Our Science – Kohn Website
Elise C. Kohn, M.D.
Dr. Kohn serves on numerous NIH and NCI committees, and is the newly elected Chair of the Integration Panel of the Department of Defense Ovarian Cancer Research Program. Dr. Kohn is a participating member and protocol investigator in the Gynecologic Oncology Group, judges the Fellows Award for Research Excellence competition yearly, and is the co-Chair of the Breast and Gynecologic Malignancies Faculty. She was recognized with the NCI Diversity Award and Mentor of Merit Award in 2007. Dr. Kohn was elected a Fellow of the American Association for the Advancement of Science.
CONVERGENCE OF SURVIVAL, PROLIFERATION, AND INVASION SIGNALS AS TRANSLATIONAL MOLECULAR TARGETS: Discovery and candidate identification approaches applied to ovarian cancer
Our working hypothesis posits there is a convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment and these events can be efficiently targeted therapeutically. This Section focused previously on the role of Ca++ as a regulator of gene expression and cellular physiology in pathways of angiogenesis and ovarian cancer (ovca). We characterized the calcium influx inhibitory drug, CAI, in the laboratory and the clinic and have used it as a tool to regulate signaling events in the tumor and endothelial cell. We have used global unbiased search technologies (transcriptomics and proteomics) to identify proteins important in tumor and endothelial cells. We have identified candidate genes upon which we are now focusing our study. These contribute to ovca pathophysiology (CAIR-1/BAG-3, Granulin-Epithelin Precursor [GEP]), and are now undergoing biochemical, molecular, and biological evaluation. We have developed models (in vitro, mouse, and Drosophila) with which to dissect the role of these candidates in tumorigenesis and invasion to develop an integrated model of the physiology and pathophysiology of the epithelial stromal interface in ovca. We are studying the signal transduction function of CAIR-1/BAG-3, identified as differentially expressed downstream of calcium influx blockade. These studies are being driven by dissection of protein functional domains and their cognate partners. We identified PLC-gamma and Hsp70 as partner proteins for CAIR-1 and have generated and studied mutants to regulate their activity. We have demonstrated that the BAG domain is important in regulating survival of polyubiqutinated proteins in response to geldanamycin exposure. Xenograft studies with the mutants demonstrate differential phenotypes and differential gene expression and invasion and motility studies are underway to characterize the mutants. In addition, we have cloned and are characterizing in vivo the Drosophila BAG protein that we have named, evil. Clinical correlative studies are investigating the role of CAIR-1 expression in ovca.
We have used both CGAP cDNA libraries we generated from microdissected ovca epithelium and novel proteomic technologies from which we identifed granulin-epithelin precursor, and demonstrated it to be a novel growth and survival factor in ovca. Further, we have shown that neutralization of GEP results in ovca apoptosis. GEP is produced in response to other known ovca growth factors, lysophosphatidic acid and endothelin. Futher studies now focus on regulation of GEP production in ovca through GEP partner proteins. Xenograft studies have been initiated to understand how modulation of GEP may result in changes in the patterns of spread and aggressiveness of GEP.
These systematic approaches will identify additional candidate genes and will provide the ability to unravel the network of signaling interactions of these candidate genes with pathways required for the cell to accomplish the steps necessary for survival, proliferation, and invasion and metastases. We will apply discovery and candidate selection to survival, angiogenesis, and invasion model systems in place in our laboratory that allow us to efficiently query tumor/host interactions. Findings will be applied to clinical samples where differential invasiveness and autonomy of the tumors have been evaluated and linked to patient outcomes. This integrated approach has and is expected to continue to lead to identification of novel biomarkers and therapeutic targets. Together, these two lines of investigation have yielded new mechanistic information into the signaling underlying progression and survival in carcinomas, focusing on ovarian cancer.
This page was last updated on 6/7/2013.