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

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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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.

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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
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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..” The Biochemical Journal 454, no. 1 (August 2013): 79–89. https://doi.org/10.1042/BJ20121701.

PMID
23750457
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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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