Notch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast Cancer

三阴性乳腺癌中 MYC 和 CCND1 的 Notch 驱动表观遗传程序

• 批准号: 10520042
• 负责人: Robert Babak Faryabi
• 金额: $ 40.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10520042
• 关键词: 3-Dimensional; Ablation; Binding; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer gene; CCND1 gene; Cell division; Cell physiology; Cells; Chemoresistance; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA; Data; Disease; Dominant-Negative Mutation; Drug resistance; Enhancers; Epigenetic Process; Frequencies; Future; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Histones; Homeostasis; Hyperactivity; Individual; Kinetics; Knowledge; Maps; Mediating; Molecular; Molecular Conformation; Mutate; Neoplasm Metastasis; Oncogenic; Patients; Pharmaceutical Preparations; Population; Positioning Attribute; Process; Proteins; Proto-Oncogenes; Regulation; Regulator Genes; Research; Resistance; Resolution; Role; SP1 gene; Signal Transduction; Subgroup; Survival Rate; Technology; Testing; Therapeutic; Therapeutically Targetable; Tumor Promotion; Zinc Fingers; cancer genome; disease heterogeneity; disorder subtype; functional genomics; genome editing; genome-wide; improved; inhibitor; malignant breast neoplasm; notch protein; novel; programs; promoter; protein expression; secretase; success; targeted treatment; therapeutically effective; therapy resistant; transcription factor; triple-negative invasive breast carcinoma; tumor growth

Project Summary Triple-negative breast cancer (TNBC) accounts for ~10% of all the breast cancer cases, but its survival rate is lower due to the lack of effective targeted treatments. This underscores the importance of finding new treatments for therapy-resistant TNBC, which is further complicated by the disease heterogeneity. Unfortunately, success of targeted therapies in TNBC has been limited, partly due to the lack of a detailed and mechanistic understanding of the drivers of each disease subgroup. An important contributor to the TNBC pathobiology is Notch signaling. Hyperactive Notch signaling promotes tumor growth, increases chemotherapy resistance, decreases survival, and increases the chance of metastases. Although the biomarkers of the Notch-active TNBC subgroup and drugs to target Notch signaling have been recently developed, treating patients with Notch inhibitory agents has been ineffective to date, partly due to the limited understanding of how the Notch signaling controls these fundamental processes. An important direct consequence of Notch signaling is to activate key TNBC genes, including MYC, CCND1 and SOX9. MYC is one of the most important proto-oncogenes promoting tumor growth and survival. CCND1 controls cell division among other cellular processes. SOX9 increases metastatic potential. Despite their importance, existing drugs fail to directly target these proteins. We propose to leverage the regulatory relationships between Notch and its target genes to selectively and efficiently target them. In order to achieve this goal, we first need to understand the mechanisms by which Notch regulates MYC, CCND1, and SOX9 in TNBC. We propose to use cutting-edge functional genomics and chromatin conformation assays to elucidate their Notch-directed regulatory mechanisms at population and single-cell resolutions. To develop more potent therapeutic options, we plan to use the latest single-cell resolution technologies to discover how drug-resistant cells circumvent the effect of Notch inhibitory drugs and maintain the expression of these critical Notch targets. We plan to use this knowledge in the future to tailor therapeutic strategies for individual TNBC patients with activated Notch signaling, and in the process, hope to improve the survival of patients with this aggressive and difficult to treat form of breast cancer. !

项目摘要 三阴性乳腺癌(TNBC)约占所有乳腺癌病例的10%，但其生存率为 由于缺乏有效的靶向治疗，死亡率较低。这就凸显了寻找新事物的重要性 治疗耐药的TNBC，这因疾病的异质性而进一步复杂化。 不幸的是，在TNBC中靶向治疗的成功有限，部分原因是缺乏详细和 对每个疾病亚组的驱动因素有机械性的理解。TNBC的重要贡献者 病理生物学是Notch信号。过度活跃的Notch信号促进肿瘤生长，增加化疗 耐药性，降低存活率，增加转移的机会。尽管生物标记物 Notch活性的TNBC亚群和靶向Notch信号的药物最近被开发出来，治疗 到目前为止，使用Notch抑制药的患者一直无效，部分原因是对 Notch信号如何控制这些基本过程。 Notch信号的一个重要的直接后果是激活关键的TNBC基因，包括MYC， CCND1和SOX9。MYC是促进肿瘤生长和生存的重要原癌基因之一。 CCND1在其他细胞过程中控制细胞分裂。SOX9增加转移潜能。尽管 它们的重要性，现有的药物不能直接针对这些蛋白质。我们建议利用监管机构的 Notch与其靶基因之间的关系，以选择性和有效地靶向它们。为了实现 为了实现这一目标，我们首先需要了解Notch调控MYC、CCND1和SOX9的机制 TNBC。我们建议使用尖端的功能基因组学和染色质构象分析来阐明 他们在群体和单细胞分辨率上的Notch指导的调节机制。开发出更强大的 治疗选择，我们计划使用最新的单细胞分辨技术来发现抗药性 细胞避开Notch抑制药物的影响，并维持这些关键的Notch靶点的表达。 我们计划在未来利用这些知识为患有以下疾病的TNBC患者量身定制治疗策略 激活Notch信号，并在此过程中，希望通过这种积极和积极的方式来提高患者的存活率 难治性乳腺癌。 好了！