Gerard Blobe

Overview:

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.



Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Associate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1995

Duke University

Ph.D. 1995

Duke University

Medical Resident, Medicine

Brigham and Women's Hospital

Adult Oncology Fellow, Medicine

Dana Farber Cancer Institute

Grants:

Dissecting ALK4 Function in Cancer Progression

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The Role of Type III TGF-beta Receptor in ALK1-mediated Tumor Angiogenesis

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Role of Type III TGF-beta Receptor Shedding in Lung Cancer Initiation and Progression

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Epigenetic Regulation of Neuroblast Differentiation

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Endoglin Regulates Biology and Signal Transduction in Vascular Smooth Muscle Cells

Administered By
Medicine, Medical Oncology
Role
Mentor
Start Date
End Date

Publications:

Endoglin mediates vascular maturation by promoting vascular smooth muscle cell migration and spreading

Authors
Tian, H; Ketova, T; Hardy, D; Xu, X; Gao, X; Zijlstra, A; Blobe, GC
MLA Citation
Tian, Hongyu, et al. “Endoglin mediates vascular maturation by promoting vascular smooth muscle cell migration and spreading.” Angiogenesis, vol. 21, no. 1, SPRINGER, 2018, pp. 156–156.
URI
https://scholars.duke.edu/individual/pub1306268
Source
wos
Published In
Angiogenesis
Volume
21
Published Date
Start Page
156
End Page
156

A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial).

PURPOSE: This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory metastatic colorectal cancer. METHODS: The first stage of this study was a standard "3 + 3" open-label dose-escalation scheme. Cohorts of 3-6 subjects were started with 120 mg of regorafenib given PO daily for 3 weeks of a 4 week cycle, plus 4.5 mg/kg of PF-03446962 given IV every 2 weeks. Doses of both drugs were adjusted according to dose-limiting toxicities (DLT). Plasma was collected for multiplexed ELISA analysis of factors related to tumor growth and angiogenesis. RESULTS: Seventeen subjects were enrolled, of whom 11 were deemed evaluable. Seven subjects were enrolled at dose level 1, and four were enrolled at level - 1. Overall, three DLTs were observed during the dose-escalation phase: two in level 1 and one in level - 1. A planned dose-expansion cohort was not started due to early termination of the clinical trial. Common adverse events were infusion-related reaction, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dehydration, nausea, back pain, anorexia, and diarrhea. One subject achieved stable disease for 5.5 months, but discontinued treatment due to adverse events. CONCLUSIONS: The regimen of regorafenib and PF-03446962 was associated with unacceptable toxicity and did not demonstrate notable clinical activity in patients with refractory metastatic colorectal cancer.
Authors
Clarke, JM; Blobe, GC; Strickler, JH; Uronis, HE; Zafar, SY; Morse, M; Dropkin, E; Howard, L; O'Neill, M; Rushing, CN; Niedzwiecki, D; Watson, H; Bolch, E; Arrowood, C; Liu, Y; Nixon, AB; Hurwitz, HI
MLA Citation
Clarke, Jeffrey Melson, 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, vol. 84, no. 4, Oct. 2019, pp. 909–17. Pubmed, doi:10.1007/s00280-019-03916-0.
URI
https://scholars.duke.edu/individual/pub1405169
PMID
31444620
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
84
Published Date
Start Page
909
End Page
917
DOI
10.1007/s00280-019-03916-0

An Automated High-throughput Array Microscope for Cancer Cell Mechanics.

