Working towards targeted therapy in H3K27M tumors: Aurora Kinase Inhibitors and the role of epigenome programming

致力于 H3K27M 肿瘤的靶向治疗：极光激酶抑制剂和表观基因组编程的作用

• 批准号: 10027382
• 负责人: David Daniels
• 金额: $ 37.06万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027382
• 关键词: Affect; Animal Experimentation; Animal Model; Animals; Automobile Driving; Brain; Brain Neoplasms; Brain Stem; Cell Cycle; Cell Cycle Arrest; Cell Line; Cell Survival; Cell physiology; Cells; Cessation of life; ChIP-seq; Child; Childhood; Childhood Glioma; Chromatin Structure; Chromosomal Instability; Clinic; Clinical; Clinical Trials; Data; Diagnosis; Diffuse; Diffuse intrinsic pontine glioma; Disease; Drug Delivery Systems; Drug Screening; Drug Targeting; Epigenetic Process; Foundations; Gene Expression; Gene Expression Profile; Genes; Glioma; Goals; Histone H3; Histones; In Vitro; Longevity; Lysine; Malignant Neoplasms; Malignant neoplasm of brain; Methionine; Mitosis; Mitotic; Molecular; Mus; Mutation; Names; Neurosurgeon; Nucleosomes; Pathologic; Patients; Pattern; Pediatric Neoplasm; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphorylation; Plasma; Radiation Oncologist; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Research; Role; Site; Somatic Mutation; Testing; Therapeutic; Tumor Cell Line; Tumor-Derived; Universities; Variant; Vision; Xenograft Model; Xenograft procedure; aurora kinase; aurora kinase A; base; cancer cell; effective therapy; epigenetic marker; epigenetic regulation; epigenome; epigenomics; experimental study; gene repression; histone methylation; inhibitor/antagonist; kinase inhibitor; live cell imaging; methylation pattern; molecular targeted therapies; neoplastic cell; non-invasive monitor; novel therapeutics; palliative; pediatric patients; potential biomarker; preclinical study; protein H(3); success; targeted treatment; treatment effect; treatment response; tumor; tumorigenesis

PROJECT SUMMARY Tumors affecting the brain result in more cancer-related deaths than any other type of tumor in children. It is therefore critical to identify new therapies for these deadly diseases. Among pediatric patients, one of the most devastating brain tumor types is diffuse midline gliomas with the H3K27M mutation, which includes the previously named Diffuse Intrinsic Pontine Glioma (DIPG). Our understanding of this deadly disease has recently been advanced by important discoveries, including the finding that almost all of DIPG tumors harbor the histone H3K27M mutation. This mutation results in global hypomethylation of H3K27 residues and is the pathological hallmark for this disease. How the H3K27M mutation is important for tumorigenesis is still being elucidated. At Mayo Clinic, we have shown that H3K27M mutation reprograms gene expression and histone methylation patterns, and is a key driver for these deadly tumors. We hypothesize this mutation creates unique therapeutic vulnerabilities, which can be exploited to develop novel therapies. In an effort to discover potential drug targets for H3K27M tumors, we performed a large scale drug screen which identified aurora kinase inhibitors (AKI) as a potent class of drugs that decreased the proliferation and survival of H3K27M tumor cell lines. Further testing revealed epigenetic changes with AKI treatment including restoring H3K27me3 levels, and decreased H3S10 and H3S28 phosphorylation. Testing of the aurora kinase A inhibitor alisertib in an orthotopic patient derived xenografts showed decreased tumor size, increased survival and on-target drug effects within the tumor. Based on these exciting results, we hypothesize that inhibition of Aurora Kinase is a targeted approach for treating tumors with the H3K27M mutation. In this proposal, we will elucidate how the H3K27M mutation effects mitosis, the mechanism how AKIs modulate the cell cycle and arrest of mitosis and understand the radiosensitizing effects of these drugs. Next we will understand the molecular mechanisms how aurora kinases modulate the epigenetic landscape and gene expression before and after inhibition. Finally, we will perform the necessary preclinical studies in animal models to support translational efforts in the clinic. We have assembled the necessary team required to successfully complete this project: including Jann Sarkaria, a radiation oncologist who specializes in translational animal research for high-grade gliomas, Ted Hinchcliffe, an expert in mitosis from the Hormel/University of MN, Steven Johnsen, an expert who studies epigenetic regulation in cancer, and the PI, David Daniels, a pediatric neurosurgeon and medicinal chemist, who has developed numerous H3K27M cell lines and studies drug delivery to the brainstem. We believe, together, the proposed studies and team, will not only make basic scientific discoveries aimed at understanding the molecular basis of tumorigenesis, but also lay the foundation for effective therapy for this deadly disease.

项目总结 影响大脑的肿瘤导致的癌症相关死亡比儿童中任何其他类型的肿瘤都要多。它是 因此，确定这些致命疾病的新疗法至关重要。在儿科患者中，最多的 毁灭性的脑肿瘤类型是带有H3K27M突变的弥漫性中线胶质瘤，其中包括 以前被称为弥漫性固有桥脑胶质瘤(DIPG)。我们对这种致命疾病的理解 最近的重大发现，包括发现几乎所有的DIPG肿瘤都有 组蛋白H3K27M突变。这种突变导致H3K27残基的全局低甲基化，是 这种疾病的病理特征。H3K27M突变在肿瘤发生中的重要作用仍在研究中 已澄清。在梅奥诊所，我们已经证明H3K27M突变重新编程了基因表达和组蛋白 甲基化模式，是这些致命肿瘤的关键驱动因素。我们假设这种突变会产生独特的 治疗的脆弱性，这可以被利用来开发新的治疗方法。为了努力发现潜力 针对H3K27M肿瘤的药物靶点，我们进行了大规模的药物筛选，确定了极光激酶 抑制物(AKI)作为一类有效的药物抑制H3K27M肿瘤细胞的增殖和存活 台词。进一步的测试显示了AKI治疗的表观遗传学变化，包括恢复H3K27me3水平， 降低H3S10和H3S28的磷酸化水平。极光激酶A抑制剂泽泻替布的检测 原位患者来源的异种移植物显示肿瘤体积缩小，存活率增加，靶向药物 对肿瘤的影响。 基于这些令人兴奋的结果，我们假设抑制Aurora Kinase是一种有针对性的方法 用H3K27M突变治疗肿瘤。在这项建议中，我们将阐明H3K27M突变如何影响 有丝分裂，Akis调节细胞周期和有丝分裂停滞的机制，并理解 这些药物的放射增敏作用。接下来，我们将了解极光激酶的分子机制 调控抑制前后的表观遗传格局和基因表达。最后，我们将执行 在动物模型中进行必要的临床前研究，以支持临床上的翻译工作。我们已经集合好了 成功完成这一项目所需的必要团队：包括Jann Sarkaria，一个辐射 肿瘤学家泰德·欣克克利夫专门从事高级别胶质瘤的动物翻译研究，他是 霍梅尔/明尼苏达大学的有丝分裂，史蒂文·约翰森，一位研究表观遗传调控的专家 癌症，和PI，大卫·丹尼尔斯，一位儿科神经外科医生和药物化学家，他已经开发出 许多H3K27M细胞株，并研究药物向脑干的输送。我们共同认为，拟议的 研究和团队，不仅将做出基本的科学发现，旨在了解分子基础 肿瘤的发生，也为这种致命疾病的有效治疗奠定了基础。