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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要有效的治疗是胰腺导管腺癌患者未满足且迫切的需求 (PDAC)。PDAC 的特点是 KRAS 基因突变，这种情况发生在 >95% 的病例中。然而，针对 KRAS 及其下游信号通路，特别是 RAF-MEK-ERK 丝裂原激活蛋白激酶（MAPK）途径由于快速的包括自噬在内的逃逸机制的出现在这项研究中，我们做出了新的观察： MAPK 抑制 (MAPKi) 导致肿瘤坏死因子 α (TNFα) 快速、大量分泌，我们发现它介导细胞存活和死亡。 (MK2) 下游 f TNF 信号传导会严格增强 MAPKi 诱导的自噬和细胞死亡。研究这些方面，我们开发了一个3维共培养系统来表明抗肿瘤 ERK 和 MK2 抑制剂联合使用的效果足以克服我们观察到，针对邻近的癌症相关成纤维细胞 (CAF) 并杀死 PDAC 细胞。 MK2 诱导有利的免疫学变化，可以增强检查点免疫疗法。我们提案的总体目标是进行更深入、更全面的机制研究支持开发可用于 PDAC 患者的新型治疗组合为了实现这一目标，我们提出以下三个目标： 1. 目标 1：我们将使用新的 3D 球体研究 MK2 在 PDAC 和 CAF 中自噬中的作用我们将确定 MAPKi 诱导自噬的机制。此外，我们将通过一种新颖的蛋白质组学方法鉴定 MK2 新的相互作用伙伴。 2. 目标 2：我们将开发具有条件 MK2 缺失的新遗传小鼠模型，以系统地剖析了 MK2 在 PDAC 进展和塑造不同细胞类型中的作用肿瘤微环境。 3. 目标 3：我们将使用一套方案评估 MK2 加 MAPKi 和化疗的组合我们将使用最先进的技术进行额外的研究，包括三十个源自患者的异种移植模型。技术和小鼠模型来开发新的免疫治疗方案，该方案将经过严格的测试已测试。