Analysis of tumor-stroma signaling that mediates HER2-therapy resistance in breast cancer

项目摘要 乳腺癌中介导HER 2治疗耐药的肿瘤-间质信号传导分析 耐药性仍然是HER 2+乳腺癌的一个重大问题，相当一部分患者（40-75%） 最终对治疗没有反应更好地了解HER 2治疗耐药的原因是 因此，为了改善患者的治疗效果，到目前为止，对促成 HER 2治疗抗性集中在促进细胞生长和存活的肿瘤细胞内在因子上。的 然而，源自肿瘤微环境（即基质）的外部信号的作用仍不清楚。 本提案的目的是研究肿瘤-间质相互作用在HER 2治疗中的作用 耐药性，并开发新的策略，重新敏感肿瘤细胞治疗（1）评估是否敏感性 拉帕替尼与一组HER 2+乳腺癌离体和体内模型中富含基质的小生境相关 (Aim 1），（2）检查肿瘤细胞凋亡引发作为HER 2+乳腺癌中肿瘤细胞存活机制 癌症患者来源的异种移植物和临床试验TRIO-US-B 07的患者样本（目的2），（3） 通过无偏质谱分析研究其他肿瘤细胞存活机制， 使用计算建模和体内研究开发和优化新型联合疗法， 患者来源的异种移植物模型（目的3）。拟议研究的结果将导致确定 微环境生态位和相关的肿瘤细胞信号传导途径，可以作为生物标志物， 患者分层，并为设计合理的联合治疗提供重要信息， 使肿瘤对治疗重新敏感。 这个建议借鉴了我的生物工程背景和癌症生物学博士后培训， 然而，为了确保完成各项目标和成功过渡到独立，我还 在我的导师Brugge博士和我的顾问团队Letai博士的指导下，我设计了一个详细的培训计划， 博士米克尔和索格医生在辅导阶段，我计划获得（1）系统分析和 建立高维蛋白质组学数据集以阐明肿瘤间质信号传导，（2）开发 用于设计有效药物组合的预测数学模型，（3）多重 免疫荧光分析肿瘤和基质细胞中原位分子标记物，和（4）分析 临床试验样品中的预测性生物标志物。哈佛医学院的环境呈现出一种 这是一个极好的机会，可以进行定量癌症生物学培训，并最大限度地发挥 我的研究我还将指导学生，并进一步发展我的实验室和实验室管理技能。的 建议的研究计划与职业发展培训相结合，将大大帮助我成为一个 肿瘤微环境生物工程领域的独立研究者。

Project abstract Analysis of tumor-stroma signaling that mediates HER2-therapy resistance in breast cancer Drug resistance remains a great concern in HER2+ breast cancer, and a significant portion of patients (40-75%) will ultimately not respond to therapy. A better understanding of the causes of HER2-therapy resistance is therefore needed, in order to improve patient outcomes. To date, investigations on mechanisms contributing to HER2-therapy resistance have focused on tumor cell intrinsic factors that promote cell growth and survival. The role of extrinsic signals stemming from the tumor microenvironment (i.e. stroma), however, remains unclear. The goal of this proposal is to investigate the role of tumor-stroma interactions in HER2-therapy resistance and develop new strategies to re-sensitize tumor cells to therapy by (1) evaluating whether sensitivity to lapatinib correlates with stroma-rich niches in a panel of HER2+ breast cancer models ex vivo and in vivo (Aim 1), (2) examining tumor cell apoptotic priming as a tumor cell survival mechanism in HER2+ breast cancer patient-derived xenografts and patient samples from the clinical trial TRIO-US-B07 (Aim 2), (3) investigating additional tumor cell survival mechanisms by an unbiased mass-spectrometry analysis and developing and optimizing novel combination-therapies using computational modeling and in vivo studies with patient-derived xenograft models (Aim 3). The results from the proposed studies will lead to the identification of microenvironmental niches and associated tumor cell signaling pathways that could serve as biomarkers for patient stratification and provide important information for the design of rational combination therapies that will re-sensitize tumors to treatment. This proposal draws on my bioengineering background and postdoctoral training in cancer biology, however in order to ensure completion of the goals and successful transition to independence, I have also devised a detailed training plan, under the guidance of my mentor Dr. Brugge and my advisory team Dr. Letai, Dr. Michor and Dr. Sorger. During the mentored phase I plan to acquire new skills in (1) systems analysis and modeling of high-dimensional proteomic datasets to elucidate tumor-stroma signaling, (2) development of predictive mathematical models for designing effective drug combinations, (3) multiplexed immunofluorescence to profile in situ molecular markers in tumor and stroma cells and (4) analysis of predictive biomarkers in samples from clinical trials. The environment at Harvard Medical School presents an excellent opportunity for training in quantitative cancer biology and maximizing the translational potential of my research. I will also mentor students and further develop my grantsmanship and lab management skills. The proposed research plan combined with the career development training will significantly aid me to become an independent investigator in the field of tumor microenvironment bioengineering.