This study was a thesis hypothesis of a WRNMMC GynOnc fellow. A previous 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 have not been fruitful in demonstrating the interaction of BAG4 and TNFR1/2 using ovarian cancer cell systems and this project has been terminated. Clinical interactions have moved forward with request for clinical priviledges for Drs. Hamilton and Stany so that they participate in the Women's Cancers Clinic. Further, per discussions with Drs. Hamilton and Stany, consideration is being made for the fellow on WRNMMC rotation to rotate into the Monday WCC clinic. SinceDr. Romano was working in the laboratory and assisted on a preclinical project, this would allow her to have continuity with protocol development and activation.
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