IDENTIFYING EPIGENETIC CHANGES CRITICAL FOR TRASTUZUMAB RESISTANCE

识别对曲妥珠单抗耐药性至关重要的表观遗传变化

• 批准号: 8881794
• 负责人: Qin Yan
• 金额: $ 18.11万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881794
• 关键词: Back; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Cells; ChIP-seq; Clinic; Clinical; DNA Methylation; Data; Development; Diagnosis; Drug Targeting; Drug resistance; Drug-sensitive; ERBB2 gene; Epigenetic Process; Event; Genomics; Goals; Knowledge; Light; Link; Malignant Neoplasms; Methods; Mission; Patients; Play; Property; Public Health; RNA library; Research; Resistance; Role; Sampling; System; Techniques; Testing; Therapeutic; Translating; Trastuzumab; Validation; Work; base; cancer diagnosis; cancer therapy; cohort; epigenetic marker; epigenetic profiling; epigenetic regulation; epigenomics; histone modification; innovation; novel; public health relevance; research study; resistance mechanism; small hairpin RNA; targeted cancer therapy; tumor; tumor initiation; tumor progression

 DESCRIPTION (provided by applicant): Drug resistance has become a major challenge in cancer treatment, but the mechanisms are just being discovered. Emerging evidence suggest that some drug resistance mechanisms are due to epigenetic changes and can be targeted to overcome drug resistance. Despite the development of modern genomic and epigenomic methods, there is no systematic approach to discriminate the "driver" and "passenger" epigenetic events. Thus, identification of the driver epigenetic changes that cause drug resistance with a systematic approach is essential for the development of cancer therapeutic strategies to target these changes. The long-term goal is to elucidate the roles of epigenetic events that drive tumor initiation and progression and to translate these findings to the clinic. The objective of this proposal is to identify the critical epigenetic events that confer trastuzuma resistance of HER2+ breast cancer cells. The central hypothesis is that epigenetic changes play a major role in trastuzumab resistance. The hypothesis is based mainly on the preliminary data produced with a unique cell-based system on trastuzumab resistance. The rationale for the proposed research is that better understanding of epigenetic driver events for trastuzumab resistance will result in new and innovative approaches to breast cancer treatment. Therefore, the hypothesis will be tested by pursuing the following two specific aims: 1) Identify the epigenetic regulators that are necessary for trastuzumab resistance, 2) Determine the roles of the epigenetic changes caused by the identified epigenetic regulators in trastuzumab resistance. The proposed research is innovative, because of the novel hypothesis that a major trastuzumab resistance mechanism is epigenetic changes and the systematic approach to integrate a functional screen with targeted epigenomic analysis of the unique cell based system. The proposed research is significant, because it is expected to vertically advance and expand our understanding of epigenetic regulation in drug resistance. Such knowledge is critical for the development of cancer therapies targeting epigenetic aberrations.

 描述(申请人提供)：抗药性已经成为癌症治疗中的一个主要挑战，但其机制才刚刚被发现。新出现的证据表明，一些耐药机制是由表观遗传变化引起的，可以靶向克服耐药性。尽管现代基因组学和表观基因组学方法得到了发展，但没有系统的方法来区分“司机”和“乘客”的表观遗传学事件。因此，用系统的方法识别导致耐药性的驱动因素表观遗传变化，对于开发针对这些变化的癌症治疗策略是至关重要的。长期目标是阐明驱动肿瘤启动和进展的表观遗传事件的作用，并将这些发现转化为临床。这项建议的目的是确定关键的表观遗传学事件，赋予HER2+乳腺癌细胞对曲妥珠玛的耐药性。中心假设是表观遗传变化在曲妥珠单抗耐药中起主要作用。这一假说主要是基于一种独特的基于细胞的系统产生的关于曲妥珠单抗耐药性的初步数据。拟议研究的基本原理是，更好地了解曲妥珠单抗耐药的表观遗传驱动事件将导致乳腺癌治疗的新的和创新的方法。因此，这一假说将通过追求以下两个具体目标来检验：1)确定曲妥珠单抗耐药所必需的表观遗传调节因子，2)确定所识别的表观遗传调节因子在曲妥珠单抗耐药中所引起的表观遗传变化的作用。这项拟议的研究是创新的，因为新的假设认为曲妥珠单抗耐药的主要机制是表观遗传变化，以及将功能筛选与独特细胞系统的有针对性的表观基因组分析相结合的系统方法。这项拟议的研究具有重要意义，因为它有望垂直推进和扩大我们对表观遗传调控耐药的理解。这些知识对于开发针对表观遗传异常的癌症治疗方法至关重要。