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: 10063491
• 负责人: Robert Babak Faryabi
• 金额: $ 19.35万
• 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/10063491
• 关键词: 3-Dimensional; 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; GTP-Binding Protein alpha Subunits, Gs; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Histones; Homeostasis; Hyperactivity; Individual; Instruction; 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; Zinc Fingers; base; cancer genome; disease heterogeneity; disorder subtype; functional genomics; gamma secretase; genome editing; genome-wide; improved; inhibitor/antagonist; malignant breast neoplasm; notch protein; novel; programs; promoter; protein expression; 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）占所有乳腺癌病例的约10%，但其生存率为10%。 由于缺乏有效的针对性治疗，这表明，寻找新的 治疗耐药性TNBC，这是进一步复杂的疾病异质性。 不幸的是，靶向疗法在TNBC中的成功是有限的，部分原因是缺乏详细的和有效的方法。 对每个疾病亚组驱动因素的机械理解。TNBC的重要贡献者 病理生物学是Notch信号传导。过度活跃的Notch信号促进肿瘤生长，增加化疗 耐药性，降低生存率，增加转移的机会。虽然生物标志物的 最近已经开发了Notch活性TNBC亚组和靶向Notch信号传导的药物， 迄今为止，Notch抑制剂对患者无效，部分原因是对Notch抑制剂的了解有限。 Notch信号如何控制这些基本过程。 Notch信号传导的一个重要的直接结果是激活关键的TNBC基因，包括MYC， CCND 1和SOX 9。MYC是促进肿瘤生长和存活的最重要的原癌基因之一。 CCND 1在其他细胞过程中控制细胞分裂。S 0X 9增加转移潜能。尽管 尽管它们的重要性，但现有的药物不能直接靶向这些蛋白质。我们建议利用监管 Notch与其靶基因之间的关系，以选择性地和有效地靶向它们。为了实现 为了实现这一目标，我们首先需要了解Notch调控MYC、CCND 1和SOX 9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 他们的Notch-directed调节机制在人口和单细胞的决议。开发出更有效的 我们计划使用最新的单细胞分辨率技术来发现耐药性是如何产生的。 细胞规避Notch抑制药物的作用并维持这些关键Notch靶点的表达。 我们计划在未来利用这些知识为患有TNBC的个体患者定制治疗策略。 激活Notch信号传导，并在此过程中，希望提高这种侵袭性和 乳腺癌是一种很难治疗的癌症。 !