(PQ3) Modulation of Osteosarcoma Biology by Inflammation and Immunity Defined through a ComparativeApproach

(PQ3) 通过比较方法定义的炎症和免疫对骨肉瘤生物学的调节

• 批准号: 9172075
• 负责人: JAIME F. MODIANO
• 金额: $ 19.86万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172075
• 关键词: Address; Adolescent; Affect; Animal Model; Applications Grants; Area; Behavior; Bioinformatics; Biological; Biological Markers; Biology; CD8B1 gene; Cancer Patient; Canis familiaris; Cells; Child; Clinical Trials; Complement; Cytotoxic Chemotherapy; DNA; Data; Development; Diagnosis; Disease; Down-Regulation; Engineering; Environment; Epidemiology; Etiology; Exploratory/Developmental Grant; Future; Generations; Genetic; Genetic Transcription; Genomics; Germ Lines; Goals; Health; Horizontal Gene Transfer; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunology; Immunotherapy; Incidence; Inflammation; Inflammatory; Inflammatory Infiltrate; Knowledge; Learning; Link; Malignant Bone Neoplasm; Malignant Neoplasms; Mediating; Methods; MicroRNAs; Minnesota; Modeling; Molecular Biology; Morbidity - disease rate; Mus; Mutation; Natural History; Patients; Pattern; Pediatric Oncology; Positioning Attribute; Property; Rare Diseases; Relapse; Research; Resources; Role; Sampling; Specimen; System; Systems Biology; T-Lymphocyte; Testing; Translations; Universities; Variant; Veterinary Medicine; Veterinary Pathology; Xenograft procedure; base; cancer risk; childhood sarcoma; comparative; design; exosome; immunoregulation; improved outcome; innovation; methylome; mortality; mouse model; next generation sequencing; novel; osteosarcoma; personalized diagnostics; personalized medicine; prevent; prognostic; receptor; response; sarcoma; statistics; success; trait; transcriptome; tumor; tumor progression

PROJECT SUMMARY This application is submitted in response to the NCI Provocative Questions (PQ) Initiative to address PQ #3, “How do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?” The intent of this PQ is to encourage research to study the causes of variable tumor- associated immune responses and/or how these variations relate to cancer risk, incidence, or progression. Our focus is osteosarcoma, a rare disease that primarily impacts children and adolescents. The research area is important to address significant unmet health needs for osteosarcoma patients with regard to the etiology of the disease, strategies to manage progression, and methods to guide personalized treatments. We chose to use the exploratory R21 mechanism as a means for hypothesis-testing and hypothesis generation from a massive sequencing effort through which we have generated a unique resource of primary and metastatic samples from humans, dogs, and mice with osteosarcoma. The effort includes sequencing of germ line DNA to identify de novo and acquired mutations, transcriptomes and methylomes. To complement these primary and autochthonous samples, we have developed robust models to study the osteosarcoma progression using xenografts as well as the role of the immune system in fully immunocompetent mice. We have assembled a robust team with diverse and comprehensive expertise in sarcoma biology and therapy, pediatric oncology, epidemiology and statistics, veterinary medicine and pathology, animal models, genetics and genomic engineering, inflammation, immunology and immunotherapy, molecular biology, transcription, microRNA networks, and systems biology and bioinformatics. The proposal includes intellectual and technical innovations in the multi-species comparative approach integrating multiple human and animal models, as well as in the conceptual frameworks that will be tested. Specifically we will investigate two issues that are directly pertinent to the PQ: For specific aim 1, we will investigate if there are correlations between inflammatory and immune cell infiltrates in the tumor environment and the biological behavior of the tumors. Data from this aim will inform the case for innate tumor traits as significant drivers of the immune response, allowing us to postulate a causality hypothesis for test it in a future larger project. Specific aim 2 is designed to determine the mechanisms that drive patterning of immune infiltrates in osteosarcoma. Data from this aim, whether conserved or species-specific, will confirm a new and exciting mechanism of tumor-mediated immunomodulation that could be used as a biomarker, and that also could be therapeutically tractable. Overall, the project has the potential to impact patient management and selection for clinical trials evaluating sarcoma immunotherapy.

项目概要 本申请是为了回应 NCI 挑衅性问题 (PQ) 倡议而提交，旨在解决 PQ #3， “肿瘤相关免疫反应的变化如何导致癌症风险、发病率、 还是进步？”该 PQ 的目的是鼓励研究可变肿瘤的原因 相关的免疫反应和/或这些变化与癌症风险、发病率或进展的关系。我们的 重点是骨肉瘤，这是一种主要影响儿童和青少年的罕见疾病。研究领域是 解决骨肉瘤患者在病因方面未得到满足的重大健康需求非常重要 疾病、控制进展的策略以及指导个性化治疗的方法。我们选择 使用探索性 R21 机制作为假设检验和假设生成的手段 通过大量的测序工作，我们生成了原发性和转移性的独特资源 来自患有骨肉瘤的人类、狗和小鼠的样本。这项工作包括对种系 DNA 进行测序，以 识别从头突变和获得性突变、转录组和甲基化组。为了补充这些主要和 本土样本，我们开发了强大的模型来研究骨肉瘤的进展 异种移植物以及免疫系统在完全免疫功能的小鼠中的作用。我们组装了一个 强大的团队在肉瘤生物学和治疗、儿科肿瘤学、 流行病学和统计学、兽医学和病理学、动物模型、遗传学和基因组学 工程学、炎症、免疫学和免疫治疗、分子生物学、转录、microRNA 网络、系统生物学和生物信息学。该提案包括智力和技术创新 在整合多种人类和动物模型的多物种比较方法中，以及在 将要测试的概念框架。具体来说，我们将调查两个直接相关的问题 致 PQ：对于具体目标 1，我们将研究炎症和免疫之间是否存在相关性 细胞在肿瘤环境中的浸润和肿瘤的生物学行为。该目标的数据将告知 先天性肿瘤特征是免疫反应的重要驱动因素，使我们能够假设 因果关系假设，以便在未来更大的项目中对其进行测试。具体目标 2 旨在确定 驱动骨肉瘤免疫浸润模式的机制。来自该目标的数据，是否 保守的或物种特异性的，将证实肿瘤介导的新的令人兴奋的机制 免疫调节可以用作生物标志物，并且在治疗上也易于处理。全面的， 该项目有可能影响患者管理和评估肉瘤临床试验的选择 免疫疗法。