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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms

Aaron J. Scott, John J. Arcaroli, Stacey M. Bagby, Rachel Yahn, Kendra M. Huber, Natalie J. Serkova, Anna Nguyen, Jihye Kim, Andrew Thorburn, Jon Vogel, Kevin S. Quackenbush, Anna Capasso, Anna Schreiber, Patrick Blatchford, Peter J. Klauck, Todd M. Pitts, S. Gail Eckhardt and Wells A. Messersmith
Aaron J. Scott
1Division of Hematology and Oncology, Banner University of Arizona Cancer Center, Tucson, Arizona.
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  • For correspondence: ajscott@email.arizona.edu
John J. Arcaroli
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Stacey M. Bagby
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Rachel Yahn
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Kendra M. Huber
3Department of Anesthesia, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Natalie J. Serkova
3Department of Anesthesia, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Anna Nguyen
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Jihye Kim
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Andrew Thorburn
4Department of Pharmacology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Jon Vogel
5Department of Surgery, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Kevin S. Quackenbush
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Anna Capasso
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Anna Schreiber
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Patrick Blatchford
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Peter J. Klauck
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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Todd M. Pitts
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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S. Gail Eckhardt
6Division of Medical Oncology, The University of Texas at Austin, Austin, Texas.
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Wells A. Messersmith
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado.
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DOI: 10.1158/1535-7163.MCT-17-0131 Published October 2018
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Abstract

Antiangiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTK) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models. In this study, we examined the mechanisms of cabozantinib sensitivity, using regorafenib as a control. The tumor growth inhibition index (TGII) was used to compare treatment effects of cabozantinib 30 mg/kg daily versus regorafenib 10 mg/kg daily for a maximum of 28 days in 10 PDX mouse models. In vivo angiogenesis and glucose uptake were assessed using dynamic contrast-enhanced (DCE)-MRI and [18F]-FDG-PET imaging, respectively. RNA-Seq, RTK assay, and immunoblotting analysis were used to evaluate gene pathway regulation in vivo and in vitro. Analysis of TGII demonstrated significant antitumor effects with cabozantinib compared with regorafenib (average TGII 3.202 vs. 48.48, respectively; P = 0.007). Cabozantinib significantly reduced vascularity and glucose uptake compared with baseline. Gene pathway analysis showed that cabozantinib significantly decreased protein activity involved in glycolysis and upregulated proteins involved in autophagy compared with control, whereas regorafenib did not. The combination of two separate antiautophagy agents, SBI-0206965 and chloroquine, plus cabozantinib increased apoptosis in vitro. Cabozantinib demonstrated significant antitumor activity, reduction in tumor vascularity, increased autophagy, and altered cell metabolism compared with regorafenib. Our findings support further evaluation of cabozantinib and combinational approaches targeting autophagy in colorectal cancer. Mol Cancer Ther; 17(10); 2112–22. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received February 10, 2017.
  • Revision received December 1, 2017.
  • Accepted July 9, 2018.
  • Published first July 19, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 17 (10)
October 2018
Volume 17, Issue 10
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Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms
Aaron J. Scott, John J. Arcaroli, Stacey M. Bagby, Rachel Yahn, Kendra M. Huber, Natalie J. Serkova, Anna Nguyen, Jihye Kim, Andrew Thorburn, Jon Vogel, Kevin S. Quackenbush, Anna Capasso, Anna Schreiber, Patrick Blatchford, Peter J. Klauck, Todd M. Pitts, S. Gail Eckhardt and Wells A. Messersmith
Mol Cancer Ther October 1 2018 (17) (10) 2112-2122; DOI: 10.1158/1535-7163.MCT-17-0131

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Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms
Aaron J. Scott, John J. Arcaroli, Stacey M. Bagby, Rachel Yahn, Kendra M. Huber, Natalie J. Serkova, Anna Nguyen, Jihye Kim, Andrew Thorburn, Jon Vogel, Kevin S. Quackenbush, Anna Capasso, Anna Schreiber, Patrick Blatchford, Peter J. Klauck, Todd M. Pitts, S. Gail Eckhardt and Wells A. Messersmith
Mol Cancer Ther October 1 2018 (17) (10) 2112-2122; DOI: 10.1158/1535-7163.MCT-17-0131
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Molecular Cancer Therapeutics
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