有望取得突破:VORASIDENIB治疗低级别胶质瘤的潜力。

Alice Bombino, Marcello Magnani, Alfredo Conti
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摘要

简介胶质瘤是常见的恶性脑肿瘤,其特点是弥漫性脑浸润。世界卫生组织II级和III级弥漫性胶质瘤被认为是低级别胶质瘤(LGG),具有异柠檬酸脱氢酶(IDH)突变。低级别胶质瘤具有浸润性,可发展为高级别恶性肿瘤,因此具有挑战性。Vorasidenib是一种靶向突变IDH1/2的新型治疗药物,引发了该领域的兴趣:Vorasidenib通过独特的机制抑制突变体IDH1/2,减少副代谢产物2-羟基戊二酸(2-HG)的产生。这种改变会影响关键酶和 DNA 甲基化,从而影响肿瘤的生长和侵袭。临床前证据:临床前研究显示,vorasidenib 能有效抑制胶质瘤模型中突变的 IDH1/2 和 2-HG 的产生。临床证据:早期临床试验证明了vorasidenib在非增强型胶质瘤中的临床活性。它能降低2-羟基戊二酸水平和肿瘤细胞增殖,客观反应率高,无进展生存期延长。该药物的安全性良好。挑战与未来方向:挑战包括确定预测性生物标志物,优化排序或与现有疗法的组合。结论:orasidenib能显著推进LGG的治疗,靶向一种流行突变并减缓肿瘤生长。有前景的临床前和临床证据以及可控的副作用表明,它对LGG的治疗具有潜在影响。然而,还需要更多的研究(包括大型试验)来证实其疗效和在治疗中的作用。
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A Promising Breakthrough: The Potential of VORASIDENIB in the Treatment of Low-grade Glioma.

Introduction: Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field.

Mechanism of action: Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion. Preclinical Evidence: Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option.

Clinical evidence: Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable. Challenges and Future Directions: Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy.

Conclusion: orasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.

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