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Definition of Immune Infiltrate Phenotype and DNA Damage Response Deficits Across Diverse Murine Mammary Carcinomas

不同鼠类乳腺癌免疫浸润表型和 DNA 损伤反应缺陷的定义

基本信息

批准号：
10589863
负责人：
Mary Helen Barcellos-Hoff
金额：
$ 49.8万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10589863
关键词：
Address Back Behavior Biological Biological Models Biological Specimen Banks Biology Breast Carcinoma Cancer Model Cancer Patient Carcinoma Cell Death Chemotherapy and/or radiation Chimera organism Cisplatin Classification Clinical Clinical Trials Combined Modality Therapy Credentialing Cytokeratin Cytotoxic Chemotherapy Cytotoxic agent DNA Damage Data Deposition Disease Disease Resistance Estrogen Receptors Evaluation Exclusion Exhibits Fatty acid glycerol esters Future Genomics Goals Growth Heterogeneity Human Immune Immune response Immunity Immunologic Stimulation Immunotherapy Infiltration Ionizing radiation Lymphocyte Malignant Neoplasms Mammary Neoplasms Modeling Molecular Mus New Agents Outcome Parents Patients Pattern Pharmaceutical Preparations Phenotype Pre-Clinical Model Protocols documentation Radiation Radiation therapy Recurrent disease Regimen Registries Reproducibility Research Personnel Standardization System T-Lymphocyte Therapeutic Tissue Viability Translational Research Transplantation Tumor Biology Tumor Escape Tumor Immunity Tumor-Derived Work cancer diagnosis cancer immunotherapy cancer therapy carcinogenesis chemotherapy cytotoxic radiation effective therapy gene therapy genomic profiles homologous recombination immune cell infiltrate immune checkpoint blockade immunotherapy trials improved in situ vaccination inhibitor malignant breast neoplasm mammary mammary epithelium novel novel strategies personalized medicine prototype radiation response response standard of care success synergism translational model translational study tumor tumor DNA

项目摘要

Abstract While major strides have been made in cancer treatment, the challenge remains to determine which patients will benefit most from a therapeutic regimen, which is the ultimate goal of personalized medicine. The key to choosing the most effective therapy for a given cancer is understanding the biological basis for differential outcomes and intrinsic sensitivity to cancer therapies. Almost all cancers are treated with cytotoxic chemotherapy and radiation therapy but the emerging clinical success of immunoncology (IO) drugs whose success is predicated on the biology of the immune infiltrate requires new tactics to model optimal combinations. As cytotoxic therapy is a critical component of cancer patient treatment, mammalian models that represent a range of DNA damage response deficits (DDRD), and hence sensitivity to different agents, would improve translational research. Likewise, the multiple mechanisms by which cancer evades the anti- tumor immunity need to be represented in translational research. Lack of diversity in most current preclinical models limits their applicability as a platform for systemic evaluation of these aspects of tumor biology. Given the range of IO approaches and the diversity of DDRD, a critical unmet translational requirement is a model system in which both the tumor DDRD and the immune infiltrate is defined so that combinations can be readily studied. We propose to use murine tumor derived transplants (mTDT) of Trp53 null mammary carcinomas that we have generated and characterized in regard to heterogeneity, relevance to human cancer, and reproducibility to credential the DDR deficits of these syngeneic carcinomas and to evaluate corresponding baseline immune cell infiltrates. We will implement multiplex analysis of tumor and immune features and correlate them with tumor response to radiation, a canonical DNA damaging therapy and arguably the most widely used cytotoxic therapy. The product of these studies is directly responsive to the FOA consisting of a protocol for standardized implementation of this model, comprehensive analysis of tumor types, and repository of specimens, data, and viable tissue. The success of this project will provide a means to conduct mechanistic and translational studies using defined tumor DDRD and immune infiltrate composition for developing patient- specific personalized therapy to IO and cytotoxic therapies.

抽象的尽管癌症治疗已取得重大进展，但仍面临确定哪些患者将从治疗方案中获益最多，这是个性化医疗的最终目标。关键是针对特定癌症选择最有效的治疗方法是了解差异化的生物学基础结果和对癌症治疗的内在敏感性。几乎所有癌症都可以用细胞毒性药物治疗化疗和放射治疗，但免疫肿瘤 (IO) 药物在临床上取得的新成功成功取决于免疫渗透的生物学特性，需要新的策略来模拟最佳效果组合。由于细胞毒疗法是癌症患者治疗的关键组成部分，因此哺乳动物模型代表一系列 DNA 损伤反应缺陷 (DDRD)，因此对不同药物的敏感性，将改善转化研究。同样，癌症逃避抗药的多种机制肿瘤免疫需要在转化研究中得到体现。目前大多数临床前研究缺乏多样性模型限制了它们作为肿瘤生物学这些方面的系统评估平台的适用性。给定 IO 方法的范围和 DDRD 的多样性，一个关键的未满足的转化要求是模型系统中定义了肿瘤 DDRD 和免疫浸润，以便可以轻松进行组合研究过。我们建议使用 Trp53 缺失乳腺癌的鼠源性肿瘤移植 (mTDT) 我们已经生成并表征了异质性、与人类癌症的相关性，以及证实这些同基因癌的 DDR 缺陷并评估相应的可重复性基线免疫细胞浸润。我们将对肿瘤和免疫特征进行多重分析，将它们与肿瘤对辐射的反应联系起来，辐射是一种典型的 DNA 损伤疗法，可以说是最有效的疗法广泛应用的细胞毒疗法。这些研究的结果直接响应由 FOA 组成的该模型标准化实施、肿瘤类型综合分析和存储库的协议样本、数据和活组织。该项目的成功将为进行机械化提供一种手段以及使用确定的肿瘤DDRD和免疫浸润组合物开发患者的转化研究针对 IO 和细胞毒性疗法的具体个性化治疗。