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

Clarke, Jeffrey Melson, Gerard C. Blobe, John H. Strickler, Hope Elizabeth Uronis, S Yousuf Zafar, Michael Morse, Evan Dropkin, et al. “A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial)..” Cancer Chemother Pharmacol 84, no. 4 (October 2019): 909–17. https://doi.org/10.1007/s00280-019-03916-0.

PMID
31444620
Full Text

Huang, Jennifer J., Armando L. Corona, Brian P. Dunn, Elise M. Cai, Jesse N. Prakken, and Gerard C. Blobe. “Increased type III TGF-β receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition..” Oncogene 38, no. 18 (May 2019): 3402–14. https://doi.org/10.1038/s41388-018-0672-7.

PMID
30643193
Full Text

Zhao, Fei, Kathy Evans, Christine Xiao, Nicholas DeVito, Balamayooran Theivanthiran, Alisha Holtzhausen, Peter J. Siska, Gerard C. Blobe, and Brent A. Hanks. “Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma..” Cancer Immunol Res 6, no. 12 (December 2018): 1459–71. https://doi.org/10.1158/2326-6066.CIR-18-0086.

PMID
30209062
Full Text

Tian, Hongyu, Jennifer J. Huang, Christelle Golzio, Xia Gao, Melissa Hector-Greene, Nicholas Katsanis, and Gerard C. Blobe. “Endoglin interacts with VEGFR2 to promote angiogenesis..” Faseb J 32, no. 6 (June 2018): 2934–49. https://doi.org/10.1096/fj.201700867RR.

PMID
29401587
Full Text

Palta, Manisha, Brian G. Czito, Eileen Duffy, Mary Malicki, Donna Niedzwiecki, James L. Abbruzzese, Hope Elizabeth Uronis, Gerard C. Blobe, Dan G. Blazer, and Christopher Willett. “A phase II trial of neoadjuvant gemcitabine/nab-paclitaxel and SBRT for potentially resectable pancreas cancer: An evaluation of acute toxicity..” In Journal of Clinical Oncology, 36:4121–4121. American Society of Clinical Oncology (ASCO), 2018. https://doi.org/10.1200/jco.2018.36.15_suppl.4121.

Full Text

Tian, Hongyu, Tatiana Ketova, Duriel Hardy, Xiaojiang Xu, Xia Gao, Andries Zijlstra, and Gerard C. Blobe. “Endoglin mediates vascular maturation by promoting vascular smooth muscle cell migration and spreading.” In Angiogenesis, 21:156–156. SPRINGER, 2018.

Scholars@Duke

Tian, Hongyu, Tatiana Ketova, Duriel Hardy, Xiaojiang Xu, Xia Gao, Andries Zijlstra, and Gerard C. Blobe. “Endoglin Mediates Vascular Maturation by Promoting Vascular Smooth Muscle Cell Migration and Spreading..” Arterioscler Thromb Vasc Biol 37, no. 6 (June 2017): 1115–26. https://doi.org/10.1161/ATVBAHA.116.308859.

PMID
28450296
Full Text

Gaviglio, Angela L., Erik H. Knelson, and Gerard C. Blobe. “Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation..” Faseb J 31, no. 5 (May 2017): 1903–15. https://doi.org/10.1096/fj.201600828R.

PMID
28174207
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Riedel, Richard F., Kellen L. Meadows, Paula H. Lee, Michael A. Morse, Hope E. Uronis, Gerard C. Blobe, Daniel J. George, et al. “Phase I study of pazopanib plus TH-302 in advanced solid tumors..” Cancer Chemother Pharmacol 79, no. 3 (March 2017): 611–19. https://doi.org/10.1007/s00280-017-3256-2.

PMID
28238078
Full Text

Hesler, Rachel A., Jennifer J. Huang, Mark D. Starr, Victoria M. Treboschi, Alyssa G. Bernanke, Andrew B. Nixon, Shannon J. McCall, Rebekah R. White, and Gerard C. Blobe. “TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3..” Carcinogenesis 37, no. 11 (November 1, 2016): 1041–51. https://doi.org/10.1093/carcin/bgw093.

PMID
27604902
Full Text

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