Mechanisms of resistance to endocrine therapy in ER positive breast cancer

项目总结/摘要：内分泌治疗抵抗机制 ER+乳腺癌 雌激素受体阳性（ER+）乳腺癌是乳腺癌中最常见的亚型，但约20%的ER+乳腺癌是乳腺癌中最常见的亚型。 在辅助内分泌治疗期间或之后，肿瘤复发，约占2010年乳腺癌死亡的50%。 美国每年CDK 4/6抑制剂palbociclib、ribociclib和abemaciclib最近已在美国获得批准。 与内分泌疗法组合用于治疗转移性ER+乳腺癌。然而，对于其他 癌症靶向治疗，所有接受CDK 4/6抑制剂治疗的转移性疾病患者最终都会进展， 这表明获得性耐药机制的发展仍有待发现。我们 我提出了一个继续的项目，我们将调查异常FGFR信号传导对耐药性的影响。 在ER+乳腺癌患者中联合CDK 4/6抑制剂进行内分泌治疗， 目的： 目的1：阐明FGFR 1扩增赋予对联合治疗耐药的机制。 氟维司群和CDK 4/6抑制剂在ER+/FGFR扩增乳腺癌中的应用 目的2：进行ER下调剂氟维司群+的Ib期和随机II期试验 Palbociclib ± pan-FGFR抑制剂erdafitinib治疗ER+/FGFR扩增的转移性乳腺癌患者 目的3：发现来源于CDK 4/6进展的肿瘤的类器官中的耐药机制 抑制剂的这些将包括：1）接受氟维司群/哌柏西利治疗后进展的患者的肿瘤± Erdafitinib用于Aim 2，和2）来自接受CDK 4/6标准治疗的乳腺癌患者的肿瘤 抑制剂 据我们所知，这是首次将FGFR抑制剂与ER和CDK 4/6联合测试 抑制剂在携带FGFR扩增的乳腺癌患者中的应用。这项临床试验的积极结果 可能为患有FGFR扩增/ ER+乳腺癌的女性提供一种新的治疗选择， 细胞毒化疗氟维司群、帕博西尼和erdafitinib联合用药的疗效增加也将 加速FGFR抑制剂的开发。我们寻求鉴定生物标志物，预测对 在适当选择的ER+转移性乳腺癌患者的试验中，可以使用这种组合。在 此外，对来自治疗进展的癌症的类器官的全面分子分析提供了 这是一个无偏见地发现新的耐药分子机制的机会。这些 反过来，这些机制可能代表了可操作的分子靶点，这些靶点可能是未来药物发现的焦点 在乳腺癌和其他FGFR依赖性癌症中的研究和/或转化/临床研究。因此，目标 本文提出的化合物可有助于根除ER+乳腺癌的进展。

PROJECT SUMMARY/ABSTRACT: MECHANISMS OF RESISTANCE TO ENDOCRINE THERAPY IN ER+ BREAST CANCER Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer, but ~20% of ER+ tumors recur during or following adjuvant endocrine therapy, accounting for ~50% of breast cancer deaths in the US each year. The CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have been recently approved in combination with endocrine therapy for the treatment of metastatic ER+ breast cancer. However, as for other cancer targeted therapies, all patients with metastatic disease on CDK4/6 inhibitors eventually progress, suggesting the development of mechanisms of acquired drug resistance that remain to be discovered. We propose a continuation project where we will investigate the effect of aberrant FGFR signaling on resistance to endocrine therapy in combination with CDK4/6 inhibitors in patients with ER+ breast cancer with the following aims:  Aim 1: To elucidate the mechanisms by which FGFR1 amplification confers resistance to the combination of fulvestrant and CDK4/6 inhibitors in ER+/FGFR amplified breast cancers  Aim 2: To conduct a phase Ib and a randomized phase II trial of the ER downregulator fulvestrant plus palbociclib ± the pan-FGFR inhibitor erdafitinib in patients with ER+/FGFR-amplified metastatic breast cancer  Aim 3: To discover mechanisms of drug resistance in organoids derived from tumors progressing on CDK4/6 inhibitors. These will include: 1) tumors from patients progressing on treatment with fulvestrant/palbociclib ± erdafitinib in Aim 2, and 2) tumors from breast cancer patients on standard-of-care therapy with CDK4/6 inhibitors To our knowledge, this is the first time an FGFR inhibitor will be tested in combination with ER and CDK4/6 inhibitors in patients with breast cancer harboring FGFR amplification. A positive outcome of this clinical trial may provide women with FGFR-amplified/ ER+ breast cancer with a novel treatment option that does not include cytotoxic chemotherapy. Increased efficacy of the combination of fulvestrant, palbociclib and erdafitinib will also accelerate the development of FGFR inhibitors. We seek to identify biomarkers predictive of response to the combination that can be used in trials in appropriately selected patients with ER+ metastatic breast cancer. In addition, the comprehensive molecular analysis of organoids from cancers progressing on treatment provides an opportunity for the unbiased discovery of novel molecular mechanisms of drug resistance. These mechanisms, in turn, may represent actionable molecular targets that can be the focus of future drug discovery efforts and/or translational/clinical investigation in breast and other FGFR-dependent cancers. As such, the aims proposed herein may contribute to progress in the eradication of ER+ breast cancers.