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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

基本信息

批准号：
10627815
负责人：
David Daniels
金额：
$ 37.36万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/10627815
关键词：
Affect Animal Experimentation Animal Model Animals Automobile Driving Brain Brain Neoplasms Brain Stem Cell Cycle 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 intrinsic pontine glioma Disease Drug Delivery Systems Drug Screening Drug Targeting Epigenetic Process Foundations Gene Expression Gene Expression Profile Genes Glioma Goals H3 K27M mutation Histone H3 Histones In Vitro Longevity Lysine Malignant Neoplasms Malignant neoplasm of brain Medicine Methionine Methylation Mitosis Mitotic Molecular Mus Mutation Names Neurosurgeon Nucleosomes Pathologic Patients Pattern Pediatric Neoplasm Pharmaceutical Preparations Pharmacotherapy Phosphorylation Plasma Proliferating 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 aurora kinase aurora kinase A cancer cell diffuse midline glioma effective therapy efficacy evaluation epigenetic marker epigenetic regulation epigenome epigenomics experimental study gene repression histone methylation inhibitor kinase inhibitor live cell imaging methylation pattern molecular targeted therapies neoplastic cell non-invasive monitor novel therapeutics palliative patient derived xenograft model pediatric patients pharmacologic potential biomarker preclinical study programs protein H(3)success targeted treatment treatment effect treatment response tumor tumorigenesis

项目摘要

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.

项目摘要影响大脑的肿瘤比儿童中任何其他类型的肿瘤导致更多的癌症相关死亡。是因此，确定治疗这些致命疾病的新疗法至关重要。在儿科患者中，具有破坏性的脑肿瘤类型是具有H3 K27 M突变的弥漫性中线胶质瘤，其包括以前称为弥漫性内在脑桥胶质瘤（DIPG）。我们对这种致命疾病的了解最近被重要的发现所推动，包括发现几乎所有的DIPG肿瘤都含有组蛋白H3 K27 M突变该突变导致H3 K27残基的整体低甲基化，并且是H3 K27残基的突变。这种疾病的病理标志H3 K27 M突变在肿瘤发生中的重要性仍在研究中。阐明。在马约诊所，我们已经证明H3 K27 M突变可以重新编程基因表达和组蛋白。甲基化模式，是这些致命肿瘤的关键驱动因素。我们假设这种突变治疗的弱点，这可以用来开发新的疗法。为了发掘潜在的针对H3 K27 M肿瘤的药物靶点，我们进行了大规模的药物筛选， AKI抑制剂（阿基）作为一类有效的药物，可降低H3 K27 M肿瘤细胞的增殖和存活线进一步的测试揭示了阿基治疗的表观遗传变化，包括恢复H3 K27 me 3水平，降低H3 S10和H3 S28磷酸化水平。极光激酶A抑制剂alisertib在受试者中的测试原位患者来源的异种移植物显示肿瘤尺寸减小、存活率增加和靶向药物治疗增加。肿瘤内的影响。基于这些令人兴奋的结果，我们假设抑制极光激酶是一种靶向治疗方法，治疗H3 K27 M突变的肿瘤。在这个建议中，我们将阐明H3 K27 M突变如何影响有丝分裂，AKI如何调节细胞周期和有丝分裂停滞的机制，并了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节抑制前后的表观遗传景观和基因表达。最后，我们将执行在动物模型中进行必要的临床前研究，以支持临床上的转化工作。我们已经组建成功完成这个项目所需的必要团队：包括Jann Sarkaria，一个辐射专门从事高级别胶质瘤转化动物研究的肿瘤学家Ted Hinchcliffe，有丝分裂的Hormel/明尼苏达大学的Steven Johnsen，一位研究表观遗传调控的专家，癌症，和PI，大卫丹尼尔斯，儿科神经外科医生和药物化学家，谁开发了许多H3 K27 M细胞系和研究药物输送到脑干。我们共同相信，拟议的研究和团队，将不仅使基本的科学发现，旨在了解分子基础，肿瘤的发生，而且也为这种致命疾病的有效治疗奠定了基础。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Overcoming translational barriers in H3K27-altered diffuse midline glioma: Increasing the drug-tumor residence time.

DOI：
10.1093/noajnl/vdad033
发表时间：
2023-01
期刊：
Neuro-oncology advances
影响因子：
0
作者：
通讯作者：

H3K27-altered diffuse midline glioma: a paradigm shifting opportunity in direct delivery of targeted therapeutics.

H3K27 改变的弥漫性中线神经胶质瘤：直接提供靶向治疗的范式转变机会。

DOI：
10.1080/14728222.2023.2177531
发表时间：
2023
期刊：
Expert opinion on therapeutic targets
影响因子：
5.8
作者：
Rechberger,JulianS;Power,BlakeT;Power,EricaA;Nesvick,CodyL;Daniels,DavidJ
通讯作者：
Daniels,DavidJ

Nanoparticle Strategies to Improve the Delivery of Anticancer Drugs across the Blood-Brain Barrier to Treat Brain Tumors.

改善抗癌药物穿过血脑屏障的递送以治疗脑肿瘤的纳米颗粒策略。

DOI：
10.3390/pharmaceutics15071804
发表时间：
2023-06-23
期刊：
PHARMACEUTICS
影响因子：
5.4
作者：
Vanbilloen, Wouter J. F.;Rechberger, Julian S.;Anderson, Jacob B.;Nonnenbroich, Leo F.;Zhang, Liang;Daniels, David J.
通讯作者：
Daniels, David J.

Feasibility of probe washing after stereotactic needle biopsy as a novel technique for developing cell lines and xenografts of H3 K27-altered diffuse midline gliomas.

立体定向针活检后探针清洗作为开发 H3 K27 改变的弥漫性中线神经胶质瘤细胞系和异种移植物的新技术的可行性。

DOI：
10.3171/2023.5.peds22557
发表时间：
2023
期刊：
Journal of neurosurgery. Pediatrics
影响因子：
0
作者：
Rechberger,JulianS;Zhang,Liang;Ge,Jizhi;Nesvick,CodyL;Miller,KaiJ;Daniels,DavidJ
通讯作者：
Daniels,DavidJ