My research focuses on the pathogenesis of brain tumors. In particular, we are interested in the cellular and molecular mechanisms that underlie the initiation and progression of glioma, which is the most common and deadly brain tumor in adults. TGF-ß is a multifunctional cytokine that has been implicated as a tumor promoter in gliomagenesis, perhaps through effects on tumor cell proliferation or migration. TGF-ß signaling may also promote angiogenesis and suppress immune function. Emerging data suggest that a subpopulation of cells within human high grade glioma has stem cell-like properties, and that TGF-ß family members regulate their differentiation. The identification of these cells in glioma uncovers a potential target for novel and effective therapies for this devastating disease. Using transgenic mouse models of glioma, we are studying the effects of silencing TGF-ß signaling in tumor cells through deletion of the TGF-ß type II receptor. In addition, using primary cell cultures and orthotopic transplant techniques, we are investigating the potential role of endogenous CNS stem cells in glioma formation.
Dr. Abel graduated Magna Cum Laude from Boise State University in 1989 with a B.A. in Psychology. He then received a Masters in the Program in Neuroscience at the University of Arizona in 1991. He furthered his education with a Ph.D. in the Program in Neuroscience at the University of Arizona in 1999 and also received an M.D. from the University of Arizona College of Medicine in 2001. Dr. Abel completed his residency from 2001-2003 in Anatomic Pathology at The Johns Hopkins Hospital, which is where he also was a Neuropathology Fellow from 2003-2005. He joined Vanderbilt University Medical Center's Neuropathology Division in the Department of Pathology as an Assistant Professor in 2005. In 2006, he was awarded a Vanderbilt Physician Scientist Development Award entitled "TGF-ß in CNS Development, Neoplasia and Inflammation." Dr. Abel also serves on the Translational Research Committee for the Pathology Department.
Advanced renal cell carcinoma (RCC) remains a challenging disease to treat effectively given its resistance to traditional chemotherapeutic approaches. Recent advances in targeted therapies have dramatically changed the paradigm for managing this disease, however these approaches tend to produce stable disease or partial responses, whereas complete eradication of disease (or “cure”) remains exceedingly rare. New and innovative approaches to treating this disease are still critically needed.
Apo2 ligand/Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is one of a family of ligands (including TNFa and Fas/CD95 ligand) that can induce programmed cell death, or apoptosis, by binding to cell surface death receptors. TRAIL is particularly relevant to cancer therapeutics since it has been found to preferentially induce apoptosis in malignant or transformed cells while sparing normal cells. This makes it a potentially powerful tool in treating a variety of malignancies. Indeed, TRAIL-related therapeutics are in early clinical trials in patients with advanced malignancies. The focus of my research is to better understand the mechanisms of TRAIL-mediated apoptosis in genitourinary malignancies with a strong emphasis on RCC. There are several ongoing projects in the lab.
For many years interferon alpha (IFNa) was a mainstay of therapy for advanced RCC. IFNa is known to modulate TRAIL-mediated apoptosis in a variety of cell types. Our work has shown that IFNa and TRAIL can act synergistically to induce cell death in RCC cells representing a potentially powerful approach to treating RCC. We are actively investigating the molecular mechanisms underlying this synergy.
We are constructing a 300 patient, annotated tissue microarray of RCC tumor tissue with matching normal kidney parenchyma with long-term patient follow-up and extensive linked clinical data. Once constructed, we plan to use this to test the prognostic significance of changes in a variety of molecular markers in patients with RCC. The first planned markers will be TRAIL and its cognate Death Receptors, with more planned depending on the findings from our other work.
Dr. Clark received his undergraduate degree at Cornell University and graduated from Harvard Medical School in 1994. He went on to complete his urologic residency at the Cleveland Clinic Foundation followed by a fellowship in urologic oncology at the University of Southern California, which was completed in 2002. His first faculty appointment was at Wake Forest University, during which time he was awarded a five year K08 NCI Mentored Training Grant on mechanisms of TRAIL mediated apoptosis in renal cell carcinoma. He joined the faculty here at VUMC in 2006 and is currently an Assistant Professor of Urologic Surgery. He currently divides his time between clinical activity and his molecular biology laboratory, which is located within his mentor's lab, Dr. Hal Moses in the Vanderbilt Ingram Cancer Center.