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 (TßRIII)  as a critical mediator/regulator of TGF-ß signaling. Specifically we have demonstrated that regulating TßRIII expression levels is sufficient to regulate TGF-ß signaling, and that decreased TßRIII expression is a common phenomenon in human cancers, resulting in cancer progression. TßRIII is also shed from the surface to generate soluble TßRIII, which we have demonstrated has a role in creating an immunotolerant tumor microenvironment. The role of TßRIII and soluble TßRIII in the tumor immune microenvironment is currently being investigated using a multidisciplinary approach.

Activin receptor-like kinase 4 (ALK4) is a type I transforming growth factor-β (TGF-β) superfamily receptor that mediates signaling for several TGF-β superfamily ligands, including activin, Nodal and GDF5. We have demonstrated that mutation or copy number loss of ALK4 occurs in 35% of pancreatic cancer patients, with loss of ALK4 expression associated with a poorer prognosis. ALK4 has also been identified in an unbiased screen as a gene whose disruption enhances Ras mediated pancreatic tumorigenesis in vivo. We have demonstrated that loss of ALK4 expression increases canonical TGF-β signaling to increase cancer invasion and metastasis in vivo. We are currently investigating the mechanism by which loss of ALK4 regulates TGF-β signaling, how it may effect other signaling pathways, and how to use this knowledge to treat pancreatic cancer patients with loss of ALK4 function.

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

Czito, Brian G., Christopher G. Willett, Johanna C. Bendell, Michael A. Morse, Douglas S. Tyler, Nishan H. Fernando, Christopher R. Mantyh, et al. “Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results..” J Clin Oncol 24, no. 4 (February 1, 2006): 656–62. https://doi.org/10.1200/JCO.2005.04.1749.

PMID
16446337
Full Text

Kirkbride, Kellye C., Bridgette N. Ray, and Gerard C. Blobe. “Cell-surface co-receptors: emerging roles in signaling and human disease..” Trends Biochem Sci 30, no. 11 (November 2005): 611–21. https://doi.org/10.1016/j.tibs.2005.09.003.

PMID
16185874
Full Text

White, Rebekah R., H Bill Xie, Marcia R. Gottfried, Brian G. Czito, Herbert I. Hurwitz, Michael A. Morse, Gerald C. Blobe, et al. “Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer..” Ann Surg Oncol 12, no. 3 (March 2005): 214–21. https://doi.org/10.1245/ASO.2005.03.105.

PMID
15827813
Full Text

Peri, Suraj, J Daniel Navarro, Ramars Amanchy, Troels Z. Kristiansen, Chandra Kiran Jonnalagadda, Vineeth Surendranath, Vidya Niranjan, et al. “Development of human protein reference database as an initial platform for approaching systems biology in humans..” Genome Res 13, no. 10 (October 2003): 2363–71. https://doi.org/10.1101/gr.1680803.

PMID
14525934
Full Text

Chen, Wei, Kellye C. Kirkbride, Tam How, Christopher D. Nelson, Jinyao Mo, Joshua P. Frederick, Xiao-Fan Wang, Robert J. Lefkowitz, and Gerard C. Blobe. “Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling..” Science 301, no. 5638 (September 5, 2003): 1394–97. https://doi.org/10.1126/science.1083195.

PMID
12958365
Full Text

Kirkbride, Kellye C., and Gerard C. Blobe. “Inhibiting the TGF-beta signalling pathway as a means of cancer immunotherapy..” Expert Opin Biol Ther 3, no. 2 (April 2003): 251–61. https://doi.org/10.1517/14712598.3.2.251.

PMID
12662140
Full Text

Mo, Jinyao, Shijing J. Fang, Wei Chen, and Gerard C. Blobe. “Regulation of ALK-1 signaling by the nuclear receptor LXRbeta..” J Biol Chem 277, no. 52 (December 27, 2002): 50788–94. https://doi.org/10.1074/jbc.M210376200.

PMID
12393874
Full Text

Schiemann, William P., Gerard C. Blobe, Dario E. Kalume, Akhilesh Pandey, and Harvey F. Lodish. “Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades..” J Biol Chem 277, no. 30 (July 26, 2002): 27367–77. https://doi.org/10.1074/jbc.M200148200.

PMID
12021267
Full Text

Pages