Physicians

Departments / Divisions

• Medicine / Medicine - Oncology
• Pharmacology & Cancer Biology

Address
Box 91004
Durham, NC 27708

Appointment Telephone
919-668-6688

Office Telephone
919-668-1352

Fax Telephone
919-681-6906, 919-613-5228

Training

• MD, Duke University School of Medicine, 1995

Residency

• Internal Medicine, Brigham and Women's Hospital (Massachusetts), 1995-1997
• Medical Oncology, Dana Farber Cancer Institute (Massachusetts), 1997-2000

Other Training

• PhD, Cell Biology, Duke University, 1995

Clinical Interests
Treatment of patients with colorectal and pancreatic cancer, with emphasis on phase 1 clinical trials and experimental therapeutics

Research Interests
Our laboratory focuses on transforming growth factor-ß (TGF-ß) superfamily signal transduction pathways, and specifically, the role of these pathways in cancer biology. The TGF-ß superfamily is comprised of a number of polypeptide growth factors, including TGF-βs, bone morphogenetic proteins (BMPs) and activin) that regulate growth, differentiation and morphogenesis in a cell and context specific manner. TGF-ß and the TGF-ß signaling pathway have a dichotomous role in cancer biology, as both tumor-suppressor genes (presumably as regulators of cellular proliferation, differentiation and apoptosis) and as tumor promoters (presumably as regulators of cellular motility, adhesion, angiogenesis and the immune system). This dichotomy of TGF-ß function remains a fundamental problem in the field both in terms of understanding the mechanism of action of the TGF-ß pathway, and directly impacting our ability to target this pathway for the chemoprevention or treatment of human cancers. Resistance to the tumor suppressor effects of TGF-ß is also a common feature of epithelial-derived human cancers (breast, colon, lung, pancreatic, prostate), however, mechanisms for TGF-ß resistance remain undefined in the majority of cases. TGF-ß regulates cellular processes by binding to three high affinity cell surface receptors, the type I, type II, and type III receptors. Recent studies by our laboratory and others have established the type III TGF-ß receptor as a critical mediator/regulator of TGF-ß signaling. Specifically we have demonstrated that regulating type III TGF-ß receptor expression levels is sufficient to regulate TGF-ß signaling, and that decreased type III receptor expression is a common phenomenon in human cancers, resulting in cancer progression. The role of the type III TGF-ß receptor and type III TGF-ß receptor-interacting proteins in TGF-ß signaling and cancer biology and the epithelial to mesenchymal transition that occurs in human breast, colon and pancreatic cancers are currently being investigated using a multidisciplinary approach.
TGF-ß and the TGF-ß superfamily signaling pathways also have an important role in vascular biology. Indeed, mutations in two endothelial specific TGF-ß superfamily receptors, endoglin and ALK-1 (a type I receptor in the TGF-ß family), are responsible for the human vascular disease, hereditary hemorrhagic telangiectasia (HHT), and mice which lack expression of these receptors are embryonic lethal due to defects in angiogenesis. In addition, endoglin expression is potently up regulated during tumor-induced angiogenesis. In endothelial cells, TGF-ß signals through the type I TGF-ß receptor (ALK-5) or through ALK-1, to mediate opposing effects on endothelial cell proliferation and migration. However, the role of endoglin in regulating the balance in signaling between these pathways is unknown. Our laboratory has identified the nuclear hormone receptor, LXR-ß, as a protein that binds to activated ALK-1, is phosphorylated by ALK-1 and modulates ALK-1 signaling,establishing a novel signaling pathway downstream of ALK-1. Investigations in our laboratory have also revealed important functions for the cytoplasmic domain of endoglin, which is highly homologous to the cytoplasmic domain of the type III TGF-ß receptor. Studies are currently underway to further elucidate the signal transduction pathway downstream from these receptors and to establish their role in regulating tumor-induced angiogenesis. The ultimate goal of these studies is the ability to target the TGF-ß pathway for the chemoprevention or treatment of human cancers.
As endoglin and the type III TGF-ß receptors are both "co-receptors," a class of poorly understood cell surface receptors that bind ligand but are not thought to signal directly, another focus for the laboratory is es

Industry Relationships and Collaborations (What's this?)

