Elucidating and overcoming endocrine resistance driven by ESR1 mutations

 描述(申请人提供)：雌激素受体(ER)是一种转录因子，可促进管腔型乳腺癌的增殖和生长，也是目前乳腺癌内分泌辅助治疗的主要靶点。虽然这样的内分泌治疗非常有效，但临床上的一个主要限制是后天内分泌抵抗的发展，这降低了治疗效果并增加了乳腺癌的死亡率。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信号仍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。这一建议的中心假设是，ESR1突变是内分泌耐药的驱动因素，突变的雌激素受体的侵袭性和靶向性增加，随着雌激素受体调节剂(SERM)或降解物的改善，再加上ER信号轴的其他关键蛋白的抑制，将导致 肿瘤消退，并最终改善临床结果。为了验证这一假设，我们将：1.建立新的体外和体内模型，以扩大我们对ESR1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，以确定克服内分泌耐药的潜在靶点3.测试第三代SERM bazedoxifene与CDK4/6抑制剂palbociclib的组合，以有效靶向突变的雌激素受体，避免内分泌耐药肿瘤的生长。这些研究有可能直接转化到临床领域，并改进内分泌抵抗型乳腺癌的治疗。

 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.