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

项目摘要/摘要 同时过度表达HER2癌基因和激素受体(HR)的乳腺癌在 年轻女性占所有乳腺癌病例的高达20%，在这一领域对死亡率有很大贡献 病人群体。这些癌症是一个独特的挑战，因为HER2和HER2 和HR通路，导致靶向治疗耐药，通常通过激活细胞周期蛋白D1/ HER2和HR信号通路下游的CDK4/6复合体。目前，绝大多数患者 转移性HR+/HER2+乳腺癌患者接受化疗并伴有多种副作用， 因为几种标准的治疗靶向药物组合在第三阶段未能提高总体存活率 临床试验。基于强大的信号理论基础和我们实验室获得的初步数据，我提出了一种 靶向药物的三重组合-HER2小分子抑制剂Tucatinib、芳香酶抑制剂来曲唑和 CDK4/6抑制剂Palbociclib--一种新的靶向治疗HR+/HER2+病的方法之后 在临床前实验中，我展示了这种组合的高活性，我打开了一个由研究人员发起的 图卡替尼、帕波西利和来曲唑治疗HR+/HER2+转移性乳腺癌的多中心临床研究 癌症。该试验于2017年11月开始，已显示出良好的安全性和有效性： AS 最长 在2018年10月1日截止的数据中，40名患者中有18名参加了试验，临床受益率为75%，其中 持续8个月的反应。三联靶向治疗具有很高的潜力 挑战HR+/HER2+转移性患者一线化疗的现行标准 疾病。因此，开发一种生物标志物以允许将患者分层为 那些最终需要化疗的人，以及那些对一线三靶向联合治疗有反应的人， 并可通过口服靶向疗法长期控制疾病并改善生活质量。在这 应用，我提出了一种综合的方法来识别内在敏感性和后天获得性 对三联靶向治疗的抵抗力，最终目标是开发一种反应的生物标记物 来接受这种治疗。我已经通过药物测序确定了几个潜在的获得性耐药性驱动因素 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分析和 动物模型。此外，图卡替尼、帕波西利和来曲唑临床试验的患者肿瘤样本将 通过总信使核糖核酸测序来确定治疗的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，使用液体活组织检查方法，我将 开发循环中肿瘤细胞的生物标记物的预测性小组，以允许对 治疗中的生物标记物。总的来说，建议的 研究 可能 投递 临床上 有价值的 工具 允许 为 分层 的 治疗 为 病人 使用 HR+/ HER2+ 转移性 乳房 癌症 和 提供个性化的 对于这一患者群体，目前还不存在医学方法。

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.