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: 10678935
• 负责人: Elena Shagisultanova
• 金额: $ 23.08万
• 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/10678935
• 关键词: Acute; Adhesions; Animal Model; Apoptotic; Aromatase Inhibitors; BAG1 gene; BCL2 gene; Biological Assay; Biological Markers; Biopsy; 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; Evaluation; FYN gene; Fibroblast Growth Factor Receptors; Genes; Genomics; Goals; Hormone Receptor; IGF1R gene; In Vitro; Inherited; Invaded; JAK2 gene; LYN gene; Laboratories; Letrozole; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic breast cancer; Metastatic/Recurrent; 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; Regimen; Research Personnel; Resistance; Resistance development; Risk; STAT3 gene; Safety; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Time; Tumor Cell Line; Up-Regulation; Xenograft Model; biomarker development; biomarker panel; biomarker validation; 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; participant enrollment; 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.

项目摘要 /摘要 乳腺癌过表达HER2癌基因和激素受体（HR）很常见 年轻女性，最多占所有乳腺癌病例的20％，并在此造成死亡 患者人数。这些癌症代表了一个独特的挑战，因为HER2之间的串扰 和HR途径，导致靶向治疗的抗性通常是通过激活Cyclin D1 /激活而介导的 HER2和HR信号级联的CDK4/6复合物。目前，绝大多数患者 与转移性HR+/HER2+乳腺癌一起用与多种副作用相关的化学疗法治疗， 因为几种护理标准的靶向药物组合无法改善第三阶段的总体生存 临床试验。基于在我们实验室获得的强烈信号原理和初步数据，我提出了一个 靶向剂的三合一组合 - HER2小分子抑制剂tucatinib，芳香酶抑制剂LETrozole和 CDK4/6抑制剂palbociclib-作为治疗HR+/HER2+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，我打开了一个研究者发起的 HR+/HER2+转移性乳房患者的Tucatinib，palbociclib和Letrozole的多中心临床试验 癌症。该试验于2017年11月开放，已经显示出有利的安全性和功效概况： 作为 最长 在2018年10月1日的数据中，有40名患者中有18名临床福利率为75％，其中临床福利率为75％ 响应持续时间为8个月，持续的持续。靶向治疗具有很高的潜力 挑战当前护理标准前线化学疗法方法用于HR+/HER2+转移性患者 疾病。因此，开发生物标志物以将患者分层分为那些非常重要 谁最终需要化学疗法，以及那些将对前线三重靶向组合做出反应的人， 通过口服靶向方案，可能具有长期的疾病控制和改善的生活质量。在这个 应用，我提出了一种综合方法来识别固有灵敏度的途径并获得 对三重组合靶向治疗的抗性，其最终目标是开发一个反应的生物标志物 接受这种疗法。我已经确定了通过药物测序的几个潜在的获得抵抗的驱动因素 抗性肿瘤细胞系。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，并且 动物模型。此外，来自Tucatinib，palbociclib和Letrozole临床试验的患者肿瘤样本将 通过总mRNA测序分析，以识别对治疗固有敏感性的途径和基因 这些途径将在体外和体内进行验证。而且，使用液体活检方法，我将 在循环肿瘤细胞中开发一个生物标志物的预测面板，以允许对 治疗生物标志物。共同提议 研究 可能 递送 临床 有价值的 工具 允许 为了 分层 的 治疗 为了 患者 和 HR+/ HER2+ 转移 胸部 癌症 和 提供个性化 医学方法目前不存在该患者人群。