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Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma
Shiva Kant1, Pravin Kesarwani1, Anthony R Guastella1
1Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
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.
Insights
Repurposing the angina drug perhexiline shows promise for glioblastoma treatment. This FYN-dependent therapy crosses the blood-brain barrier, offering new hope against this aggressive brain cancer.
Area of Science:
- Oncology
- Cancer Metabolism
- Neuro-oncology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- Targeting tumor metabolism, specifically fatty acid oxidation (FAO), is a key therapeutic strategy.
- Existing treatments for GBM are insufficient, necessitating novel therapeutic approaches.
Purpose of the Study:
- To investigate the potential repurposing of perhexiline, an established angina medication, as a novel therapy for glioblastoma.
- To elucidate the mechanism of action of perhexiline in glioblastoma cells, particularly its effect on FAO.
- To identify the molecular targets and therapeutic efficacy of perhexiline in glioblastoma models.
Main Methods:
- In vitro cytotoxicity assays and apoptosis induction studies in glioblastoma cell lines.
- Mitochondrial respiration and lipid dynamics analysis to assess FAO inhibition.
- In silico target identification and subsequent in vitro/in vivo validation.
- Pharmacokinetic studies evaluating blood-brain barrier penetration.
- In vivo efficacy studies in flank and orthotopic glioblastoma xenograft models.
Main Results:
- Perhexiline exhibited potent in vitro cytotoxicity and induced apoptosis in glioblastoma cells.
- Contrary to expectations, perhexiline did not inhibit FAO; its mechanism differs from known FAO inhibitors like etomoxir.
- In silico analysis identified FYN as a key target, and its role in perhexiline sensitivity was validated.
- Perhexiline demonstrated significant antitumor activity in vivo and successfully crossed the blood-brain barrier.
- FYN was validated as a potential therapeutic target in patient-derived glioma samples.
Conclusions:
- Perhexiline demonstrates significant FYN-dependent antitumor activity in glioblastoma, independent of FAO inhibition.
- The drug effectively penetrates the blood-brain barrier and shows efficacy in preclinical glioblastoma models.
- Perhexiline represents a promising candidate for repurposing in glioblastoma treatment, targeting the FYN pathway.
