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
Awarded By
HHT Foundation International, Inc.
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

Endoglin interacts with VEGFR2 to promote angiogenesis.

Endoglin, a TGF-β coreceptor predominantly expressed in endothelial cells, plays an important role in vascular development and tumor-associated angiogenesis. However, the mechanism by which endoglin regulates angiogenesis, especially during tip cell formation, remains largely unknown. In this study, we report that endoglin promoted VEGF-induced tip cell formation. Mechanistically, endoglin interacted with VEGF receptor (VEGFR)-2 in a VEGF-dependent manner, which sustained VEGFR2 on the cell surface and prevented its degradation. Endoglin mutants deficient in the ability to interact with VEGFR2 failed to sustain VEGFR2 on the cell surface and to promote VEGF-induced tip cell formation. Further, an endoglin-targeting monoclonal antibody (mAb), TRC105, cooperated with a VEGF-A targeting mAb, bevacizumab, to inhibit VEGF signaling and tip cell formation in vitro and to inhibit tumor growth, metastasis, and tumor-associated angiogenesis in a murine tumor model. This study demonstrate a novel mechanism by which endoglin initiates and regulates VEGF-driven angiogenesis while providing a rationale for combining anti-VEGF and anti-endoglin therapy in patients with cancer.-Tian, H., Huang, J. J., Golzio, C., Gao, X., Hector-Greene, M., Katsanis, N., Blobe, G. C. Endoglin interacts with VEGFR2 to promote angiogenesis.
Authors
Tian, H; Huang, JJ; Golzio, C; Gao, X; Hector-Greene, M; Katsanis, N; Blobe, GC
MLA Citation
Tian, Hongyu, et al. “Endoglin interacts with VEGFR2 to promote angiogenesis.Faseb J, vol. 32, no. 6, June 2018, pp. 2934–49. Pubmed, doi:10.1096/fj.201700867RR.
URI
https://scholars.duke.edu/individual/pub1302166
PMID
29401587
Source
pubmed
Published In
Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology
Volume
32
Published Date
Start Page
2934
End Page
2949
DOI
10.1096/fj.201700867RR

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction.

UNLABELLED: Hypertrophic scar contraction (HSc) is caused by granulation tissue contraction propagated by myofibroblast and fibroblast migration and contractility. Identifying the stimulants that promote migration and contractility is key to mitigating HSc. Angiotensin II (AngII) promotes migration and contractility of heart, liver, and lung fibroblasts; thus, we investigated the mechanisms of AngII in HSc. Human scar and unwounded dermis were immunostained for AngII receptors angiotensin type 1 receptor (AT1 receptor) and angiotensin type 2 receptor (AT2 receptor) and analyzed for AT1 receptor expression using Western blot. In vitro assays of fibroblast contraction and migration under AngII stimulation were conducted with AT1 receptor, AT2 receptor, p38, Jun N-terminal kinase (JNK), MEK, and activin receptor-like kinase 5 (ALK5) antagonism. Excisional wounds were created on AT1 receptor KO and wild-type (WT) mice treated with AngII ± losartan and ALK5 and JNK inhibitors SB-431542 and SP-600125, respectively. Granulation tissue contraction was quantified, and wounds were analyzed by immunohistochemistry. AT1 receptor expression was increased in scar, but not unwounded tissue. AngII induced fibroblast contraction and migration through AT1 receptor. Cell migration was inhibited by ALK5 and JNK, but not p38 or MEK blockade. In vivo experiments determined that absence of AT1 receptor and chemical AT1 receptor antagonism diminished granulation tissue contraction while AngII stimulated wound contraction. AngII granulation tissue contraction was diminished by ALK5 inhibition, but not JNK. AngII promotes granulation tissue contraction through AT1 receptor and downstream canonical transforming growth factor (TGF)-β signaling pathway, ALK5. Further understanding the pathogenesis of HSc as an integrated signaling mechanism could improve our approach to establishing effective therapeutic interventions. KEY MESSAGE: AT1 receptor expression is increased in scar tissue compared to unwounded tissue. AngII stimulates expression of proteins that confer cell migration and contraction. AngII stimulates fibroblast migration and contraction through AT1 receptor, ALK5, and JNK. AngII-stimulated in vivo granulation tissue contraction is AT1 receptor and ALK5 dependent.
Authors
Ehanire, T; Ren, L; Bond, J; Medina, M; Li, G; Bashirov, L; Chen, L; Kokosis, G; Ibrahim, M; Selim, A; Blobe, GC; Levinson, H
MLA Citation
Ehanire, Tosan, et al. “Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction.J Mol Med (Berl), vol. 93, no. 3, 2015, pp. 289–302. Pubmed, doi:10.1007/s00109-014-1211-9.
URI
https://scholars.duke.edu/individual/pub1048451
PMID
25345602
Source
pubmed
Published In
J Mol Med (Berl)
Volume
93
Published Date
Start Page
289
End Page
302
DOI
10.1007/s00109-014-1211-9

Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-β receptor (TGFBR3) decreases with advancing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse outcome. In vitro, TβRIII expression was epigenetically suppressed by MYCN-mediated recruitment of histone deacetylases to regions of the TGFBR3 promoter. TβRIII bound FGF2 and exogenous FGFR1, which promoted neuronal differentiation of neuroblastoma cells. TβRIII and FGF2 cooperated to induce expression of the transcription factor inhibitor of DNA binding 1 via Erk MAPK. TβRIII-mediated neuronal differentiation suppressed cell proliferation in vitro as well as tumor growth and metastasis in vivo. These studies characterize a coreceptor function for TβRIII in FGF2-mediated neuronal differentiation, while identifying potential therapeutic targets and clinical biomarkers for neuroblastoma.
Authors
Knelson, EH; Gaviglio, AL; Tewari, AK; Armstrong, MB; Mythreye, K; Blobe, GC
MLA Citation
Knelson, Erik H., et al. “Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.J Clin Invest, vol. 123, no. 11, Nov. 2013, pp. 4786–98. Pubmed, doi:10.1172/JCI69657.
URI
https://scholars.duke.edu/individual/pub999532
PMID
24216509
Source
pubmed
Published In
J Clin Invest
Volume
123
Published Date
Start Page
4786
End Page
4798
DOI
10.1172/JCI69657

Research Areas:

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