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

项目摘要 乳腺癌HER2耐药的肿瘤间质信号转导机制分析 耐药性仍然是HER2+乳腺癌的一个严重问题，相当一部分患者(40%-75%) 最终不会对治疗有反应。更好地理解HER2治疗抵抗的原因是 因此需要，以改善患者的预后。到目前为止，对促进 HER2治疗耐药性主要集中在促进细胞生长和存活的肿瘤细胞内在因素上。这个 然而，来自肿瘤微环境(即间质)的外部信号的作用尚不清楚。 这项建议的目标是研究肿瘤-间质相互作用在HER2治疗中的作用。 并开发新的策略，通过以下方式使肿瘤细胞对治疗重新敏感：(1)评估 在一组体内和体外HER2+乳腺癌模型中，拉帕替尼与富含基质的利基环境相关 (目标1)，(2)检测HER2+乳腺中肿瘤细胞凋亡启动作为肿瘤细胞存活机制 癌症患者来源的异种移植和患者样本来自临床试验Trio-US-B07(目标2)，(3) 通过无偏向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的联合疗法 患者来源的异种移植模型(目标3)。拟议研究的结果将导致对 微环境生态位和相关的肿瘤细胞信号通路可作为 患者分层，并为设计合理的联合疗法提供重要信息 使肿瘤对治疗重新敏感。 这项提议借鉴了我的生物工程背景和癌症生物学的博士后培训， 然而，为了确保完成各项目标并成功过渡到独立，我还 在我的导师布鲁格博士和我的顾问团队乐泰博士的指导下，制定了详细的培训计划， 米高医生和索格医生。在指导阶段，我计划获得(1)系统分析和 高维蛋白质组数据集的建模以阐明肿瘤间质信号，(2)发展 用于设计有效药物组合的预测数学模型，(3)多路 免疫荧光法检测肿瘤和间质细胞的原位分子标记及(4)分析 临床试验样本中的预测生物标志物。哈佛医学院的环境呈现出一种 提供量化癌症生物学培训的绝佳机会，并最大限度地发挥 我的研究。我还将指导学生，进一步发展我的资质和实验室管理技能。这个 建议的研究计划结合职业发展培训将极大地帮助我成为一名 肿瘤微环境生物工程领域的独立研究员。

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.