Changes in cellular mechanical properties correlate with the progression of metastatic cancer along the epithelial-to-mesenchymal transition (EMT). Few high-throughput methodologies exist that measure cell compliance, which can be used to understand the impact of genetic alterations or to screen the efficacy of chemotherapeutic agents. We have developed a novel array high-throughput microscope (AHTM) system that combines the convenience of the standard 96-well plate with the ability to image cultured cells and membrane-bound microbeads in twelve independently-focusing channels simultaneously, visiting all wells in eight steps. We use the AHTM and passive bead rheology techniques to determine the relative compliance of human pancreatic ductal epithelial (HPDE) cells, h-TERT transformed HPDE cells (HPNE), and four gain-of-function constructs related to EMT. The AHTM found HPNE, H-ras, Myr-AKT, and Bcl2 transfected cells more compliant relative to controls, consistent with parallel tests using atomic force microscopy and invasion assays, proving the AHTM capable of screening for changes in mechanical phenotype.
Authors
Cribb, JA; Osborne, LD; Beicker, K; Psioda, M; Chen, J; O'Brien, ET; Taylor Ii, RM; Vicci, L; Hsiao, JP-L; Shao, C; Falvo, M; Ibrahim, JG; Wood, KC; Blobe, GC; Superfine, R
MLA Citation
Cribb, Jeremy A., et al. “An Automated High-throughput Array Microscope for Cancer Cell Mechanics..” Sci Rep, vol. 6, June 2016. Pubmed, doi:10.1038/srep27371.
URI
https://scholars.duke.edu/individual/pub1133992
PMID
27265611
Source
pubmed
Published In
Scientific Reports
Volume
6
Published Date
Start Page
27371
DOI
10.1038/srep27371

Heparan sulfate signaling in cancer.

Heparan sulfate (HS) is a biopolymer consisting of variably sulfated repeating disaccharide units. The anticoagulant heparin is a highly sulfated intracellular variant of HS. HS has demonstrated roles in embryonic development, homeostasis, and human disease via non-covalent interactions with numerous cellular proteins, including growth factors and their receptors. HS can function as a co-receptor by enhancing receptor-complex formation. In other contexts, HS disrupts signaling complexes or serves as a ligand sink. The effects of HS on growth factor signaling are tightly regulated by the actions of sulfyltransferases, sulfatases, and heparanases. HS has important emerging roles in oncogenesis, and heparin derivatives represent potential therapeutic strategies for human cancers. Here we review recent insights into HS signaling in tumor proliferation, angiogenesis, metastasis, and differentiation. A cancer-specific understanding of HS signaling could uncover potential therapeutic targets in this highly actionable signaling network.
Authors
Knelson, EH; Nee, JC; Blobe, GC
MLA Citation
Knelson, Erik H., et al. “Heparan sulfate signaling in cancer..” Trends Biochem Sci, vol. 39, no. 6, June 2014, pp. 277–88. Pubmed, doi:10.1016/j.tibs.2014.03.001.
URI
https://scholars.duke.edu/individual/pub1028175
PMID
24755488
Source
pubmed
Published In
Trends in Biochemical Sciences
Volume
39
Published Date
Start Page
277
End Page
288
DOI
10.1016/j.tibs.2014.03.001

Endoglin mediates fibronectin/α5β1 integrin and TGF-β pathway crosstalk in endothelial cells.

Both the transforming growth factor β (TGF-β) and integrin signalling pathways have well-established roles in angiogenesis. However, how these pathways integrate to regulate angiogenesis is unknown. Here, we show that the extracellular matrix component, fibronectin, and its cellular receptor, α5β1 integrin, specifically increase TGF-β1- and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-β superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and α5β1 integrin increase Smad1/5/8 signalling by promoting endoglin/ALK1 cell surface complex formation. In a reciprocal manner, TGF-β1 activates α5β1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglin-dependent manner. α5β1 integrin and endoglin form a complex on the cell surface and co-internalize, with their internalization regulating α5β1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/α5β1 integrin and TGF-β pathway crosstalk alter the responses of endothelial cells to TGF-β1, switching TGF-β1 from a promoter to a suppressor of migration, inhibiting TGF-β1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-β superfamily signalling and endothelial function through crosstalk with integrin signalling pathways.
Authors
Tian, H; Mythreye, K; Golzio, C; Katsanis, N; Blobe, GC
MLA Citation
Tian, Hongyu, et al. “Endoglin mediates fibronectin/α5β1 integrin and TGF-β pathway crosstalk in endothelial cells..” Embo J, vol. 31, no. 19, Oct. 2012, pp. 3885–900. Pubmed, doi:10.1038/emboj.2012.246.
URI
https://scholars.duke.edu/individual/pub749176
PMID
22940691
Source
pubmed
Published In
The Embo Journal
Volume
31
Published Date
Start Page
3885
End Page
3900
DOI
10.1038/emboj.2012.246

Research Areas:

Cancer
Cellular signal transduction
Gastrointestinal system--Cancer
Metastasis
TGF-beta Superfamily Proteins
Tumor Microenvironment