Defining the role of aberrant signal pathway activation in melanoma on the immune microenvironment

定义黑色素瘤中异常信号通路激活对免疫微环境的作用

• 批准号: 9918757
• 负责人: Amanda Truong
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918757
• 关键词: Antineoplastic Agents; BRAF gene; Biological; Biological Models; C57BL/6 Mouse; CDKN2A gene; CTLA4 gene; Cell Line; Cell surface; Cells; Cessation of life; Clinical Trials; Combined Modality Therapy; Complement; Congenic Mice; Data; Disease; Drug resistance; Enrollment; Environment; Failure; Genetic; Genetic Engineering; Goals; Human; Human Genetics; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immunity; Immunocompetent; Immunotherapeutic agent; Immunotherapy; Incidence; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular Abnormality; Mouse Cell Line; Mus; Mutate; Mutation; Neoplasm Metastasis; Oncogenes; Oncoproteins; Other Genetics; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Phosphotransferases; Pre-Clinical Model; Prior Therapy; Protein p53; Ras Signaling Pathway; Resistance; Role; Signal Pathway; Signal Transduction; Surface; Surface Antigens; Testing; Time; Transplantation; Treatment Protocols; Tumor Escape; Tumor Immunity; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Work; base; cell behavior; chemokine; clinically relevant; congenic; cytokine; driver mutation; experimental study; high risk; human disease; immune checkpoint blockade; improved; in vivo; innovation; insight; melanoma; mouse model; neoplasm immunotherapy; neoplastic cell; optimal treatments; outcome forecast; pre-clinical; predicting response; programmed cell death protein 1; recruit; response; restoration; targeted treatment; treatment optimization; treatment response; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT ABSTRACT Melanoma is a deadly malignancy of increasing incidence, with approximately 90,000 deaths estimated in 2018. Although recent advances in pathway targeted therapy (PTT) and immune therapy have revolutionized the treatment landscape of metastatic disease, these therapies are limited by acquired resistance and low response rates. Therefore, there is an urgent need to optimize treatment regimens, particularly in combination therapies in order to utilize the rapid response benefits of PTT and the durability of immunotherapy. Because clinical trials are limited by patient enrollment, there is a heavy reliance on preclinical models to provide translatable justification of treatment regimens. Unfortunately, the high rates of clinical trial failures have been historically attributed to the lack of preclinical models that efficiently recapitulate human disease, both in genetics and immune response. Thus this study seeks to establish an immunocompetent mouse model in which congenic mouse cell lines with defined melanoma genetic alterations can be transplanted into C57BL/6 mouse hosts. This will allow for the study of tumor immunity and immunotherapy response in an immunocompetent host using melanomas that accurately reflect the genetics of human melanoma. Aberrations in the RAS and CDKN2A signaling pathways are universally present in melanoma. PTT of BRAF, the most common mutation in melanoma and a downstream target of RAS, has been previously been shown to upregulate tumor immunity. In addition, downstream tumor suppressor pathways of CDKN2A have also been shown to enhance tumor immunity, although the direct role of CDKN2A on the tumor immune and immunotherapy response is not clear. Thus, a major goal of this study is to determine whether loss of CDKN2A contributes to immune evasion and immunotherapy resistance. Successful completion of these aims will not only provide biological insight into the role of aberrant signaling in melanoma on the tumor immune environment, but also better inform treatment regimens that can improve patient survival.

项目摘要 黑色素瘤是一种发病率不断增加的致命恶性肿瘤，2018年估计约有90，000人死亡。 尽管通路靶向治疗（PTT）和免疫治疗的最新进展已经彻底改变了免疫系统， 转移性疾病的治疗前景，这些疗法受到获得性耐药性和低应答的限制 rates.因此，迫切需要优化治疗方案，特别是联合治疗 以便利用PTT的快速反应益处和免疫疗法的持久性。由于临床试验 受患者入组的限制，严重依赖临床前模型来提供可翻译的 治疗方案的合理性。不幸的是，临床试验失败的高比率一直是历史性的， 这归因于缺乏有效概括人类疾病的临床前模型，无论是在遗传学上， 免疫反应因此，本研究旨在建立一种免疫活性小鼠模型，其中同源基因 具有确定的黑色素瘤遗传改变的小鼠细胞系可以移植到C57 BL/6小鼠宿主中。这 将允许在免疫活性宿主中使用 准确反映人类黑色素瘤遗传学的黑色素瘤。RAS和CDKN 2A中的畸变 信号通路普遍存在于黑素瘤中。BRAF的PTT，黑色素瘤中最常见的突变 和RAS的下游靶点，先前已显示上调肿瘤免疫。此外，本发明还提供了一种方法， CDKN 2A的下游肿瘤抑制途径也显示出增强肿瘤免疫， 尽管CDKN 2A对肿瘤免疫和免疫治疗应答的直接作用尚不清楚。因此 本研究的主要目的是确定CDKN 2A的缺失是否有助于免疫逃避， 免疫治疗抵抗。这些目标的成功实现不仅将提供生物学上的洞察力， 异常信号在黑色素瘤中的作用对肿瘤免疫环境的影响，也更好的告知治疗 可以提高患者生存率的方案。