Harnessing TNFa Signaling To Improve Therapeutic Response In Pancreatic Cancer

利用 TNFa 信号传导改善胰腺癌的治疗反应

• 批准号: 10587590
• 负责人: Kian H Lim
• 金额: $ 61.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587590
• 关键词: 3-Dimensional; Autoimmune Diseases; Autophagocytosis; Bioinformatics; Biological Assay; Biology; Biometry; Biotin; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell Death; Cell Death Induction; Cell Survival; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Coculture Techniques; Collaborations; Cytolysis; Data; Development; Elements; Ensure; Exposure to; Fibroblasts; Foundations; Genes; Genetic; Genetically Engineered Mouse; Genotoxic Stress; Goals; Hydroxychloroquine; Immune; Immunocompetent; Immunologics; Immunotherapeutic agent; Immunotherapy; Label; MAPKAPK2 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Modeling; Modernization; Mus; Mutation; Myeloid Cells; Oncogenes; Oncogenic; Oncology; PIK3CG gene; Pancreatic Ductal Adenocarcinoma; Pathology; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Phosphorylation; Principal Investigator; Process; Production; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Regimen; Research Personnel; Role; Safety; Shapes; Signal Pathway; Signal Transduction; Solid; Structure; System; T-Lymphocyte; TNF gene; Techniques; Testing; Therapeutic Effect; Tumor-associated macrophages; Work; antitumor effect; cancer cell; cell type; checkpoint therapy; chemotherapy; clinical efficacy; cost effective; cytokine; design; effective therapy; factor A; improved; inhibitor; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; patient derived xenograft model; preclinical efficacy; preclinical trial; programs; response; small molecular inhibitor; success; translational impact; translational potential; treatment response; tumor immunology; tumor microenvironment; tumorigenic

PROJECT SUMMARY Effective treatment is an unmet and urgent need for patients with pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by mutations of the KRAS gene, which occurs in >95% of cases. However, targeting KRAS and its downstream signaling pathways, particularly the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway has been clinically unsuccessful due to rapid emergence of escape mechanism including autophagy. In this study, we made novel observation that MAPK inhibition (MAPKi) results in rapid and dramatic secretion of tumor necrosis factor alpha (TNF), which we found mediates both cell survival and death. Selective targeting of the pro-survival MAPKAPK2 (MK2) downstream f TNF signaling augments MAPKi-induced autophagy and cell death. To rigorously study these aspects, we have developed a 3-dimensional co-culture system to show that the anti-tumor effect of combined ERK and MK2 inhibitors is powerful enough to overcome the protection provided by adjacent cancer-associated fibroblasts (CAFs) and kill PDAC cells. We made observations that targeting MK2 induces favorable immunological changes that could potentiate checkpoint immunotherapy. The overarching goal of our proposal is to perform deeper and more comprehensive mechanistic studies to support development of novel therapeutic combinations that can be delivered to PDAC patients as clinical trials. To achieve this goal, we propose the following three Aims: 1. Aim 1: We will study the role of MK2 in autophagy in PDAC and CAFs using a new 3D spheroid culture system. We will determine the mechanism by which MAPKi-induces autophagy. Furthermore, we will identify new interacting partners of MK2 through a novel proteomic approach. 2. Aim 2: We will develop new genetic mouse models with conditional MK2-deletion to systematically dissect the role of MK2 in different cell types in PDAC progression and shaping the tumor microenvironment. 3. Aim 3: We will assess the combination of MK2 plus MAPKi and chemotherapy using a repertoire of thirty patient-derived xenograft models. We will perform additional studies using state-of-the art techniques and mouse models to develop novel immunotherapy regimens that will be rigorously tested.

项目总结 有效的治疗是胰腺导管腺癌患者尚未得到满足和迫切需要的 (PDAC)。PDAC的特征是KRAS基因突变，这种突变发生在95%的病例中。 然而，针对KRAS及其下游信号通路，特别是RAF-MEK-ERK 丝裂原活化蛋白激酶(MAPK)通路在临床上并不成功 逃逸机制的出现，包括自噬。在这项研究中，我们进行了新的观察， 丝裂原活化蛋白激酶抑制(MAPKI)导致肿瘤坏死因子α()的快速而显著的分泌， 我们发现它既能调节细胞存活又能调节细胞死亡。支持生存的MAPKAPK2的选择性靶向 (MK2)下游的肿瘤坏死因子信号增强了MAPKi诱导的自噬和细胞死亡。严谨地 研究这些方面，我们开发了三维共培养系统，以显示其抗肿瘤作用 ERK和MK2抑制剂的联合作用足以克服 邻近的癌症相关成纤维细胞(CAF)和杀伤PDAC细胞。我们观察到，目标是 MK2可诱导良好的免疫学变化，从而加强检查点免疫治疗。 我们建议的首要目标是进行更深入和更全面的机制研究。 支持开发可提供给PDAC患者的新型治疗组合 临床试验。为了实现这一目标，我们提出了以下三个目标： 1.目标1：我们将使用新的3D球体研究MK2在PDAC和CAF自噬中的作用 文化体系。我们将确定MAPKi诱导自噬的机制。 此外，我们将通过一种新的蛋白质组学方法寻找新的MK2相互作用伙伴。 2.目标2：我们将建立新的有条件缺失MK2的遗传性小鼠模型 系统剖析不同细胞类型中MK2在PDAC进展和形成PDAC中的作用 肿瘤微环境。 3.目标3：我们将使用一套方案来评估MK2+MAPKi和化疗的组合 30个患者来源的异种移植模型。我们将使用最先进的技术进行更多的研究 技术和小鼠模型，以开发新的免疫治疗方案，将严格 测试过。