Integrating targeted therapy and immunotherapy to break through cancer

项目摘要/摘要 我们实验室的研究集中在了解不同的信令网络调节必不可少的 癌症中的细胞过程，以及这些过程如何影响肿瘤、间质和免疫细胞之间的相互作用。我们的 研究计划结合了多管齐下的方法，将基本的科学发现推进到临床前， 转化性研究，并最终用于临床开发。我们的主要目标是发展安全有效的 治疗癌症患者的疗法。具体地说，我们的研究计划将I)调查 PI3K/PTEN信号在乳腺癌和前列腺癌免疫反应形成中的作用，II)细胞和 免疫系统影响乳腺癌靶向治疗反应的分子机制， 和三)研究转移到大脑的机制和乳腺癌的治疗策略 脑转移瘤(BCBM)。为此，我们将利用我们在信号转导和 药理学在基因工程小鼠模型(GEMM)和患者来源的异种移植中的应用 (PDX)进行多组学研究，以及旨在显著推进的详细机制研究 我们对肿瘤发生、免疫逃避和治疗抵抗的理解。对于这些目标中的每一个，我们 将开展以生物学功能和反应的细胞和分子机制为重点的研究 治疗，还将评估靶向治疗和免疫调节剂的合理组合 临床相关的小鼠模型。我们将专注于不同的致癌改变如何不同地影响抗- 肿瘤免疫反应，并将特别强调了解肿瘤之间的相互作用 免疫细胞影响治疗结果。我们已经并将继续开发新的GEMM和PXD 适合这些研究的模型，除了采用强大的新技术来最大限度地 我们研究的潜在影响。我们拥有进行这些研究的经验、专业知识和支持，以及 我们有信心继续为癌症生物学和癌症领域做出重大贡献。 免疫肿瘤学，以及许多受这种疾病困扰的患者和家庭。

Project Summary/Abstract Research in our laboratory is centered on understanding the diverse signaling networks regulating essential cellular processes in cancer, and how these affect the interplay between tumor, stromal and immune cells. Our research program combines a multi-pronged approach to advance basic scientific discoveries to pre-clinical, translational research and, ultimately, to clinical development. Our major goal is to develop safe and effective therapies for treating patients with cancer. Specifically, our research program will i) investigate the role of PI3K/PTEN signaling in shaping immune response in breast and prostate cancer, ii) investigate cellular and molecular mechanisms by which the immune system affects response to targeted therapies in breast cancer, and iii) investigate mechanisms of metastatic spread to the brain and treatment strategies against breast cancer brain metastasis (BCBM). To this end, we will capitalize on our expertise on signal transduction and pharmacology applied to genetically-engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) to conduct multi-omics studies, as well as detailed mechanistic studies aimed to significantly advance our understanding of tumorigenesis, immune evasion and therapeutic resistance. For each of these aims, we will carry out studies focused on cellular and molecular mechanisms underlying biological functions and response to therapies, and will also evaluate rational combinations of targeted therapies and immune modulators in clinically relevant mouse models. We will focus on how distinct oncogenic alterations differentially affect the anti- tumor immune response, and will place a particular emphasis on understanding how the interplay between tumor and immune cells affects therapeutic outcome. We have and will continue to develop novel GEMMs and PXD models suitable for these studies, in addition to incorporating powerful new technologies to maximize the potential impact of our research. We have the experience, expertise and support to carry out these studies, and we are confident that we can continue to make significant contributions to the fields of cancer biology and immuno-oncology, and to the many patients and families afflicted by this disease.