Gerard Conrad Blobe, MD, PhD

Professor of Medicine
Professor of Pharmacology and Cancer Biology
Associate of the Duke Initiative for Science & Society
Member of the Duke Cancer Institute
Campus mail B354 Levine Science Research Center, 450 Research Drive, Durham, NC 27708
Phone (919) 668-6688

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 establishing the role of these co-receptors in orchestrating signaling in physiological and pathophysiological settings.

Education and Training

  • Adult Oncology Fellow, Medicine, Dana Farber Cancer Institute, 1997 - 2000
  • Medical Resident, Medicine, Brigham and Women's Hospital, 1995 - 1997
  • Ph.D., Duke University, 1995
  • M.D., Duke University, 1995

Publications

Elderbroom, Jennifer L., Jennifer J. Huang, Catherine E. Gatza, Jian Chen, Tam How, Mark Starr, Andrew B. Nixon, and Gerard C. Blobe. “Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion..” Mol Biol Cell 25, no. 16 (August 15, 2014): 2320–32. https://doi.org/10.1091/mbc.E13-09-0524.

PMID
24966170
Full Text

Meyer, Alison E., Catherine E. Gatza, Tam How, Mark Starr, Andrew B. Nixon, and Gerard C. Blobe. “Role of TGF-β receptor III localization in polarity and breast cancer progression..” Mol Biol Cell 25, no. 15 (August 1, 2014): 2291–2304. https://doi.org/10.1091/mbc.E14-03-0825.

PMID
24870032
Full Text

Knelson, Erik H., Angela L. Gaviglio, Jasmine C. Nee, Mark D. Starr, Andrew B. Nixon, Stephen G. Marcus, and Gerard C. Blobe. “Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth..” J Clin Invest 124, no. 7 (July 2014): 3016–31. https://doi.org/10.1172/JCI74270.

PMID
24937430
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Gatza, Catherine E., Jennifer L. Elderbroom, Sun Young Oh, Mark D. Starr, Andrew B. Nixon, and Gerard C. Blobe. “The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells..” Neoplasia 16, no. 6 (June 2014): 489–500. https://doi.org/10.1016/j.neo.2014.05.008.

PMID
25077702
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Hanks, Brent Allen, Alisha Holtzhausen, Kathy Evans, Michelle Heid, and Gerard C. Blobe. “Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma..” In Journal of Clinical Oncology, 32:3011–3011. American Society of Clinical Oncology (ASCO), 2014. https://doi.org/10.1200/jco.2014.32.15_suppl.3011.

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Strickler, John H., Shannon McCall, Andrew B. Nixon, John C. Brady, Herbert Pang, Christel Rushing, Allen Cohn, et al. “Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer..” Invest New Drugs 32, no. 2 (April 2014): 330–39. https://doi.org/10.1007/s10637-013-0042-9.

PMID
24173967
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Holtzhausen, Alisha, Christelle Golzio, Tam How, Yong-Hun Lee, William P. Schiemann, Nicholas Katsanis, and Gerard C. Blobe. “Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development..” Faseb J 28, no. 3 (March 2014): 1248–67. https://doi.org/10.1096/fj.13-239178.

PMID
24308972
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Bendell, Johanna C., Michael S. Gordon, Herbert I. Hurwitz, Suzanne F. Jones, David S. Mendelson, Gerard C. Blobe, Neeraj Agarwal, et al. “Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer..” Clin Cancer Res 20, no. 2 (January 15, 2014): 480–89. https://doi.org/10.1158/1078-0432.CCR-13-1840.

PMID
24173543
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Knelson, Erik H., Angela L. Gaviglio, Alok K. Tewari, Michael B. Armstrong, Karthikeyan Mythreye, and Gerard C. Blobe. “Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma..” J Clin Invest 123, no. 11 (November 2013): 4786–98. https://doi.org/10.1172/JCI69657.

PMID
24216509
Full Text

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