Discovering mechanisms of sensitivity and resistance to triple combination targeted therapy in HR+/HER2+ breast cancer

项目概要/摘要 HER 2癌基因和激素受体（HR）过表达的乳腺癌在以下人群中很常见： 年轻妇女，占所有乳腺癌病例的20%，并在这一领域大大增加了死亡率。 患者人群。这些癌症代表了一个独特的挑战，因为HER 2之间的串扰， 和HR途径，导致靶向治疗抵抗，通常由细胞周期蛋白D1 / CDK 4/6复合物下游的HER 2和HR信号级联。目前，绝大多数患者 转移性HR+/HER 2+乳腺癌患者用化疗治疗，化疗伴随多种副作用， 因为在III期试验中，几种标准治疗靶向药物组合未能改善总生存率 临床试验基于强有力的信号原理和我们实验室获得的初步数据，我提出了一个 靶向药物的三联组合-HER 2小分子抑制剂tucatinib，芳香酶抑制剂来曲唑，和 CDK 4/6抑制剂palbociclib -作为治疗HR+/HER 2+疾病的新型靶向方法。后 在临床前实验中证明了这种组合的高活性，我打开了一个 Tucatinib、Palbociclib和来曲唑治疗HR+/HER 2+转移性乳腺癌患者的多中心临床试验 癌该试验于2017年11月开始，已经显示出良好的安全性和疗效特征： 作为 最长 截止2018年10月1日的数据，40例患者中有18例入组，临床获益率为75%， 缓解持续时间为8个月并持续。三联靶向治疗具有很高的潜力， 挑战HR+/HER 2+转移性患者的当前标准治疗一线化疗方法 疾病因此，至关重要的是开发生物标志物，以允许将患者分层为那些 那些最终需要化疗的人，以及那些对一线三联靶向组合有反应的人， 并且可以通过口服靶向方案具有长期疾病控制和改善的生活质量。在这 应用，我提出了一个全面的方法来确定途径的内在敏感性和获得 对三联靶向治疗的耐药性，最终目标是开发反应的生物标志物 这种治疗。我已经通过药物测序确定了获得性耐药的几个潜在驱动因素， 耐药肿瘤细胞系。这些潜在的生物标志物将在基于细胞系的功能测定中得到验证， 动物模型此外，来自tucatinib、palbociclib和来曲唑临床试验的患者肿瘤样本将 通过总mRNA测序进行分析，以鉴定对治疗具有内在敏感性的途径和基因， 这些途径将在体外和体内得到验证。此外，使用液体活检方法，我将 开发循环肿瘤细胞中的生物标志物的预测面板，以允许非侵入性监测 生物标志物的作用总体而言，拟议的 研究 可以 提供 临床 宝贵 工具 允许 为 分层 的 治疗 为 患者 与 HR+/ HER2+ 转移性 乳腺 癌 和 提供个性化的 目前不存在针对该患者人群的药物治疗方法。

Project summary / abstract Breast cancers overexpressing both the HER2 oncogene and hormone receptors (HR) are common among young women, comprising up to 20% of all breast cancer cases and significantly contributing to mortality in this patient population. These cancers represent a unique challenge because of a cross-talk between the HER2 and HR pathways, leading to targeted therapy resistance commonly mediated by activation of the cyclin D1 / CDK4/6 complex downstream of HER2 and HR signalling cascades. At present, the vast majority of patients with metastatic HR+/HER2+ breast cancer are treated with chemotherapy associated with multiple side effects, because several standard of care targeted drug combinations failed to improve overall survival in phase III clinical trials. Based on a strong signalling rationale and preliminary data obtained in our laboratory, I proposed a triple combination of targeted agents - HER2 small molecule inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib - as a novel targeted approach for treatment of HR+/HER2+ disease. After demonstrating high activity of this combination in preclinical experiments, I opened an investigator-initiated multicenter clinical trial of tucatinib, palbociclib and letrozole for patients with HR+/HER2+ metastatic breast cancer. This trial was opened in November 2017 and has already shown a favourable safety and efficacy profile: as longest of the October 1 st 2018 data cut off, with 18 out of 40 patients enrolled, clinical benefit rate was 75%, with the duration of response of 8 months and ongoing.Triple combination targeted therapy has high potential to challenge current standard of care front line chemotherapy approach for patients with HR+/HER2+ metastatic disease. Therefore, it is critically important to develop a biomarker to allow stratification of patients into those who will ultimately need chemotherapy, and those who will respond to front line triple targeted combination, and may have long term disease control and improved quality of life with an oral targeted regimen. In this application, I propose a comprehensive approach to identify pathways of intrinsic sensitivity and acquired resistance to triple combination targeted therapy with the ultimate goal of developing a biomarker of response to this therapy. I have already identified several potential drivers of acquired resistance via sequencing of drug resistant tumor cell lines. These potential biomarkers will be validated in cell line based functional assays and animal models. Additionally, patient tumor samples from the tucatinib, palbociclib and letrozole clinical trial will be analyzed by total mRNA sequencing to identify the pathways and genes of intrinsic sensitivity to therapy, and these pathways will be validated in vitro and in vivo. Moreover, using a liquid biopsy approach, I will develop a predictive panel of biomarkers in circulating tumor cells, to allow a non-invasive monitoring of biomarkers on therapy. Collectively, the proposed studies may deliver clinically valuable tools allowing for stratification of treatment for patients with HR+/ HER2+ metastatic breast cancer and offering a personalized medicine approach currently non-existent for this patient population.