Elucidating and overcoming endocrine resistance driven by ESR1 mutations

 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，是目前乳腺癌基于内分泌的辅助治疗的主要靶点。虽然这种内分泌疗法非常有效，但主要的临床限制是获得性内分泌抗性的发展，其降低治疗功效并增加乳腺癌的死亡率。然而，临床前和临床观察表明，即使在这种内分泌抵抗的发展之后，ER信号传导继续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ESR 1（编码ER的基因）突变。该提议的中心假设是，ESR 1突变是内分泌抗性的驱动因素，并且用改进的雌激素受体调节剂（SERM）或降解剂结合对ER信号传导轴的其他关键蛋白的抑制来增加突变雌激素受体的侵袭性和靶向，将导致 肿瘤消退并最终改善临床结果。为了验证这个假设，我们将：1。建立新的体外和体内模型，以扩大我们对ESR 1突变在内分泌耐药和侵袭性中的功能作用的研究2。描绘由ER突变体激活的转录网络，以确定克服内分泌抗性的潜在靶点3。测试第三代SERM巴多昔芬与CDK 4/6抑制剂palbociclib的联合用药，以有效靶向突变型雌激素受体并避免内分泌耐药肿瘤生长。这些研究有可能直接转化为临床竞技场，并改善内分泌抵抗性乳腺癌的治疗。

 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.