TRANSCRIPTIONAL REPROGRAMMING OF ESR1 MUTANT BREAST CANCER IN METASTASIS AND TREATMENT RESISTANCE

ESR1 突变乳腺癌的转录重编程导致转移和治疗抵抗

• 批准号: 10580788
• 负责人: SARAH HERZOG
• 金额: $ 4.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580788
• 关键词: Address; Aromatase Inhibitors; Automobile Driving; Bioinformatics; Biological Assay; Breast Cancer Patient; Candidate Disease Gene; Cells; ChIP-seq; Clinical; Clinical Management; Clonal Evolution; Computational Biology; Computer Analysis; Computing Methodologies; DNA; DNA sequencing; Data; Development; Disease; Disease Management; Disease Progression; Disease Resistance; Enzyme Inhibitor Drugs; Estrogen Receptors; Estrogen receptor positive; Estrogens; Evolution; Exhibits; FDA approved; Frequencies; Gene Mutation; Genetic Transcription; Goals; Growth; Growth Factor Receptors; In Vitro; Induced Mutation; Knowledge; Laboratories; MAP Kinase Gene; Malignant Neoplasms; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modeling; Mutation; Neoplasm Metastasis; Oncogenic; Other Genetics; Outcome; Pathway interactions; Patients; Phenotype; Pilot Projects; Prevalence; Primary Neoplasm; Proliferating; Publishing; RNA; Receptor Gene; Recurrence; Recurrent disease; Resistance; Signal Pathway; Site; Somatic Mutation; Testing; Treatment Efficacy; United States; Validation; Woman; cell growth; hormonal signals; hormone therapy; improved; in vivo; inhibitor; malignant breast neoplasm; metastatic process; mortality; mutant; pressure; resistance mechanism; standard of care; targeted treatment; therapeutic target; therapy resistant; transcriptional reprogramming; transcriptome sequencing; tumor

Project Summary Up to 1 in 8 women in the United States will develop invasive breast cancer in their lifetime, with 70-80% of cases being estrogen receptor positive (ER+). These cancers rely on hormonal signaling, allowing for treatment with endocrine therapy (ET), including inhibitors of the aromatase enzyme, lowering estrogen levels, or targeting of the ER itself using modulators and degraders. While these therapies reduce mortality by up to 40%, the disease often recurs and progresses to metastasis as a result of ET resistance. The main mechanism of resistance is the acquisition of estrogen receptor gene (ESR1) mutations. These mutations confer constitutive activation to ER, exhibiting reduced sensitivity to endocrine therapies, and are found in up to 38% of metastases. There is currently no approved therapy specific to patients harboring these mutations, which should be a clinical priority given their prevalence in metastatic disease. The Fuqua laboratory has identified distinct transcriptional changes between primary and metastatic site tumors, and between therapy-resistant ESR1 mutants and wild type ER cells. In a study of 900 metastatic breast cancer patients, ESR1 mutations were mutually exclusive with other ER+ breast cancer mutations including Myc and MAPK pathways at the DNA level, but current data in the Fuqua laboratory and others indicates ESR1 mutations activate these same growth and proliferation pathways at the transcriptional level. Given the ESR1 mutant’s proclivity for metastasis and therapy-resistance, this proposal’s central hypothesis is ESR1 mutations generate a transcriptionally reprogrammed phenotype promoting both metastasis and ET resistance in breast cancer. The rationale for this proposal is that identifying transcriptional changes in ESR1 metastases and resistant tumors, improves understanding of ESR1 mutant disease evolution. By targeting transcriptional changes occurring during this evolution, patients can remain on ET longer and extend metastasis-free survival. To test this central hypothesis, we propose two Specific Aims. Aim 1: What clonal and transcriptional changes accompany metastasis in ESR1 mutant-containing tumors subjected to ET pressure? This Aim uses computational methods to identify clonal evolution and transcriptional drivers of metastasis using single cell RNA/DNA-seq and ChIP-seq. Transcriptional drivers will be validated using FDA-approved inhibitors of these candidates in combination with ET using ex vivo assays. Aim 2: Does ET enhance the acquisition of ESR1 mutations, promoting subclonal evolution to drive therapy resistance? This Aim is addressed by developing models with ESR1 mutations acquired during long-term ET and utilizing computational biology via a combination of single cell DNA-seq and RNA-seq to determine the clonal evolution and transcriptional driver candidates of ET resistance. Driver candidates will be validated using selective inhibitors in combination with ET in vitro and in vivo. The results of this proposal will have a positive impact on the field as they lay the groundwork for mutant-specific therapeutic targets to slow the progression of disease by prolonging metastasis-free survival and ET sensitivity by enhancing the durability of treatment.

项目摘要 在美国，每8名女性中就有1人会在一生中患上浸润性乳腺癌，70-80%的病例 雌激素受体阳性（ER+）。这些癌症依赖于激素信号传导，允许用 内分泌治疗（ET），包括芳香酶抑制剂，降低雌激素水平，或靶向 ER本身使用调节剂和降解剂。虽然这些疗法可将死亡率降低高达40%，但疾病 由于ET耐药，经常复发并进展为转移。耐药的主要机制是 雌激素受体基因（ESR 1）突变的获得。这些突变赋予组成性激活， ER，表现出对内分泌治疗的敏感性降低，并且在高达38%的转移瘤中发现。有 目前还没有针对携带这些突变的患者的批准治疗，这应该是临床优先考虑的问题。 因为它们在转移性疾病中很常见福库实验室已经发现了不同的转录变化 原发和转移部位肿瘤之间，以及治疗抗性ESR 1突变体和野生型ER之间 细胞在一项900例转移性乳腺癌患者的研究中，ESR 1突变与其他突变相互排斥。 ER+乳腺癌突变，包括DNA水平的Myc和MAPK通路，但Fuqua研究中的当前数据 实验室和其他研究表明，ESR 1突变激活了这些相同的生长和增殖途径， 转录水平。考虑到ESR 1突变体的转移和治疗抗性倾向， 中心假设是ESR 1突变产生转录重编程表型， 乳腺癌的转移和ET抵抗。这项建议的理由是， ESR 1转移和耐药肿瘤中的转录变化，提高了对ESR 1突变体的理解 疾病演变通过靶向在这一演变过程中发生的转录变化，患者可以保持 ET时间延长，无转移生存期延长。为了验证这一核心假设，我们提出了两个具体目标。 目的1：在含有ESR 1突变的肿瘤中，伴随转移的克隆和转录变化是什么 是否承受ET压力？本目标使用计算方法来确定克隆进化和转录 使用单细胞RNA/DNA-seq和ChIP-seq的转移驱动程序。转录驱动程序将使用 FDA批准的这些候选物的抑制剂与ET的组合，使用离体测定。目标2：ET是否 增强ESR 1突变的获得，促进亚克隆进化以驱动治疗抗性？这一目标 通过开发在长期ET期间获得的ESR 1突变模型并利用 通过单细胞DNA-seq和RNA-seq的组合来确定克隆进化的计算生物学 和ET抗性的转录驱动候选物。将使用选择性的 抑制剂与ET的组合在体外和体内。这项提案的结果将对以下方面产生积极影响： 该领域，因为他们奠定了基础，为特定的治疗目标，以减缓疾病的进展， 通过增强治疗的持久性延长无转移生存期和ET敏感性。