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

Howard, L. A., K. E. Bullock, J. C. Bendell, H. E. Uronis, G. Vlahovic, G. C. Blobe, R. F. Riedel, A. B. Nixon, J. P. Gockerman, and H. I. Hurwitz. “Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors..” J Clin Oncol 27, no. 15_suppl (May 20, 2009).

PMID
27961368
Scholars@Duke

Bullock, K. E., H. I. Hurwitz, H. E. Uronis, M. A. Morse, G. C. Blobe, S. D. Hsu, S. Y. Zafar, A. B. Nixon, L. A. Howard, and J. C. Bendell. “Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC).” In Journal of Clinical Oncology, Vol. 27. AMER SOC CLINICAL ONCOLOGY, 2009.

Scholars@Duke

Howard, L. A., K. E. Bullock, J. C. Bendell, H. E. Uronis, G. Vlahovic, G. C. Blobe, R. F. Riedel, A. B. Nixon, J. P. Gockerman, and H. I. Hurwitz. “Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors.” In Journal of Clinical Oncology, Vol. 27. AMER SOC CLINICAL ONCOLOGY, 2009.

Scholars@Duke

Mythreye, Karthikeyan, and Gerard C. Blobe. “The type III TGF-beta receptor regulates epithelial and cancer cell migration through beta-arrestin2-mediated activation of Cdc42..” Proc Natl Acad Sci U S A 106, no. 20 (May 19, 2009): 8221–26. https://doi.org/10.1073/pnas.0812879106.

PMID
19416857
Full Text

Gordon, Kelly J., Kellye C. Kirkbride, Tam How, and Gerard C. Blobe. “Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2..” Carcinogenesis 30, no. 2 (February 2009): 238–48. https://doi.org/10.1093/carcin/bgn274.

PMID
19056927
Full Text

Finger, Elizabeth C., Nam Y. Lee, Hye-jin You, and Gerard C. Blobe. “Endocytosis of the type III transforming growth factor-beta (TGF-beta) receptor through the clathrin-independent/lipid raft pathway regulates TGF-beta signaling and receptor down-regulation..” J Biol Chem 283, no. 50 (December 12, 2008): 34808–18. https://doi.org/10.1074/jbc.M804741200.

PMID
18845534
Full Text

Lee, Nam Y., Bridgette Ray, Tam How, and Gerard C. Blobe. “Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC..” J Biol Chem 283, no. 47 (November 21, 2008): 32527–33. https://doi.org/10.1074/jbc.M803059200.

PMID
18775991
Full Text

Hempel, Nadine, Tam How, Simon J. Cooper, Tyler R. Green, Mei Dong, John A. Copland, Christopher G. Wood, and Gerard C. Blobe. “Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta..” Carcinogenesis 29, no. 5 (May 2008): 905–12. https://doi.org/10.1093/carcin/bgn049.

PMID
18299279
Full Text

Gordon, Kelly J., and Gerard C. Blobe. “Role of transforming growth factor-beta superfamily signaling pathways in human disease..” Biochimica Et Biophysica Acta 1782, no. 4 (April 2008): 197–228. https://doi.org/10.1016/j.bbadis.2008.01.006.

PMID
18313409
Full Text

Kirkbride, Kellye C., Todd A. Townsend, Monique W. Bruinsma, Joey V. Barnett, and Gerard C. Blobe. “Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor..” J Biol Chem 283, no. 12 (March 21, 2008): 7628–37. https://doi.org/10.1074/jbc.M704883200.

PMID
18184661
Full Text

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