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Integrating targeted therapy and immunotherapy to break through cancer

整合靶向治疗和免疫治疗突破癌症

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/摘要我们实验室的研究集中在理解调节关键的不同信号网络。癌症中的细胞过程，以及这些过程如何影响肿瘤、基质细胞和免疫细胞之间的相互作用。我们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，最终用于临床开发。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 PI 3 K/PTEN信号传导在乳腺癌和前列腺癌中形成免疫应答，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，和iii）研究转移性扩散到脑的机制和针对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方面的专业知识，应用于基因工程小鼠模型（GEMM）和患者源性异种移植物的药理学（PDX）进行多组学研究，以及详细的机制研究，旨在显着提高我们对肿瘤发生、免疫逃避和治疗抗性的理解。对于每一个目标，我们将开展重点研究生物功能和反应的细胞和分子机制并将评估靶向治疗和免疫调节剂的合理组合，临床相关小鼠模型。我们将重点关注不同的致癌性改变如何不同地影响抗肿瘤细胞。肿瘤免疫反应，并将特别强调了解肿瘤之间的相互作用，免疫细胞影响治疗效果。我们已经并将继续开发新型GEMM和PXD 模型适合这些研究，除了纳入强大的新技术，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，我们有信心继续为癌症生物学领域做出重大贡献，免疫肿瘤学，以及受这种疾病折磨的许多患者和家庭。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer.

DOI：
10.1038/s41467-022-30568-1
发表时间：
2022-05-31
期刊：
Nature communications
影响因子：
16.6
作者：
通讯作者：

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

DOI：
10.1158/0008-5472.can-21-3605
发表时间：
2021-12-15
期刊：
Cancer research
影响因子：
11.2
作者：
Bergholz JS;Zhao JJ
通讯作者：
Zhao JJ

Targeting CDK4 and CDK6 in cancer.

DOI：
10.1038/s41568-022-00456-3
发表时间：
2022-06
期刊：
Nature reviews. Cancer
影响因子：
0
作者：
通讯作者：

Integrating Immunotherapy and Targeted Therapy in Cancer Treatment: Mechanistic Insights and Clinical Implications.

DOI：
10.1158/1078-0432.ccr-19-2300
发表时间：
2020-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Bergholz JS;Wang Q;Kabraji S;Zhao JJ
通讯作者：
Zhao JJ

STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer.