Elucidating and overcoming endocrine resistance driven by ESR1 mutations

阐明并克服 ESR1 突变驱动的内分泌抵抗

• 批准号: 9105818
• 负责人: Rinath M. Jeselsohn
• 金额: $ 17.71万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105818
• 关键词: Adjuvant Therapy; Affinity; Automobile Driving; Binding Sites; Biological Assay; Breast Cancer therapy; CDK4 gene; Cell Cycle Regulation; Cell Line; Clinical; DNA Binding; Data; Development; Drug Combinations; ESR1 gene; Endocrine; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen receptor positive; Estrogens; Event; Fulvestrant; Generations; Growth; Health; Hormones; Immunoprecipitation; In Vitro; Lead; Ligand Binding Domain; Mass Spectrum Analysis; Mediating; Metastatic breast cancer; Methods; Modeling; Molecular; Mutation; Neoplasm Metastasis; Nuclear; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Proteins; Receptor Signaling; Resistance; Resistance development; Role; Sampling; Selective Estrogen Receptor Modulators; Signal Pathway; Tamoxifen; Testing; Therapeutic; Translating; Treatment Efficacy; Xenograft procedure; actionable mutation; base; chromatin immunoprecipitation; design; estrophilin; genome-wide; hormone therapy; improved; in vivo; in vivo Model; inhibitor/antagonist; loss of function; malignant breast neoplasm; mortality; mutant; novel; overexpression; pre-clinical; protein protein interaction; stable cell line; transcription factor; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): The estrogen receptor (ER) is a transcriptional factor that drives both the proliferation and growth of luminal type breast cancers and is the major target of current endocrine-based adjuvant therapies for breast cancer. Although such endocrine therapies are very effective, a major clinical limitation is the development of acquired endocrine resistance that diminishes therapeutic efficacy and increases mortality from breast cancer. Nevertheless, pre-clinical and clinical observations suggest that even following the development of such endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression. We have recently detected ESR1 (the gene that encodes for ER) mutations in 14% of patients ER positive metastatic breast cancer. The central hypothesis of this proposal is that the ESR1 mutations are drivers of endocrine resistance and increased invasiveness and targeting of the mutant estrogen receptor with improved estrogen receptor modulators (SERMs) or degraders combined with the inhibition of other key proteins of the ER signaling axis, will lead to tumor regression and eventually improved clinical outcomes. To test this hypothesis we will: 1. Establish new in-vitro and in- vivo models to expand our studies on the functional roles of the ESR1 mutations in endocrine resistance and invasiveness 2. Delineate the transcriptional network activated by the ER mutants to identify potential targets to overcome endocrine resistance 3. Test the combination of bazedoxifene, a third generation SERM, together with palbociclib, a CDK4/6 inhibitor, to effectively target the mutant estrogen receptors and circumvent endocrine resistant tumor growth. These studies have the potential to be directly translated to the clinical arena and improve the treatment of endocrine resistant breast cancer.

 描述（由申请人提供）：雌激素受体（ER）是一种转录因子，可驱动管腔型乳腺癌的增殖和生长，并且是当前基于内分泌的乳腺癌辅助治疗的主要靶标。尽管此类内分泌疗法非常有效，但主要的临床限制是获得性内分泌抵抗的发展，这会降低乳腺癌的治疗效果并增加死亡率。然而，临床前和临床观察表明，即使出现这种内分泌抵抗，ER 信号传导仍然在肿瘤进展中发挥关键作用。我们最近在 14% 的 ER 阳性转移性乳腺癌患者中检测到 ESR1（编码 ER 的基因）突变。该提案的中心假设是，ESR1 突变是内分泌抵抗和侵袭性增加的驱动因素，通过改进的雌激素受体调节剂 (SERM) 或降解剂靶向突变雌激素受体，并结合抑制 ER 信号轴的其他关键蛋白，将导致 肿瘤消退并最终改善临床结果。为了检验这一假设，我们将： 1. 建立新的体外和体内模型，以扩展我们对 ESR1 突变在内分泌抵抗和侵袭性中的功能作用的研究 2. 描绘 ER 突变体激活的转录网络，以确定克服内分泌抵抗的潜在靶点 3. 测试第三代 SERM 巴多昔芬与 CDK4/6 帕博西尼的组合 抑制剂，有效靶向突变雌激素受体并规避内分泌耐药肿瘤的生长。这些研究有可能直接转化为临床领域并改善内分泌抵抗性乳腺癌的治疗。