Characterizing the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastoma

表征 MYC 扩增的髓母细胞瘤对 BET 溴结构域抑制的耐药机制

• 批准号: 9902350
• 负责人: Pratiti Bandopadhayay
• 金额: $ 24.9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-03 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902350
• 关键词: Advisory Committees; Appointment; Award; BCL2 gene; BETA2 protein; Binding; Biology; Bromodomain; CCND1 gene; CCND2 gene; CRISPR library; Cancer Biology; Cell Cycle; Cell Survival; Cells; Child; Childhood; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Clinic; Clinical; Combined Modality Therapy; Complex; Copy Number Polymorphism; DNA Sequence Alteration; Dana-Farber Cancer Institute; Data; Development; Diagnosis; Disease; Drug resistance; Effectiveness; Enhancers; Ensure; Environment; Epigenetic Process; Essential Genes; Evolution; Exhibits; Family member; G1 Arrest; Gene Expression; Gene Family; Genes; Genetic Transcription; Genomic approach; Genomics; Goals; Growth; Human; In Vitro; Induction of Apoptosis; Institutes; International; Laboratories; Learning; Malignant Neoplasms; Mentors; Mentorship; Methodology; Methyltransferase; Modeling; Mutation; NFIB gene; Oncogenes; Oncogenic; Oncologist; PIK3CA gene; Pathway interactions; Pediatrics; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Pre-Clinical Model; Protein Isoforms; Proteins; Reader; Recurrence; Regulation; Research; Research Training; Resistance; Resistance development; Resources; Role; Scientist; Signal Transduction; Testing; Therapeutic; Training; Training Programs; Translating; Up-Regulation; Work; cancer cell; cancer genome; cancer genomics; cancer heterogeneity; cell determination; clinical efficacy; design; drug efficacy; early phase clinical trial; efficacy testing; epigenomics; exome sequencing; experience; experimental study; in vivo; in vivo Model; inhibitor/antagonist; insight; instructor; interest; medulloblastoma; medulloblastoma cell line; member; neuro-oncology; neurodevelopment; novel; novel strategies; novel therapeutics; overexpression; pleiotropism; post-doctoral training; pre-clinical; prevent; resistance gene; resistance mechanism; response; skills; small molecule inhibitor; structural genomics; success; targeted treatment; therapeutic development; transcription factor; tumor; tumor growth; tumor progression; whole genome

Project Description/Abstract The targeting of chromatin modifiers is an increasingly attractive novel strategy to therapeutically inhibit transcription factors. MYC, one of the most frequently amplified oncogenes in cancer, is one such transcription factor that has proved difficult to target directly. Pediatric MYC-amplified medulloblastoma is a devastating disease. 25% of all medulloblastoma harbor amplification of MYC-isoforms that result in activation of MYC pathways. These tumors exhibit resistance to standard therapies used to treat medulloblastoma and are characterized by rapid and rampant tumor progression. Strategies to inhibit MYC activation pathways are desperately needed in the clinic for children diagnosed with this disease. Recently, inhibition of the epigenetic readers, BET-bromodomain proteins, has been found to be effective in suppressing the growth of preclinical models of MYC driven tumors, including medulloblastoma. Indeed, early phase clinical trials involving BET-bromodomain inhibitors are planned for children with recurrent MYC-driven tumors including medulloblastoma. However, the precise mechanism of action of these inhibitors remains unclear. In addition, clinical experience with other novel small molecule inhibitors has revealed that cancers evolve to acquire resistance to targeted therapeutics. Characterizing resistance mechanisms allows for novel therapeutic strategies to be designed to overcome these mechanisms and increase clinical efficacy of targeted therapeutics. The goal of this proposal is to systematically characterize cancer cell evolution in response to BET-bromodomain inhibition. This project will shed insight on the mechanism of action of BET-bromodomain inhibitors and guide the development of combination therapies to optimize efficacy. Cancers have been shown to acquire genetic alterations to develop resistance to targeted therapeutics. However, the mechanisms by which cancers evolve to acquire resistance to inhibition of chromatin modifiers have not been determined. BET-bromodomain proteins regulate the transcription of genes key to determination of cell-identity and cell-state. BET-bromodomain inhibitors have been shown to alter cell-state and cell-identity. It is thus possible that changes in cell-state can influence sensitivity to BET-bromodomain inhibition and contribute to the development of resistance. This proposal will systematically characterize the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastoma. To achieve this, a number of novel methodologies will be applied to characterize the genomic and epigenomic alterations that contribute to the acquisition of resistance to BET-bromodomain inhibition. This proposal will determine whether the acquisition of resistance is predetermined, will identify specific alterations in genes that contribute to resistance and will explore how resistance to BET-bromodomain inhibition is influenced by This work will guide the development of therapeutic strategies that will increase the clinical efficacy of these drugs. The results will also provide insights about cancers evolution following inhibition of chromatin modifiers that are likely to have pleiotropic effects. The modulation of chromatin modifiers is likely to be relevant to multiple cancers across all lineages. The mechanism(s) through which resistance accrues has not yet been determined in any of these cancers. This project will lay the framework for the study of chromatin modifiers that can translate across these diseases. An Instructor in Pediatrics and a Pediatric Neuro-Oncologist, Dr. Pratiti Bandopadhayay is completing post- doctoral training in the laboratory of Dr. Rameen Beroukhim at the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard. Building on her clinical expertise and strong background in cancer biology, Pratiti is gaining expertise in cancer genomics and epigenomics, with a specific focus on studying cancer evolution. Dr. Bandopadhayay will complete this project under the co-mentorship of Dr. Beroukhim and Dr. Myles Brown, both physician-scientists. Dr. Beroukhim, himself a neuro-oncologist, is an international expert of cancer genomics, in particular of copy-number variations in cancers. He has developed methodologies, including GISTIC to profile copy-number alterations in cancer. He also has considerable experience in studying cancer genomes from data generated by whole genome and whole exome sequencing, with an interest in studying cancer heterogeneity and evolution. His appointments at the Broad Institute and the Dana-Farber Cancer Institute ensure that Dr. Bandopadhayay will have access to a tremendous range of resources to develop the project and to apply novel genomic approaches. Dr. Brown is a leader of chromatin biology, and has extensive experience in mentoring physician scientists. Under their mentorship, with the guidance of a strong scientific advisory committee, Dr. Bandopadhayay has proposed an ambitious research and training program that will equip her with the highest research skills to ensure her success in the mentored and independent phases of the award. The rich research environment of Dana-Farber Cancer Institute and the Broad Institute, in combination with the mentorship team of Drs. Beroukhim and Brown will provide the perfect training environment for Dr. Bandopadhayay to further her scientific training to emerge as an independent physician- scientist in the field of Pediatric Neuro-Oncology.

