New therapeutics that target pathways essential for tumor angiogenesis are of significant interest in the treatment of tumor growth and metastasis. FDA-approved antiangiogenic agents such as bevacizumab that inhibit VEGF signaling have yielded varying results. While anti-VEGF therapies can be quite effective at suppressing tumor vasculatures, recent reports suggest that long-term treatment may yield serious toxicity or result in development of resistance. Endoglin is a transforming growth factor-? (TGF-?) co-receptor that is emerging as a unique target in antiangiogenic therapy. Endoglin is: 1) required for both normal and tumor- induced angiogenesis;2) the gold standard biomarker of tumor vasculatures;and 3) strongly correlated with tumor progression, survival rate, and metastases. TRC105 is a humanized endoglin monoclonal antibody (mAb) currently in phase I/II trials for treatment of advanced solid or metastatic cancer. While early reports indicate that TRC105 improves tumor response and has a safety mechanism distinct from VEGF inhibitors, its long-term efficacy (i.e. sensitivity, resistance, and side effects) remains to be determined. Moreover, despite recent advances, the fundamental mechanism by which TRC105 and related endoglin mAbs inhibit tumor vasculatures is poorly understood. Our preliminary studies reveal unique antiangiogenic properties of TRC105 that are independent of cell-growth inhibition or apoptosis. Instead, TRC105 critically alters the critical balance of TGF-? signaling to the Smad pathways, impairs endothelial migration, and promotes endoglin shedding to produce a circulating antiangiogenic factor (soluble endoglin). Based on our initial findings, we will investigate the underlying mechanisms, evaluate other endoglin-targeting mAbs for distinct epitope-related effects, and test for enhanced efficacy in combination therapy with bevacizumab. We will employ multidisciplinary approaches including TGF-? and VEGF signaling PCR arrays to identify novel drug-sensitive targets and biomarkers, innovative biophysical studies to characterize important Ab-induced ligand binding characteristics, and validate the key mechanisms in vivo. Together, these studies will provide the first molecular and cellular data for endoglin-targeting therapies, identify new pharmacological targets for intervention, and help develop new strategies for antiangiogenic therapies.

Public Health Relevance

Endoglin is a critical regulator of angiogenesis during tumor growth and metastasis. Our research proposal defines the elusive mechanisms by which endoglin promotes angiogenesis, and determines how targeted inhibition of endoglin function can suppress tumor angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA178443-01A1
Application #
8649342
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Snyderwine, Elizabeth G
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
Pan, Christopher C; Shah, Nirav; Kumar, Sanjay et al. (2017) Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy. Oncotarget 8:12675-12685
Varadaraj, Archana; Jenkins, Laura M; Singh, Priyanka et al. (2017) TGF-? triggers rapid fibrillogenesis via a novel T?RII-dependent fibronectin-trafficking mechanism. Mol Biol Cell 28:1195-1207
Kumar, Sanjay; Pan, Christopher C; Shah, Nirav et al. (2016) Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion. Mol Cell 62:520-31
Jenkins, Laura M; Singh, Priyanka; Varadaraj, Archana et al. (2016) Altering the Proteoglycan State of Transforming Growth Factor ? Type III Receptor (T?RIII)/Betaglycan Modulates Canonical Wnt/?-Catenin Signaling. J Biol Chem 291:25716-25728
Shah, Nirav; Lee, Nam Y (2016) Regulation of gene expression and mitochondrial dynamics by SMAD. Mol Cell Oncol 3:e1204492
Pan, Christopher C; Kumar, Sanjay; Shah, Nirav et al. (2015) Endoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy. J Biol Chem 290:14884-92
Long 3rd, Victor P; Bonilla, Ingrid M; Vargas-Pinto, Pedro et al. (2015) Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling. Life Sci 123:61-71
Varadaraj, Archana; Patel, Pratik; Serrao, Anne et al. (2015) Epigenetic Regulation of GDF2 Suppresses Anoikis in Ovarian and Breast Epithelia. Neoplasia 17:826-38
Pan, Christopher C; Kumar, Sanjay; Shah, Nirav et al. (2014) Src-mediated post-translational regulation of endoglin stability and function is critical for angiogenesis. J Biol Chem 289:25486-96
Kumar, S; Pan, C C; Bloodworth, J C et al. (2014) Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-? signaling. Oncogene 33:3970-9

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