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

• 批准号: 10374803
• 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
• 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/10374803
• 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; Institutes; Iowa; Japan; KRAS2 gene; KRASG12D; Knowledge; Lead; 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; base; 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; targeted biomarker; therapeutic target; tumor; tumor microenvironment

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.

尽管最近在分子靶向治疗和免疫治疗的发展方面取得了进展，但肺癌仍是一个潜在的问题。 仍然是癌症死亡的主要原因，因为这种疗法不适用于超过一半的肺癌 患者肺腺癌是肺癌的主要病理类型。肺腺癌一直是 基于遗传改变（例如，KRAS或EGFR突变和ALK融合）和 分化状态（包括组织病理学亚型，如腺泡、鳞屑、乳头状、实体和粘液）。 在大多数情况下，这种遗传改变与肺的组织病理学亚型并不严格相关。 腺癌然而，导致侵袭性粘液性肿瘤发生的遗传和分子途径， 肺腺癌（IMA）在过去几年中已经被我们的团队和其他人揭示（例如， HNF 4A通路），这表明这些分子通路可以靶向治疗IMA， 目前没有有效的治疗方法。值得注意的是，IMA的组织学类似于粘液产生的癌症， 在胃肠道中（例如，胰腺癌），这阻碍了从肺中正确诊断IMA的努力 源自其他粘液产生器官的转移。鉴别IMA与肺的生物标志物 转移尚未确定。我们的长期目标是确定IMA的治疗方法。这里的目标是 1）确定HNF 4A及其下游基因是否在IMA中特异性表达，但在 正常肺可以作为IMA的治疗靶点; 2）全面鉴定治疗靶点， 使用新技术，如单细胞mRNA-seq和3D类肿瘤（类器官）培养， 大量IMA标本（>200）。中心假设是IMA由不同的分子驱动， 可以作为治疗靶点的途径。理论基础是基于我们以前和初步的研究 表明1）HNF 4A途径是IMA生长所需的，2）这种途径产生特异性的 影响肿瘤相关细胞的肿瘤微环境，其呈现特异性治疗靶点， 生物标志物。该假设将在以下具体目的中进行测试：1）确定HNF 4A和/或HNF 4 B是否与HNF 4A和/或HNF 4 B的表达相关。 其下游基因可作为IMA的治疗靶点; 2）在单细胞水平上分析IMA的异质性， 水平，和3）发现IMA的诊断生物标志物。该方法是创新的，因为它将侧重于 这些分子途径尚未被探索为IMA的治疗靶点。本研究将：（1） 利用IMA的模型小鼠（GEMM和PDX）和IMA和肺转移的人类样本，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。的 拟议的研究是重要的，因为我们的团队，包括一些IMA研究人员从几个 研究所将把他们的知识和专业知识结合起来，为IMA开发一种新的治疗方法。