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

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

Hanks, B. A., J. D. Lee, M. Morse, T. M. Clay, H. K. Lyerly, and G. C. Blobe. “Role of the type III TGF-b receptor in mediating immunosuppression during breast cancer progression.” In Journal of Clinical Oncology, 28:10577–10577. American Society of Clinical Oncology (ASCO), 2010. https://doi.org/10.1200/jco.2010.28.15_suppl.10577.

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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.

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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

Dugan, Elizabeth, Roxanne Truax, Kellen L. Meadows, Andrew B. Nixon, William P. Petros, Justin Favaro, Nishan H. Fernando, Michael A. Morse, Gerard C. Blobe, and Herbert I. Hurwitz. “A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors.” Anticancer Res 30, no. 4 (April 2010): 1251–56.

PMID
20530436
Scholars@Duke

Ray, Bridgette N., Nam Y. Lee, Tam How, and Gerard C. Blobe. “ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration.” Carcinogenesis 31, no. 3 (March 2010): 435–41. https://doi.org/10.1093/carcin/bgp327.

PMID
20042635
Full Text

Lee, Jason D., Nadine Hempel, Nam Y. Lee, and Gerard C. Blobe. “The type III TGF-beta receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-beta signaling.” Carcinogenesis 31, no. 2 (February 2010): 175–83. https://doi.org/10.1093/carcin/bgp271.

PMID
19955393
Full Text

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