This faculty member (or a member of their immediate family) has a working relationship (i.e. consulting, research, and/or educational services) with the companies listed below. These relations have been reported to the health system leadership and, when appropriate, management plans are in place to address potential conflicts.

• Genentech, Inc (Roche Holding)
• Novartis
• Rheomics, Inc.

Representative Publications
Mythreye, K; Knelson, EH; Gatza, CE; Gatza, ML; Blobe, GC. TßRIII/ß-arrestin2 regulates integrin ¿5ß1 trafficking, function, and localization in epithelial cells. Oncogene. 2013;32:1416-1427. (2013) Abstract

Lee, NY; Golzio, C; Gatza, CE; Sharma, A; Katsanis, N; Blobe, GC. Endoglin regulates PI3-kinase/Akt trafficking and signaling to alter endothelial capillary stability during angiogenesis. Molecular Biology of the Cell. 2012;23:2412-2423. (2012) Abstract

Lambert, KE; Huang, H; Mythreye, K; Blobe, GC. The type III transforming growth factor-ß receptor inhibits proliferation, migration, and adhesion in human myeloma cells. Molecular Biology of the Cell. 2011;22:1463-1472. (2011) Abstract

Swaminathan, V; Mythreye, K; O'Brien, ET; Berchuck, A; Blobe, GC; Superfine, R. Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Cancer Research. 2011;71:5075-5080. (2011) Abstract

Lee, NY; Haney, JC; Sogani, J; Blobe, GC. Casein kinase 2beta as a novel enhancer of activin-like receptor-1 signaling. The FASEB Journal. 2009;23:3712-3721. (2009) Abstract

Lee, NY; Kirkbride, KC; Sheu, RD; Blobe, GC. The transforming growth factor-beta type III receptor mediates distinct subcellular trafficking and downstream signaling of activin-like kinase (ALK)3 and ALK6 receptors. Molecular Biology of the Cell. 2009;20:4362-4370. (2009) Abstract

Mythreye, K; Blobe, GC. The type III TGF-beta receptor regulates epithelial and cancer cell migration through beta-arrestin2-mediated activation of Cdc42. Proceedings of the National Academy of Sciences of USA. 2009;106:8221-8226. (2009) Abstract

Finger, EC; Lee, NY; You, HJ; Blobe, GC. Endocytosis of the type III transforming growth factor-beta (TGF-beta) receptor through the clathrin-independent/lipid raft pathway regulates TGF-beta signaling and receptor down-regulation. Journal of Biological Chemistry. 2008;283:34808-34818. (2008) Abstract

Kirkbride, KC; Townsend, TA; Bruinsma, MW; Barnett, JV; Blobe, GC. Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor. Journal of Biological Chemistry. 2008;283:7628-7637. (2008) Abstract

Lee, NY; Ray, B; How, T; Blobe, GC. Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. Journal of Biological Chemistry. 2008;283:32527-32533. (2008) Abstract

Dong, M; How, T; Kirkbride, KC; Gordon, KJ; Lee, JD; Hempel, N; Kelly, P; Moeller, BJ; Marks, JR; Blobe, GC. The type III TGF-beta receptor suppresses breast cancer progression. Journal of Clinical Investigation. 2007;117:206-217. (2007) Abstract

Hempel, N; How, T; Dong, M; Murphy, SK; Fields, TA; Blobe, GC. Loss of betaglycan expression in ovarian cancer: role in motility and invasion. Cancer Research. 2007;67:5231-5238. (2007) Abstract

Lee, NY; Blobe, GC. The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells. Journal of Biological Chemistry. 2007;282:21507-21517. (2007) Abstract

Turley, RS; Finger, EC; Hempel, N; How, T; Fields, TA; Blobe, GC. The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. Cancer Research. 2007;67:1090-1098. (2007) Abstract

Elliott, RL; Blobe, GC. Role of transforming growth factor Beta in human cancer. Journal of Clinical Oncology. 2005;23:2078-2093. (2005) Abstract

Chen, W; Kirkbride, KC; How, T; Nelson, CD; Mo, J; Frederick, JP; Wang, XF; Lefkowitz, RJ; Blobe, GC. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science. 2003;301:1394-1397. (2003) Abstract