Targeting Mechanisms of Endocrine Resistance in Breast Cancer

乳腺癌内分泌抵抗的靶向机制

• 批准号: 10434104
• 负责人: MYLES A BROWN
• 金额: $ 34.08万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434104
• 关键词: Alleles; Aromatase Inhibitors; Bar Codes; Binding; Biopsy; Breast Cancer Patient; CRISPR screen; Cell Line; Cells; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Dana-Farber Cancer Institute; Data; Dependence; Development; Disseminated Malignant Neoplasm; ESR1 gene; Elements; Endocrine; Enhancers; Epigenetic Process; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Exhibits; Feedback; Fulvestrant; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetic study; Growth; Heterogeneity; Immune; Investigation; Ligands; Link; Luteinizing Hormone-releasing Hormone Agonist; Mediating; Metastatic breast cancer; Modeling; Mus; Mutation; NF1 gene; Neoplasm Metastasis; PTEN gene; Patients; Pharmacology; Phenotype; Phosphotransferases; Play; Postmenopause; Premenopause; Property; Receptor Gene; Receptor Signaling; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; TSC1/2 gene; Tamoxifen; Woman; Xenograft procedure; advanced disease; antagonist; base; cancer cell; clinically relevant; genome-wide; hormone therapy; inhibitor; malignant breast neoplasm; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; prevent; programs; refractory cancer; resistance mechanism; single-cell RNA sequencing; src-Family Kinases; success; targeted treatment; therapy resistant; tumor; tumor heterogeneity; tumor microenvironment; tumor xenograft

Project Summary/Abstract Endocrine therapies that inhibit estrogen receptor (ER) signaling are the mainstay of the systemic treatment of ER+ breast cancers. These therapies consist of approaches to reduce estrogen levels including luteinizing hormone-releasing hormone (LHRH) agonists in premenopausal women and aromatase inhibitors (AI) in postmenopausal women, and direct ER antagonists such as tamoxifen and fulvestrant. In the advanced disease setting, however, endocrine therapy-resistant cancers almost invariably emerge and are the major cause of breast cancer deaths. Multiple genetic and epigenetic mechanisms have been proposed to explain the emergence of endocrine therapy resistance. Several groups including our own have characterized mutations in the ER gene (ESR1) itself as a mechanism of resistance in approximately 20-30% of cases. We have developed cell line and patient-derived xenograft (PDX) models of endocrine therapy-resistant ER+ breast cancer driven by these ESR1 mutations and have found that these mutations exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that confer on ER novel signaling functions that promote a pro-metastatic EMT-like phenotype. In addition, using genome-wide CRISPR screens, we have identified genes essential for the growth of ER+ breast cancers. Importantly, we have also identified genes whose loss confers endocrine therapy resistance in the setting of the wild-type ER, including NF1, TSC1/2, PTEN and CSK. In these studies, we have found that loss of CSK leads to activation of SRC-family kinases (SFK), thereby promoting estrogen-independent growth and a pro-metastatic cancer cell phenotype. Notably, expression of CSK is regulated by estrogen through binding of ER directly to a transcriptional enhancer in the CSK gene. This reveals the existence of an estrogen-induced negative feedback loop that constrains the growth of ER+ tumors thereby limiting the efficacy of current therapies that target ER. The existence of this feedback loop suggests the provocative hypothesis that current endocrine therapies may themselves promote a pro- metastatic phenotype. Consistent with the overarching theme of this program to define new therapeutic vulnerabilities, we will study how genetic and epigenetic heterogeneity impact the development of resistance to endocrine therapy. Success of this project will allow the development integrative models of the mechanisms of endocrine therapy resistance that include the effect of tumor heterogeneity that can be used to predict effective new therapeutic targets and will allow the investigation of the link between endocrine therapy resistance, endocrine therapy and metastasis.

项目摘要/摘要 抑制雌激素受体（ER）信号传导的内分泌疗法是全身治疗的支柱 ER+乳腺癌。这些疗法包括降低雌激素水平的方法 绝经前女性和芳香酶抑制剂（AI）中释放激素激素（LHRH）激动剂 绝经后妇女，以及诸如他莫昔芬和富伏者之类的直接ER拮抗剂。在晚期疾病中 但是，设置内分泌疗法的癌症几乎总是出现 乳腺癌死亡。已经提出了多种遗传和表观遗传机制来解释 内分泌疗法抗性的出现。包括我们自己在内的几个小组都表征了突变 在大约20-30％的病例中，ER基因（ESR1）本身是抗药性机制。我们已经发展了 细胞系和患者衍生的异种移植（PDX）模型的内分泌治疗ER+乳腺癌的模型 这些ESR1突变，发现这些突变表现出与配体无关的功能 雌二醇结合的野生型ER以及等位基因特异性的新形态特性，赋予ER新型信号 促进促源性EMT样表型的功能。此外，使用全基因组CRISPR屏幕， 我们已经确定了对ER+乳腺癌生长至关重要的基因。重要的是，我们还确定了 损失在野生型ER中赋予内分泌疗法抗性的基因，包括NF1，TSC1/2， PTEN和CSK。在这些研究中，我们发现CSK的损失导致SRC家庭激酶的激活 （SFK），从而促进与雌激素无关的生长和促逆转癌细胞表型。尤其， CSK的表达通过ER直接与转录增强子的结合来调节 CSK基因。这揭示了存在雌激素诱导的负反馈回路的存在，从而限制了生长 ER+肿瘤的局限性，从而限制了靶向ER的当前疗法的功效。这种反馈的存在 循环表明了一个挑衅的假设，即当前内分泌疗法本身可能促进 转移表型。与该程序的总体主题一致，以定义新的治疗性 脆弱性，我们将研究遗传和表观遗传异质性如何影响抗性的发展 内分泌疗法。该项目的成功将允许开发综合模型 内分泌疗法抗性的机制，包括肿瘤异质性的作用 用于预测有效的新治疗靶标，并将调查 内分泌疗法耐药性，内分泌疗法和转移。