|Harry Drabkin, M.D.|
Robert Gemmill, Ph.D.
|Dr. Drabkin graduated with a BA degree in Performance in 1970. He received his M.D. degree from the University of Kansas in 1977. He then went on to complete his internship and residency in Internal Medicine at the University of Cincinnati. Dr. Drabkin completed his Fellowship in Hematology-Oncology at the University of Colorado in 1983.||Dr. Gemmill received his BA degree (Magna Cum Laude, with Honors) in Biology with a minor in Chemistry from the University of Connecticut in 1975 and his Ph.D. in Biochemistry from Cornell University in 1981. He underwent post-doctoral training in Molecular Biology for one year at Cornell University and for a second year at Arizona State University in Molecular Genetics.|
Hollings Cancer Center
|Drew Kornhauser||Research Technician|
|Joyce Nair-Menon, Ph.D.||Research Specialist|
|Patrick Nasarre, Ph.D.||Assistant Professor|
|Stefanka Spassieva, Ph.D.||Research Assistant Professor|
Dr. Drabkin’s research is centered on genes and pathways that impact lung and kidney cancer, focusing on tumor suppressor genes and their function. In lung cancer, the focus is on the secreted molecule, SEMA3F, which is frequently downregulated or lost in lung cancer. Dr. Drabkin and colleagues have shown that restored SEMA3F blocks tumor formation by lung cancer cells in vivo. Mechanistically, this involves downregulation of activated integrin signaling. In addition, studies have shown that ZEB, the major transcriptional repressor, downregulates SEMA3F and E-cadherin in lung cancer. Developing SEMA3F as a therapeutic modality, along with continued efforts to elucidate the effects of ZEB1, was the focus for renewal of their lung cancer SPORE project. Drabkin and Dr. Robert Gemmill are also working on a unique gene discovery. Through chromosome mapping, they identified the TRC8 gene in a family with hereditary kidney cancer. TRC8/RNF 139 is an E3-uboquitin ligase that has tumor suppressor and growth inhibitory activity that interacts with regulatory components of endogenous lipid and protein biosynthesis. TRC8 promises novel and key insights into the pathogenesis of kidney cancer. This gene also links lipid and protein homeostasis with growth control in kidney tumors. In addition, Dr. Drabkin has carried out extensive analysis of HOX gene expression patterns in acute myelogenous leukemia (AML) and identified a common expression signature for favorable AMLs.
Genetic alterations in cancer reveal a complex tapestry of pathways contributing to the malignant phenotype. Identification of novel tumor suppressor genes has elucidated processes as diverse as nerve growth cone guidance, epithelial-mesenchymal transition (EMT), ubiquitin conjugation, and lipid biosynthesis, as contributors to cancer development. Dr. Gemmill, together with Dr. Harry Drabkin, has found that E-cadherin is regulated in lung cells by the WNT signaling pathway, helping to establish and maintain the epithelial state. Lung tumors inhibit E-cadherin primarily through activation of ZEB1, which induces an EMT, invasive behavior and metastasis, along with resistance to inhibitors of the epidermal growth factor receptor. Identifying the targets of ZEB1 in lung tumors, elucidating the mechanism of ZEB1-induced drug resistance, and discovering new agents that may interfere with ZEB function are current experimental challenges. The EMT process and ZEB1 also modulate expression of the neuropilin-semaphorin axis. Understanding the contribution of these targets to migratory and invasive behaviors of lung cancers is a critical area of investigation.
A familial form of kidney cancer led to the identification of another novel tumor suppressor gene, TRC8/RNF139. TRC8 encodes an ERresident, multi-membrane spanning E3-ubiquitin ligase whose coding sequence was disrupted by a constitutional translocation in these families. In kidney cells, TRC8 blocks growth and arrests cells at G2/M, effects which are dependent upon an ubiquitylationcompetent RING domain. Remarkably, TRC8 protein levels are regulated by sterols and interact with two components of the cholesterol and lipid homeostasis mechanism, INSIG and SREBP. The precise mechanism(s) regulating TRC8 levels and its impact on lipid homeostasis and cancer development are current areas of investigation. One focus is identification of ubiquitylation targets, which has led to the discovery that TRC8 ubiquitylates and destabilizes the important immune system molecule ,MHC class I.