Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy

项目总结 在2.6万例新诊断的脑和中枢神经系统恶性肿瘤中，神经胶质瘤占80% 肿瘤每年在美国发生，是最致命和最耐药的人类癌症之一。 尽管迫切需要新的方法来对抗这种疾病，但胶质瘤的标准治疗方法还没有。 自2005年以来发生了变化，在过去十年中没有批准任何新的胶质瘤药物治疗方法。作为回应 为了应对这一挑战，我们设计了一种新的方法来治疗具有IDH1基因突变的胶质瘤。IDH1 突变存在于70%-90%的低级别胶质瘤和继发性胶质母细胞瘤中，这是一种高度侵袭性的 胶质瘤的亚型。我们调查了数百种药物，发现有一类药物可以抑制特定的 代谢途径优先杀死IDH1突变的脑瘤细胞。我们的建议是建立在这个基础上的 通过解决三个具体目标来发现。第一个具体目标是了解分子机制。 通过它，IDH1突变增加了对这一代谢途径的抑制剂的敏感性。我们将使用培养的 含有或缺乏IDH1突变的脑瘤细胞系来验证我们的假设，即IDH1的联合作用 突变和这些抑制物严重损害了肿瘤细胞的蛋白质加工和脂肪生产，从而产生 最终引发细胞死亡的压力。具体目标2是使用源自人脑胶质瘤的器官模型 组织来评估IDH1突变的存在是否成功地预测了对该抑制剂的反应 代谢途径，我们建议靶向。有机化合物代表了强大的临床前疾病模型，因为它们 允许我们在细胞系统中测试新的治疗策略，准确地反映人类的组成 脑瘤。具体目标#3是使用胶质瘤的小鼠模型来评估抑制代谢 我们已经确定的对IDH1突变脑瘤细胞重要的途径导致理想的治疗 反应，包括阻止肿瘤生长和延长宿主生存。这些研究将澄清 靶向这一途径可能会为患有IDH1突变脑瘤的人类患者提供好处。已被占用 我们的工作将共同勾勒和测试一种新的脑瘤患者的治疗策略，该策略可能会迅速 如果我们的研究成功，就会被移植到临床上。此外，我们的努力可能会证明IDH1 突变可以用来忠实地识别其肿瘤对治疗有反应的个体。 我们正在开发的策略，从而提供了一种方法来设计潜在的未来临床试验，这些试验具有 为胶质瘤患者提供福利的机会。

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. Although there is a dire need for new ways to combat this disease, the standard treatment for gliomas has not changed since 2005 and no new glioma medical therapies have been approved in the last decade. In response to this challenge, we have devised a new way to treat gliomas that have a mutation in a gene called IDH1. IDH1 mutations are present in 70-90% of lower grade gliomas and secondary glioblastomas, a highly aggressive subtype of glioma. We surveyed hundreds of drugs and discovered that a class of drugs that inhibit a particular metabolic pathway preferentially killed brain tumor cells with IDH1 mutations. Our proposal builds on this discovery by addressing three Specific Aims. Specific Aim #1 is to understand the molecular mechanisms through which IDH1 mutations increase sensitivity to inhibitors of this metabolic pathway. We will use cultured brain tumor cell lines that harbor or lack IDH1 mutations to test our hypothesis that the combined effects of IDH1 mutations and these inhibitors severely impair protein processing and lipid production in tumor cells, creating stress that ultimately triggers cell death. Specific Aim #2 is to use organoid models derived from human glioma tissue to assess whether the presence of an IDH1 mutation successfully predicts response to inhibitors of the metabolic pathway we propose targeting. Organoids represent powerful preclinical disease models because they allow us to test new therapeutic strategies in a cellular system that accurately reflects the makeup of human brain tumors. Specific Aim #3 is to use a mouse model of glioma to assess whether inhibiting the metabolic pathway we've identified to be important for IDH1 mutant brain tumor cells leads to desirable therapeutic responses, including a block in tumor growth and extension of host survival. These studies will clarify whether targeting this pathway is likely to provide benefit for human patients with IDH1 mutated brain tumors. Taken together, our work will outline and test a new treatment strategy for brain tumor patients that could be rapidly translated to the clinic if our studies are successful. Furthermore, our efforts may demonstrate that IDH1 mutations can be used to faithfully identify individuals whose tumors are poised to respond to the treatment strategy we are developing, thereby providing a way to design potential future clinical trials that have the greatest chance to provide benefit for glioma patients.