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:

The role of the extracellular matrix protein TGFBI in cancer.

The secreted extracellular protein, transforming growth factor beta induced (TGFBI or βIGH3), has roles in regulating numerous biological functions, including cell adhesion and bone formation, both during embryonic development and during the pathogenesis of human disease. TGFBI has been most studied in the context of hereditary corneal dystrophies, where mutations in TGFBI result in accumulation of TGFBI in the cornea. In cancer, early studies focused on TGFBI as a tumor suppressor, in part by promoting chemotherapy sensitivity. However, in established tumors, TGFBI largely has a role in promoting tumor progression, with elevated levels correlating to poorer clinical outcomes. As an important regulator of cancer progression, TGFBI expression and function is tightly regulated by numerous mechanisms including epigenetic silencing through promoter methylation and microRNAs. Mechanisms to target TGFBI have potential clinical utility in treating advanced cancers, while assessing TGFBI levels could be a biomarker for chemotherapy resistance and tumor progression.
Authors
Corona, A; Blobe, GC
MLA Citation
Corona, Armando, and Gerard C. Blobe. “The role of the extracellular matrix protein TGFBI in cancer.Cell Signal, vol. 84, Aug. 2021, p. 110028. Pubmed, doi:10.1016/j.cellsig.2021.110028.
URI
https://scholars.duke.edu/individual/pub1482332
PMID
33940163
Source
pubmed
Published In
Cell Signal
Volume
84
Published Date
Start Page
110028
DOI
10.1016/j.cellsig.2021.110028

Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer.

LESSONS LEARNED: Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted. BACKGROUND: The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance. METHODS: In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. RESULTS: Twenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3-7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5-14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib. CONCLUSION: The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.
Authors
Strickler, JH; Rushing, CN; Uronis, HE; Morse, MA; Niedzwiecki, D; Blobe, GC; Moyer, AN; Bolch, E; Webb, R; Haley, S; Hatch, AJ; Altomare, IP; Sherrill, GB; Chang, DZ; Wells, JL; Hsu, SD; Jia, J; Zafar, SY; Nixon, AB; Hurwitz, HI
MLA Citation
Strickler, John H., et al. “Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer.Oncologist, vol. 26, no. 6, June 2021, pp. 465-e917. Pubmed, doi:10.1002/onco.13678.
URI
https://scholars.duke.edu/individual/pub1472247
PMID
33469991
Source
pubmed
Published In
Oncologist
Volume
26
Published Date
Start Page
465
End Page
e917
DOI
10.1002/onco.13678

ALK1 regulates the internalization of endoglin and the type III TGF-β receptor.

Complex formation and endocytosis of transforming growth factor-β (TGF-β) receptors play important roles in signaling. However, their interdependence remained unexplored. Here, we demonstrate that ALK1, a TGF-β type I receptor prevalent in endothelial cells, forms stable complexes at the cell surface with endoglin and with type III TGF-β receptors (TβRIII). We show that ALK1 undergoes clathrin-mediated endocytosis (CME) faster than ALK5, type II TGF-β receptor (TβRII), endoglin, or TβRIII. These complexes regulate the endocytosis of the TGF-β receptors, with a major effect mediated by ALK1. Thus, ALK1 enhances the endocytosis of TβRIII and endoglin, while ALK5 and TβRII mildly enhance endoglin, but not TβRIII, internalization. Conversely, the slowly endocytosed endoglin has no effect on the endocytosis of either ALK1, ALK5, or TβRII, while TβRIII has a differential effect, slowing the internalization of ALK5 and TβRII, but not ALK1. Such effects may be relevant to signaling, as BMP9-mediated Smad1/5/8 phosphorylation is inhibited by CME blockade in endothelial cells. We propose a model that links TGF-β receptor oligomerization and endocytosis, based on which endocytosis signals are exposed/functional in specific receptor complexes. This has broad implications for signaling, implying that complex formation among various receptors regulates their surface levels and signaling intensities.
Authors
Tazat, K; Pomeraniec-Abudy, L; Hector-Greene, M; Szilágyi, SS; Sharma, S; Cai, EM; Corona, AL; Ehrlich, M; Blobe, GC; Henis, YI
MLA Citation
Tazat, Keren, et al. “ALK1 regulates the internalization of endoglin and the type III TGF-β receptor.Mol Biol Cell, vol. 32, no. 7, Apr. 2021, pp. 605–21. Pubmed, doi:10.1091/mbc.E20-03-0199.
URI
https://scholars.duke.edu/individual/pub1474250
PMID
33566682
Source
pubmed
Published In
Molecular Biology of the Cell
Volume
32
Published Date
Start Page
605
End Page
621
DOI
10.1091/mbc.E20-03-0199

TGF-β superfamily co-receptors in cancer.

Transforming growth factor-β (TGF-β) superfamily signaling via their cognate receptors is frequently modified by TGF-β superfamily co-receptors. Signaling through SMAD-mediated pathways may be enhanced or depressed depending on the specific co-receptor and cell context. This dynamic effect on signaling is further modified by the release of many of the co-receptors from the membrane to generate soluble forms that are often antagonistic to the membrane-bound receptors. The co-receptors discussed here include TβRIII (betaglycan), endoglin, BAMBI, CD109, SCUBE proteins, neuropilins, Cripto-1, MuSK, and RGMs. Dysregulation of these co-receptors can lead to altered TGF-β superfamily signaling that contributes to the pathophysiology of many cancers through regulation of growth, metastatic potential, and the tumor microenvironment. Here we describe the role of several TGF-β superfamily co-receptors on TGF-β superfamily signaling and the impact on cellular and physiological functions with a particular focus on cancer, including a discussion on recent pharmacological advances and potential clinical applications targeting these co-receptors.
Authors
Pawlak, JB; Blobe, GC
MLA Citation
Pawlak, John B., and Gerard C. Blobe. “TGF-β superfamily co-receptors in cancer.Dev Dyn, Apr. 2021. Pubmed, doi:10.1002/dvdy.338.
URI
https://scholars.duke.edu/individual/pub1478712
PMID
33797167
Source
pubmed
Published In
Dev Dyn
Published Date
DOI
10.1002/dvdy.338

Specific interactions of the protein kinase C beta isoenzymes

Authors
Stribling, S; Feng, X; Blobe, G; Hannun, YA
MLA Citation
Stribling, S., et al. “Specific interactions of the protein kinase C beta isoenzymes.” Molecular Biology of the Cell, vol. 7, 1996, pp. 3037–3037.
URI
https://scholars.duke.edu/individual/pub1449246
Source
wos-lite
Published In
Molecular Biology of the Cell
Volume
7
Published Date
Start Page
3037
End Page
3037

Research Areas:

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