Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
Metabolomics and Obstetrics/Gynecology, Beaumont Research Institute, Beaumont Health, Royal Oak, Michigan.
Mol Cancer Ther. 2020 Jul;19(7):1415-1422. doi: 10.1158/1535-7163.MCT-19-1047. Epub 2020 May 19.
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 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 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 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.
胶质母细胞瘤是成年人中最常见的原发性恶性脑肿瘤。尽管进行了积极的治疗，但预后仍然很差，很少有长期存活者。因此，人们正在努力寻找这种恶性肿瘤的新疗法。靶向肿瘤代谢代表了一种很有前途的治疗策略，已经确定脂肪酸氧化 (FAO) 的激活是促进神经胶质瘤发生的中央代谢节点。哌克昔林是一种在心绞痛治疗中有长期临床记录的化合物，通常被描述为 FAO 抑制剂。因此，我们试图确定这种化合物是否可以重新用于胶质母细胞瘤的新型治疗。哌克昔林在一系列胶质母细胞瘤细胞系中表现出强烈的细胞毒性、氧化应激和细胞凋亡诱导作用。然而，与已确立的 FAO 抑制剂 etomoxir 相比，哌克昔林的抗肿瘤活性是不同的。通过评估哌克昔林处理后胶质母细胞瘤细胞中的线粒体呼吸和脂质动态，我们证实了这种化合物在我们的模型中没有抑制 FAO。通过使用 方法，我们确定了 FYN 是哌克昔林的一个可能靶点，并验证了该蛋白在哌克昔林敏感性中的作用。我们将研究扩展到患者样本，验证了 FYN 作为神经胶质瘤治疗靶点的潜力。当评估时，哌克昔林显示出在侧翼和原位胶质母细胞瘤模型中穿过血脑屏障和抗肿瘤活性的能力。总的来说，我们在胶质母细胞瘤中确定了哌克昔林的强烈依赖 FYN 的抗肿瘤活性，从而代表了一种有前途的重新用于治疗这种毁灭性恶性肿瘤的药物。