项目说明/摘要 以染色质修饰剂为靶点是一种越来越有吸引力的治疗抑制的新策略 转录因子。MYC是癌症中最常被扩增的癌基因之一，它就是这样一种转录 事实证明很难直接瞄准的因素。儿童MYC扩增髓母细胞瘤是一种毁灭性的 疾病。在所有髓母细胞瘤中，25%存在导致MYC激活的MYC亚型扩增 小路。这些肿瘤对用于治疗髓母细胞瘤的标准疗法表现出抵抗力，并且 以迅速和猖獗的肿瘤进展为特征。抑制MYC激活途径的策略是 临床上迫切需要为确诊为这种疾病的儿童提供帮助。 最近，抑制表观遗传阅读器BET-溴域蛋白被发现在 抑制MYC驱动的肿瘤的临床前模型的生长，包括髓母细胞瘤。事实上，很早 计划对复发的MYC驱动的儿童进行涉及BET-溴域抑制剂的阶段临床试验 包括髓母细胞瘤在内的肿瘤。然而，这些抑制剂的确切作用机制仍然存在。 不清楚。此外，其他新型小分子抑制剂的临床经验表明，癌症 进化为对靶向治疗产生抵抗力。对抗性机制的表征允许新的 设计治疗策略以克服这些机制并提高靶向治疗的临床疗效 治疗学。这项提议的目标是系统地描述癌症细胞的进化 对BET-溴域抑制的反应。本项目将深入了解黄连的作用机制。 BET-溴域抑制剂，并指导开发组合疗法，以优化疗效。 癌症已被证明会获得基因改变，从而对靶向治疗产生抵抗力。 然而，癌症进化为对染色质修饰物的抑制产生抵抗力的机制 还没有确定。BET-溴域蛋白调节决定关键基因的转录 细胞身份和细胞状态。更好的溴域抑制剂已被证明可以改变细胞状态和细胞特性。 因此，细胞状态的变化可能会影响对BET-溴域抑制的敏感性，并 有助于抗药性的发展。这项提案将系统地描述抵抗运动的特征 MYC扩增的髓母细胞瘤中BET-溴域抑制的机制。为了实现这一目标，许多 将应用新的方法来表征基因组和表观基因组的改变，这些改变有助于 获得对BET-溴域抑制的抗性。这项提议将决定是否 抗药性的获得是预先确定的，将识别导致抗药性的基因的特定变化 并将探索如何影响对BET-溴域抑制的抵抗力 这项工作将指导治疗策略的发展，从而提高这些疾病的临床疗效。 毒品。这些结果还将为抑制染色质修饰物后的癌症进化提供深入的见解 很可能会产生多效性的影响。染色质修饰物的调制很可能与 所有血统都有多种癌症。抵抗力积累的机制(S)还没有 确定为这些癌症中的任何一种。该项目将为染色质修饰剂的研究奠定框架 可以在这些疾病之间传播。 作为儿科讲师和儿科神经肿瘤学家，普拉蒂·班多帕亚伊医生正在完成- 在Dana-Farber癌症研究所和布罗德大学Rameen Beroukhim博士的实验室接受博士培训 麻省理工学院和哈佛大学。凭借她在癌症生物学方面的临床专业知识和深厚背景，普拉蒂蒂 正在获得癌症基因组学和表观基因组学方面的专业知识，重点是研究癌症的进化。 Bandopadhayay博士将在Beroukhim博士和Myles Brown博士的共同指导下完成这一项目， 都是内科医生和科学家。Beroukhim博士本人是一名神经肿瘤学家，也是国际癌症专家 基因组学，特别是癌症中的拷贝数变异。他开发了方法论，包括 GISTIC将对癌症中的拷贝数改变进行分析。他在研究癌症方面也有相当多的经验 从全基因组和整个外显子组测序产生的数据中提取基因组，并对研究感兴趣 癌症的异质性和进化。他在布罗德研究所和达纳-法伯癌症中心的任命 研究所确保Bandopadhayay博士将能够获得大量资源来制定 项目和应用新的基因组方法。布朗博士是染色质生物学的领导者，并拥有广泛的 指导内科科学家的经验。在他们的指导下，在强大的科学工作者的指导下 Bandopadhayay博士提出了一项雄心勃勃的研究和培训计划，将 让她具备最高的研究技能，以确保她在有指导和独立的阶段取得成功 颁奖典礼。达纳-法伯癌症研究所和布罗德研究所丰富的研究环境 与Beroukhim博士和Brown博士的指导团队相结合将提供完美的培训 为Bandopadhayay博士继续她的科学训练成为一名独立的医生提供了环境- 儿童神经肿瘤学领域的科学家。