Patho-Genetic Analysis of Invasive Mucinous Adenocarcinoma of the Lung

肺侵袭性粘液性腺癌的病理遗传学分析

基本信息

批准号：
10596503
负责人：
Yutaka Maeda
金额：
$ 61.93万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596503
关键词：
3-Dimensional Adenocarcinoma Appendix Adenocarcinoma Biological Markers Biology Boston Cancer Etiology Cancer Patient Candidate Disease Gene Cell Communication Cell Line Cells Cellular Morphology Cessation of life Cities Classification Data Development Diagnosis Epidermal Growth Factor Receptor Europe Evaluation Gastrointestinal tract structure Gene Expression Genes Genetic Goals Goblet Cells Growth HNF4A gene Heterogeneity Histology Human Immune Immunohistochemistry Immunotherapy In Vitro Iowa Japan KRAS2 gene KRASG12D Knowledge Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Metastatic Neoplasm to the Lung Mission Molecular Molecular Analysis Morphology Mucinous Mucinous Neoplasm Mucins Mucous body substance Mutation New York City Nuclear Receptors Oncologist Organ Organoids Outcome Pancreatic Adenocarcinoma Papillary Pathologic Pathologist Pathway interactions Patients Pharmaceutical Preparations Public Health Reporting Research Research Personnel Sodium Chloride Solid Specimen Stromal Cells Surgeon Testing Therapeutic Therapeutic antibodies United States National Institutes of Health autocrine biomarker identification cell type diagnostic biomarker driver mutation effective therapy gastrointestinal genetic analysis genetic signature human disease in vivo innovation mRNA sequencing molecular targeted therapies mouse model neoplastic cell new technology new therapeutic target next generation sequencing novel therapeutics paracrine programmed cell death ligand 1 programs single-cell RNA sequencing small molecular inhibitor small molecule therapeutic biomarker therapeutic target tumor tumor microenvironment

项目摘要

Despite recent progress in the development of molecularly-targeted therapy and immunotherapy, lung cancer is still the leading cause of cancer death since such therapies are not applicable for more than half of lung cancer patients. Lung adenocarcinoma is the major pathological type of lung cancer. Lung adenocarcinoma has been further subdivided based on both genetic alterations (e.g., KRAS or EGFR mutations and ALK fusions) and differentiation state (including histopathologic subtypes such as acinar, lepidic, papillary, solid and mucinous). In most cases, such genetic alterations do not strictly correlate with the histopathologic subtypes of lung adenocarcinomas. However, genetic and molecular pathways that lead to the development of invasive mucinous adenocarcinoma of the lung (IMA) have been revealed by our team and others in the past several years (e.g., HNF4A pathway), suggesting that such molecular pathways can be targeted to treat IMA for which there is currently no effective therapy. Notably, the histology of IMA resembles that of mucus-producing cancers found in the gastrointestinal tract (e.g., pancreatic cancer), which hampers efforts to properly diagnose IMA from lung metastases originating from other mucus-producing organs. A biomarker to distinguish IMA from lung metastases has not been established. Our long-term goal is to identify a therapy for IMA. The objective here is to 1) determine whether HNF4A and its downstream genes that are specifically expressed in IMA but not in normal lung can be therapeutic targets for IMA and 2) comprehensively identify therapeutic targets and biomarkers using novel technologies such as single-cell mRNA-seq and 3D tumoroid (organoid) culture with a large number of IMA specimens (>200). The central hypothesis is that IMA is driven by distinct molecular pathways that can be therapeutically targeted. The rationale is based on our previous and preliminary studies indicating that 1) the HNF4A pathway is required for the growth of IMA and 2) such a pathway creates a specific tumor microenvironment that influences tumor-associated cells, which presents specific therapeutic targets and biomarkers. This hypothesis will be tested in the following specific aims: 1) determine whether HNF4A and/or its downstream genes can be therapeutic targets for IMA, 2) analyze the heterogeneity of IMA at a single-cell level, and 3) discover diagnostic biomarkers for IMA. The approach is innovative because it will focus on molecular pathways that have not been explored as therapeutic targets for IMA. The proposed research will: 1) utilize model mice for IMA (GEMM and PDX) and human specimens of IMA and lung metastases and 2) determine whether small molecular inhibitors and therapeutic antibodies can reduce the growth of IMA. The proposed research is significant because our team, comprised of a number of IMA researchers from several institutes, will bring their knowledge and expertise together to develop a novel therapy for IMA.

尽管在分子靶向疗法和免疫疗法的发展方面最近取得了进展，但肺癌是由于这种疗法不适用于肺癌的一半以上，因此仍然是癌症死亡的主要原因患者。肺腺癌是肺癌的主要病理类型。肺腺癌已经基于遗传改变（例如KRAS或EGFR突变和ALK融合）的进一步细分分化状态（包括组织病理亚型，例如腺泡，鳞片，乳头状，固体和粘液）。在大多数情况下，这种遗传改变与肺的组织病理学亚型不严格相关腺癌。然而，导致侵入性粘液的发展的遗传和分子途径在过去的几年中，我们的团队和其他人揭示了肺腺癌（IMA）（例如， HNF4A途径），提示可以针对这种分子途径来治疗存在的IMA 目前没有有效的疗法。值得注意的是，IMA的组织学类似于发现粘液的癌症的组织学在胃肠道（例如胰腺癌）中，这阻碍了正确诊断肺IMA的努力源自其他产生粘液的器官的转移。将IMA与肺部区分开的生物标志物尚未建立转移。我们的长期目标是确定对IMA的疗法。这里的目的是至1）确定在IMA中专门表达但不在IN中表达的HNF4A及其下游基因是否正常肺可以是IMA的治疗靶标，2）全面识别治疗靶标和使用新型技术（例如单细胞mRNA-seq和3D肿瘤（Organoid）培养）的生物标志物大量IMA标本（> 200）。中心假设是IMA由不同的分子驱动可以针对治疗的途径。理由是基于我们以前的初步研究表明1）IMA的生长需要HNF4A途径和2）这样的途径创造了特定的途径影响肿瘤相关细胞的肿瘤微环境，该细胞提出了特定的治疗靶标和生物标志物。该假设将在以下具体目的中进行检验：1）确定是否HNF4A和/或它的下游基因可以是IMA的治疗靶标，2）分析单细胞处IMA的异质性级别和3）发现IMA的诊断生物标志物。这种方法是创新的，因为它将专注于尚未探索的分子途径是IMA的治疗靶标。拟议的研究将：1）利用IMA的模型小鼠（GEMM和PDX）以及IMA和肺转移的人类标本以及2）确定小分子抑制剂和治疗性抗体是否可以减少IMA的生长。这拟议的研究很重要，因为我们的团队由几个IMA研究人员组成研究所将把他们的知识和专业知识融合在一起，为IMA开发一种新颖的疗法。