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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma

Shiva Kant, Pravin Kesarwani, Anthony R. Guastella, Praveen Kumar, Stewart F. Graham, Katie L. Buelow, Ichiro Nakano and Prakash Chinnaiyan
Shiva Kant
1Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
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Pravin Kesarwani
1Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
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Anthony R. Guastella
1Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
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Praveen Kumar
2Metabolomics and Obstetrics/Gynecology, Beaumont Research Institute, Beaumont Health, Royal Oak, Michigan.
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Stewart F. Graham
2Metabolomics and Obstetrics/Gynecology, Beaumont Research Institute, Beaumont Health, Royal Oak, Michigan.
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  • ORCID record for Stewart F. Graham
Katie L. Buelow
1Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
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Ichiro Nakano
3Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
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Prakash Chinnaiyan
1Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
4Oakland University William Beaumont School of Medicine, Royal Oak, Michigan.
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  • For correspondence: prakash.chinnaiyan@beaumont.edu
DOI: 10.1158/1535-7163.MCT-19-1047 Published July 2020
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Abstract

Glioblastoma is the most common primary malignant brain tumor in adults. Despite aggressive treatment, outcomes remain poor with few long-term survivors. Therefore, considerable effort is being made to identify novel therapies for this malignancy. Targeting tumor metabolism represents a promising therapeutic strategy and activation of fatty acid oxidation (FAO) has been identified as a central metabolic node contributing toward gliomagenesis. Perhexiline is a compound with a long clinical track record in angina treatment and commonly described as an FAO inhibitor. We therefore sought to determine whether this compound might be repurposed to serve as a novel therapy in glioblastoma. Perhexiline demonstrated potent in vitro cytotoxicity, induction of redox stress and apoptosis in a panel of glioblastoma cell lines. However, the antitumor activity of perhexiline was distinct when compared with the established FAO inhibitor etomoxir. By evaluating mitochondrial respiration and lipid dynamics in glioblastoma cells following treatment with perhexiline, we confirmed this compound did not inhibit FAO in our models. Using in silico approaches, we identified FYN as a probable target of perhexiline and validated the role of this protein in perhexiline sensitivity. We extended studies to patient samples, validating the potential of FYN to serve as therapeutic target in glioma. When evaluated in vivo, perhexiline demonstrated the capacity to cross the blood–brain barrier and antitumor activity in both flank and orthotopic glioblastoma models. Collectively, we identified potent FYN-dependent antitumor activity of perhexiline in glioblastoma, thereby, representing a promising agent to be repurposed for the treatment of this devastating malignancy.

Footnotes

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

  • Mol Cancer Ther 2020;19:1415–22

  • Received November 7, 2019.
  • Revision received March 16, 2020.
  • Accepted April 13, 2020.
  • Published first May 19, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (7)
July 2020
Volume 19, Issue 7
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Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma
Shiva Kant, Pravin Kesarwani, Anthony R. Guastella, Praveen Kumar, Stewart F. Graham, Katie L. Buelow, Ichiro Nakano and Prakash Chinnaiyan
Mol Cancer Ther July 1 2020 (19) (7) 1415-1422; DOI: 10.1158/1535-7163.MCT-19-1047

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Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma
Shiva Kant, Pravin Kesarwani, Anthony R. Guastella, Praveen Kumar, Stewart F. Graham, Katie L. Buelow, Ichiro Nakano and Prakash Chinnaiyan
Mol Cancer Ther July 1 2020 (19) (7) 1415-1422; DOI: 10.1158/1535-7163.MCT-19-1047
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Molecular Cancer Therapeutics
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