Integrating targeted therapy and immunotherapy to break through cancer

整合靶向治疗和免疫治疗突破癌症

• 批准号: 10737039
• 负责人: Jean Zhao
• 金额: $ 102.76万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2030-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737039
• 关键词: Affect; Biological Process; Brain; Cancer Biology; Cancer Patient; Cell physiology; Cells; Development; Disease; Family; Genetic Models; Genetically Engineered Mouse; Goals; Immune; Immune Evasion; Immune response; Immune system; Immunomodulators; Immunooncology; Immunotherapeutic agent; Immunotherapy; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic malignant neoplasm to brain; Modeling; Molecular; Neoplasm Metastasis; Oncogenic; PIK3CG gene; PTEN gene; Patient Care; Patients; Pharmacology; Research; Role; Shapes; Signal Transduction; Therapeutic; Translational Research; anti-tumor immune response; cancer subtypes; cancer therapy; clinical development; clinically relevant; effective therapy; experience; malignant breast neoplasm; mouse genetics; mouse model; multiple omics; new technology; novel; patient derived xenograft model; pre-clinical; programs; response; success; targeted treatment; therapeutic development; therapy outcome; therapy resistant; treatment response; treatment strategy; tumor; tumorigenesis

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.

项目概要/摘要 我们实验室的研究重点是了解调节基本信号的不同信号网络 癌症中的细胞过程，以及这些过程如何影响肿瘤、基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，将基础科学发现推进到临床前、 转化研究并最终进入临床开发。我们的主要目标是开发安全有效的 用于治疗癌症患者的疗法。具体来说，我们的研究计划将 i) 调查 PI3K/PTEN 信号传导在乳腺癌和前列腺癌中形成免疫反应，ii) 研究细胞和 免疫系统影响乳腺癌靶向治疗反应的分子机制， iii) 研究乳腺癌转移扩散到大脑的机制和治疗策略 脑转移（BCBM）。为此，我们将利用我们在信号转导和 药理学应用于基因工程小鼠模型（GEMM）和患者来源的异种移植物 （PDX）进行多组学研究以及详细的机制研究，旨在显着推进 我们对肿瘤发生、免疫逃避和治疗耐药性的理解。对于每一个目标，我们 将开展侧重于生物功能和反应的细胞和分子机制的研究 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。我们将重点关注不同的致癌改变如何不同地影响抗癌药物 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型 GEMM 和 PXD 适合这些研究的模型，除了结合强大的新技术以最大限度地提高 我们研究的潜在影响。我们拥有开展这些研究的经验、专业知识和支持，并且 我们有信心能够继续为癌症生物学和癌症领域做出重大贡献 免疫肿瘤学，以及许多患有这种疾病的患者和家庭。

项目成果

PI(3,5)P 2 Controls the Signaling Activity of Class I PI3K.

PI(3,5)P 2 控制 I 类 PI3K 的信号传导活动。

• 发表时间: 2023-01-25
• 作者: Sun, Jiachen;Song, Seohyeon;Singaram, Indira;Sharma, Ashutosh;Wang, Wei;Hu, Yusi;Lo, Wen;Koch, Philipp Alexander;Zhao, Jean J;Haucke, Volker;Gao, Ruixuan;Cho, Wonhwa
• 通讯作者: Cho, Wonhwa

How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer.

补偿机制和适应性重连如何塑造我们对癌症治疗耐药性的理解。

• 发表时间: 2021-12-15
• 影响因子: 11.2
• 作者: Bergholz, Johann S;Zhao, Jean J
• 通讯作者: Zhao, Jean J

p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases.

p16INK4A 缺陷可预测 HER2 乳腺癌脑转移对 HER2 和 CDK4/6 联合抑制的反应。

• 发表时间: 2022-03-18
• 影响因子: 16.6
• 作者: Ni, Jing;Kabraji, Sheheryar;Xie, Shaozhen;Wang, Yanzhi;Pan, Peichen;He, Xiaofang;Liu, Zongming;Leone, Jose Palbo;Long, Henry W;Brown, Myles A;Winer, Eric P;Dillon, Deborah A R;Lin, Nancy U;Zhao, Jean J
• 通讯作者: Zhao, Jean J

Targeting CDK4 and CDK6 in cancer.

靶向癌症中的 CDK4 和 CDK6。

• 发表时间: 2022-06
• 作者: Goel, Shom;Bergholz, Johann S;Zhao, Jean J
• 通讯作者: Zhao, Jean J

Improving orthotopic mouse models of patient-derived breast cancer brain metastases by a modified intracarotid injection method.

通过改良颈动脉注射方法改善患者源性乳腺癌脑转移的原位小鼠模型。

• 发表时间: 2019
• 影响因子: 4.6
• 作者: Liu, Zongming;Wang, Yanzhi;Kabraji, Sheheryar;Xie, Shaozhen;Pan, Peichen;Liu, Zhenning;Ni, Jing;Zhao, Jean J
• 通讯作者: Zhao, Jean J