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

发现HR/HER2乳腺癌三联联合靶向治疗的敏感性和耐药机制

• 批准号: 10460233
• 负责人: Elena Shagisultanova
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460233
• 关键词: Acute; Adhesions; Animal Model; Apoptotic; Aromatase Inhibitors; BAG1 gene; BCL2 gene; Biological Assay; Biological Markers; Biopsy; Breast; CD47 gene; CDK4 gene; Cell Line; Cell Proliferation; Cessation of life; Chromosomal Rearrangement; Clinical; Clinical Research; Clinical Trials; Complex; Copy Number Polymorphism; Cyclin D1; Data; Disease; Drug Combinations; Drug Targeting; Drug resistance; ERBB2 gene; Enrollment; Evaluation; FYN gene; Fibroblast Growth Factor Receptors; Genes; Goals; Hormone Receptor; IGF1R gene; In Vitro; Inherited; JAK2 gene; LYN gene; Laboratories; Letrozole; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic breast cancer; Multi-Institutional Clinical Trial; Mus; Mutation; Neoplasm Circulating Cells; Oncogenes; Oral; Pathway interactions; Patients; Phase; Phase III Clinical Trials; Proteins; Quality of life; Receptor Signaling; Recurrence; Regimen; Research Personnel; Resistance; Resistance development; Risk; STAT3 gene; Safety; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Time; Tumor Cell Line; Up-Regulation; Xenograft Model; base; biomarker development; biomarker panel; biomarker validation; breast cancer genomics; cancer cell; cancer subtypes; career development; chemotherapy; design; disorder control; drug metabolism; experimental study; improved; in vivo; inhibitor; insight; knock-down; liquid biopsy; mRNA Expression; mRNA sequencing; malignant breast neoplasm; mortality; non-invasive monitor; novel; overexpression; patient derived xenograft model; patient population; patient stratification; personalized medicine; potential biomarker; pre-clinical; predictive marker; predictive panel; prevent; protein biomarkers; protein expression; resistance gene; resistance mechanism; response; response biomarker; side effect; skills; small molecule inhibitor; standard of care; targeted agent; targeted treatment; therapy resistant; tool; treatment response; treatment stratification; tumor; young woman

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.

项目概要/摘要 过度表达 HER2 癌基因和激素受体 (HR) 的乳腺癌在女性中很常见 年轻女性，占所有乳腺癌病例的 20%，并且是该地区死亡率的显着原因 患者群体。由于 HER2 之间的串扰，这些癌症代表了独特的挑战 和 HR 途径，导致通常由细胞周期蛋白 D1 激活介导的靶向治疗耐药性/ HER2 和 HR 信号级联下游的 CDK4/6 复合体。目前，绝大多数患者 转移性 HR+/HER2+ 乳腺癌接受化疗并伴有多种副作用， 因为几种标准护理靶向药物组合未能提高 III 期的总体生存率 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 靶向药物的三重组合——HER2小分子抑制剂图卡替尼、芳香酶抑制剂来曲唑和 CDK4/6 抑制剂 palbociclib - 作为治疗 HR+/HER2+ 疾病的新型靶向方法。后 为了在临床前实验中证明这种组合的高活性，我打开了一个研究者发起的 图卡替尼、哌柏西利和来曲唑治疗 HR+/HER2+ 转移性乳腺患者的多中心临床试验 癌症。该试验于 2017 年 11 月启动，已显示出良好的安全性和有效性： 作为 最长 截至2018年10月1日数据，40名患者中有18名入组，临床受益率为75%， 反应持续时间为 8 个月并持续。三联靶向治疗具有很高的潜力 挑战当前 HR+/HER2+ 转移性患者一线化疗方法的护理标准 疾病。因此，开发一种生物标志物以将患者分为不同类型至关重要 谁最终需要化疗，以及谁会对前线三重靶向组合产生反应， 通过口服靶向治疗方案可以实现长期疾病控制并提高生活质量。在这个 应用程序中，我提出了一种综合方法来识别内在敏感性和后天敏感性的途径 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 到这种疗法。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，以确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预测组，以实现非侵入性监测 治疗中的生物标志物。总的来说，拟议的 研究 可能 递送 临床上 有价值的 工具 允许 为了 分层 的 治疗 为了 患者 和 人力资源+/ HER2+ 转移性的 胸部 癌症 和 提供个性化的 对于这一患者群体，目前尚不存在医学方法。