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

Bullock, Karen E., William P. Petros, Islam Younis, Hope E. Uronis, Michael A. Morse, Gerard C. Blobe, S Yousuf Zafar, et al. “A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE).” Cancer Chemother Pharmacol 67, no. 2 (February 2011): 465–74. https://doi.org/10.1007/s00280-010-1507-6.

PMID
21079958
Full Text

Swaminathan, V., K. Mythreye, C. Guilluy, E. O’Brien, G. C. Blobe, K. Burridge, and R. Superfine. “Role of stiffness and force response in integrin mediated signaling and metastasis.” In Molecular Biology of the Cell, Vol. 22. AMER SOC CELL BIOLOGY, 2011.

Scholars@Duke

Wong, Nan Soon, Nishan H. Fernando, Andrew B. Nixon, Stephanie Cushman, Mebea Aklilu, Johanna C. Bendell, Michael A. Morse, et al. “A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer.” Anticancer Res 31, no. 1 (January 2011): 255–61.

PMID
21273607
Scholars@Duke

Townsend, Todd A., Jamille Y. Robinson, Christopher R. Deig, Cynthia R. Hill, Andrew Misfeldt, Gerard C. Blobe, and Joey V. Barnett. “BMP-2 and TGFβ2 shared pathways regulate endocardial cell transformation.” Cells Tissues Organs 194, no. 1 (2011): 1–12. https://doi.org/10.1159/000322035.

PMID
21212630
Full Text

Altomare, Ivy, Johanna C. Bendell, Karen E. Bullock, Hope E. Uronis, Michael A. Morse, S David Hsu, S Yousuf Zafar, et al. “A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer.” Oncologist 16, no. 8 (2011): 1131–37. https://doi.org/10.1634/theoncologist.2011-0078.

PMID
21795432
Full Text

Jima, Dereje D., Jenny Zhang, Cassandra Jacobs, Kristy L. Richards, Cherie H. Dunphy, William W. L. Choi, Wing Yan Au, et al. “Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs.” Blood 116, no. 23 (December 2, 2010): e118–27. https://doi.org/10.1182/blood-2010-05-285403.

PMID
20733160
Full Text

Cooper, S. J., H. Zou, S. N. Legrand, L. A. Marlow, C. A. von Roemeling, D. C. Radisky, K. J. Wu, et al. “Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma.” Oncogene 29, no. 20 (May 20, 2010): 2905–15. https://doi.org/10.1038/onc.2010.64.

PMID
20208565
Full Text

Gatza, Catherine E., and Gerard C. Blobe. “Abstract 3971: The type III tgf-β receptor mediates bmp signaling in normal and cancerous mammary epithelial cells.” Cellular and Molecular Biology, April 15, 2010. https://doi.org/10.1158/1538-7445.am10-3971.

Full Text

Randrianarison-Huetz, Voahangy, Benoit Laurent, Valérie Bardet, Gerard C. Blobe, François Huetz, and Dominique Duménil. “Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-beta signaling at the bipotent erythro-megakaryocytic progenitor stage.” Blood 115, no. 14 (April 8, 2010): 2784–95. https://doi.org/10.1182/blood-2009-09-241752.

PMID
20124515
Full Text

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