Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood–brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.

中文翻译：

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一种有效的血脑屏障可渗透突变 IDH1 抑制剂抑制患者来源的原位异种移植模型中具有 IDH1 突变的胶质母细胞瘤的生长

胶质瘤是成人中第二常见的原发性脑肿瘤。他们接受联合疗法治疗，包括手术、放疗和化疗。目前复发性胶质瘤的治疗选择有限，需要确定新的靶向疗法，尤其是预后较差的胶质母细胞瘤。在包括神经胶质瘤在内的各种肿瘤中检测到异柠檬酸脱氢酶 (IDH) 突变。大多数 IDH 突变型胶质瘤患者具有 IDH1R132H 亚型。突变 IDH 催化 α-酮戊二酸转化为癌代谢物 2-羟基戊二酸 (2-HG)，这会诱导异常的表观遗传状态并促进恶性进展，因此是 IDH 突变肿瘤的潜在治疗靶点。本研究描述了一种新型的、口服生物可利用的选择性突变 IDH1 抑制剂 DS-1001b。该药物具有高血脑屏障 (BBB) 渗透性并抑制 IDH1R132H。在来自具有 IDH1 突变的胶质母细胞瘤患者的皮下和颅内异种移植模型中，持续给予 DS-1001b 会损害肿瘤生长并降低 2-HG 水平。此外，DS-1001b 强烈诱导胶质纤维酸性蛋白的表达，表明抑制突变体 IDH1 促进了胶质细胞分化。这些结果揭示了 BBB 可渗透性 DS-1001b 在原位患者来源的异种移植模型中的功效，并为 DS-1001b 在复发性神经胶质瘤中的临床测试提供了临床前理论依据。在来自具有 IDH1 突变的胶质母细胞瘤患者的皮下和颅内异种移植模型中，持续给予 DS-1001b 会损害肿瘤生长并降低 2-HG 水平。此外，DS-1001b 强烈诱导胶质纤维酸性蛋白的表达，表明抑制突变体 IDH1 促进了胶质细胞分化。这些结果揭示了 BBB 可渗透性 DS-1001b 在原位患者来源的异种移植模型中的功效，并为 DS-1001b 在复发性神经胶质瘤中的临床测试提供了临床前理论依据。在来自具有 IDH1 突变的胶质母细胞瘤患者的皮下和颅内异种移植模型中，持续给予 DS-1001b 会损害肿瘤生长并降低 2-HG 水平。此外，DS-1001b 强烈诱导胶质纤维酸性蛋白的表达，表明抑制突变体 IDH1 促进了胶质细胞分化。这些结果揭示了 BBB 可渗透性 DS-1001b 在原位患者来源的异种移植模型中的功效，并为 DS-1001b 在复发性神经胶质瘤中的临床测试提供了临床前理论依据。