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.

项目描述/摘要 染色质修饰剂的靶向是一种越来越有吸引力的新型策略，可以抑制 转录因子。 MYC是癌症中最常见的癌基因之一，就是这样的转录 事实证明很难直接靶向的因素。小儿MYC扩增的髓母细胞瘤是一种毁灭性的 疾病。在所有髓母细胞瘤港口放大的Myc-异型型中的25％，导致MYC激活 途径。这些肿瘤表现出对用于治疗髓母细胞瘤的标准疗法的耐药性，并且是 以快速和猖ramp的肿瘤进展为特征。抑制MYC激活途径的策略是 在诊所迫切需要被诊断出患有这种疾病的儿童。 最近，抑制表观遗传读取器BET-溴ab蛋白已被发现有效 抑制了包括髓母细胞瘤在内的MYC驱动肿瘤的临床前模型的生长。确实，早 计划针对MYC驱动的儿童进行涉及BET-溴结构域抑制剂的临床试验 包括髓母细胞瘤在内的肿瘤。但是，这些抑制剂的确切作用机理仍然存在 不清楚。此外，其他新型小分子抑制剂的临床经验表明癌症 进化以获得对靶向治疗剂的抵抗力。表征抗性机制可以实现新颖 旨在克服这些机制并提高目标的临床功效的治疗策略 疗法。该提案的目的是系统地表征 对BET-溴结构域抑制的反应。该项目将洞悉 BET-溴结构域抑制剂并指导组合疗法的开发以优化功效。 癌症已被证明可以获取遗传改变，以发展对靶向治疗剂的抗性。 但是，癌症发展以获得对抑制染色质修饰剂的抗性的机制 尚未确定。 BET-溴结构域蛋白调节基因的转录关键确定 细胞认同和细胞状态。 BET-溴结构域抑制剂已被证明会改变细胞状态和细胞认同。 因此，细胞状态的变化可能会影响对BET-溴结构域抑制的敏感性，并且 有助于发展抵抗。该建议将系统地表征抵抗力 MYC扩增的髓母细胞瘤中BET-溴结构域抑制的机制。为了实现这一目标 新的方法将用于表征有助于的基因组和表观基因组改变 对BET-溴结构域抑制的抵抗力。该建议将确定是否 抗药性的获取是预先确定的，将确定有助于抗性的基因的特定变化 并将探讨对BET-溴化域抑制的抵抗力如何受到 这项工作将指导制定治疗策略，以提高这些策略 毒品。结果还将提供有关抑制染色质修饰剂后癌症进化的见解 可能具有多效性。染色质修饰符的调节可能与 在所有谱系中多次癌症。阻力尚未产生的机制 在这些癌症中的任何一个中确定。该项目将为研究染色质修饰剂的研究奠定框架 可以在这些疾病中翻译。 Pratiti Bandopadhayay博士是儿科教练和儿科神经综合医生的 Dana-Farber Cancer Institute和Broad的Rameen Beroukhim博士实验室的博士培训 麻省理工学院和哈佛研究所。 Pratiti以她的临床专业知识和强大的癌症生物学背景为基础 正在获得癌症基因组学和表观基因组学方面的专业知识，特别着眼于研究癌症的进化。 Bandopadhayay博士将在Beroukhim博士和Myles Brown博士的合法下完成该项目 两位医师科学家。 Beroukhim博士本人是神经综合医生，是癌症的国际专家 基因组学，尤其是癌症中拷贝数的变化。他开发了方法论，包括 对癌症中拷贝数的变化的概念。他在研究癌症方面也有丰富的经验 来自整个基因组和整个外显子组测序产生的数据的基因组，对研究感兴趣 癌症异质性和进化。他在Broad Institute和Dana-Farber Cancer任命 研究所确保Bandopadhayay博士将可以使用大量资源来开发 项目并应用新颖的基因组方法。布朗博士是染色质生物学的领导者，并且有广泛的 有指导医师科学家的经验。在他们的指导下，在强大的科学方面的指导 Bandopadhayay博士咨询委员会提出了一项雄心勃勃的研究和培训计划，将 为她配备最高的研究技能，以确保她在指导和独立阶段的成功 奖项。达纳 - 法伯癌症研究所和广大研究所的丰富研究环境 结合DRS的指导团队。 Beroukhim和Brown将提供完美的培训 Bandopadhayay博士的环境，以进一步发展科学培训，以成为独立医师 小儿神经肿瘤学领域的科学家。