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

Meadows, Kellen L., Paula H. Lee, Richard F. Riedel, Michael A. Morse, Hope E. Uronis, Gerard C. Blobe, Daniel J. George, Jeffrey Crawford, and Herbert I. Hurwitz. “Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302.” Clinical Trials, November 2013. https://doi.org/10.1158/1535-7163.targ-13-c61.

Full Text

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

Hanks, Brent A., Alisha Holtzhausen, Katherine S. Evans, Rebekah Jamieson, Petra Gimpel, Olivia M. Campbell, Melissa Hector-Greene, et al. “Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.” J Clin Invest 123, no. 9 (September 2013): 3925–40. https://doi.org/10.1172/JCI65745.

PMID
23925295
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Oh, Sun Young, Erik H. Knelson, Gerard C. Blobe, and Karthikeyan Mythreye. “The type III TGFβ receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells.” Biochem J 454, no. 1 (August 15, 2013): 79–89. https://doi.org/10.1042/BJ20121701.

PMID
23750457
Full Text

Uronis, Hope E., Stephanie M. Cushman, Johanna C. Bendell, Gerard C. Blobe, Michael A. Morse, Andrew B. Nixon, Andrew Dellinger, et al. “A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.” Cancer Med 2, no. 3 (June 2013): 316–24. https://doi.org/10.1002/cam4.65.

PMID
23930208
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Knelson, Erik H., Angela L. Gaviglio, Alok K. Tewari, Michael B. Armstrong, Andrew B. Nixon, Mark D. Starr, Karthikeyan Mythreye, and Gerard C. Blobe. “Abstract 5041: The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.” In Tumor Biology. American Association for Cancer Research, 2013. https://doi.org/10.1158/1538-7445.am2013-5041.

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Mythreye, K., E. H. Knelson, C. E. Gatza, M. L. Gatza, and G. C. Blobe. “TβRIII/β-arrestin2 regulates integrin α5β1 trafficking, function, and localization in epithelial cells.” Oncogene 32, no. 11 (March 14, 2013): 1416–27. https://doi.org/10.1038/onc.2012.157.

PMID
22562249
Full Text

Osborne, L. D., G. Li, E. O’Brien, G. C. Blobe, R. Superfine, and K. Mythreye. “TGF-beta regulates the Rho GEFs LARG and GEF-H1 during EMT to impact stiffening response to force and cell invasion.” Molecular Biology of the Cell 24 (2013).

Scholars@Duke

Uronis, Hope E., Johanna C. Bendell, Ivy Altomare, Gerard C. Blobe, S David Hsu, Michael A. Morse, Herbert Pang, et al. “A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas.” Oncologist 18, no. 3 (2013): 271–72. https://doi.org/10.1634/theoncologist.2012-0404.

PMID
23485624
Full Text

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