Overcoming mechanisms of therapeutic resistance in pancreatic ductal adenocarcinoma

克服胰腺导管腺癌的治疗耐药机制

基本信息

批准号：
10629062
负责人：
TONY R. HUNTER
金额：
$ 295.32万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2023-07-06 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629062
关键词：
Automobile Driving Autophagocytosis Biology Biometry Biostatistics Core CA-19-9 Antigen Cancer Etiology Cell Communication Cell Survival Cells Cessation of life Chemoresistance Clinical Coculture Techniques Coupled Cues DNA Damage Desmoplastic Development Drug Delivery Systems Drug resistance Epidermal Growth Factor Receptor Epigenetic Process Fibroblasts Genome Goals Growth HDAC1 gene Heterogeneity Histone Deacetylase Histone Deacetylase Inhibitor Human Hypoxia Immune Immune checkpoint inhibitor Immunotherapy Individual Inflammatory Informatics LIF gene Macrophage Macrophage Activation Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Metabolism Modeling Mus Mutation Nature Nutrient Depletion Nutrient availability Organoids Outcome Pancreatic Ductal Adenocarcinoma Paracrine Communication Pathway interactions Patients Polysaccharides Post-Translational Protein Processing Production Refractory Disease Regulation Research Personnel Research Project Grants Research Support Resistance Resource Sharing Role STAT3 gene Sampling Signal Pathway Signal Transduction Specimen Stress Stromal Cells Survival Rate System Testing Therapeutic Toxic effect Treatment Efficacy Tumor Promotion Vascularization cell type checkpoint inhibition chemotherapy combinatorial cytokine digital epigenome glycosylation immunogenic cell death improved inhibition of autophagy inhibitor innovation interest mortality mouse model nanoparticle drug neoplastic cell novel novel therapeutics paracrine programs resistance factors resistance mechanism response single cell analysis stem support network synergism targeted treatment therapy outcome therapy resistant treatment response treatment strategy tumor tumor growth tumor microenvironment tumorigenic

项目摘要

PROJECT SUMMARY – Overall While mortality rates for many cancers are declining, pancreatic ductal adenocarcinoma (PDA) remains a highly lethal malignancy with the worst 5-year survival rate of the common malignancies. Unfortunately, current therapies are largely ineffective in PDA, an outcome attributed in large part to therapeutic resistance. The highly fibrotic and poorly vascularized tumor microenvironment (TME) restricts both nutrient availability and drug delivery, and provides pro-survival and immunosuppressive cues. These limitations create energy stresses that drive metabolic adaptations to support tumor growth and therapeutic resistance. Moreover, the hyperactivation of pro-survival and resistance pathways in tumor and stromal cell types results in an integrated resistance network. The induction of these pathways is orchestrated by cell-to-cell communications within the TME, including aberrant glycosylation (CA-19-9) and the secretion of immunosuppressive and pro-survival paracrine factors, such as Leukemia Inhibitory Factor (LIF) from cancer-associated fibroblasts (CAFs). In addition, cells adapt to the hypoxic, nutrient-depleted TME by upregulating cell type-specific survival programs, including autophagy. Ultimately, to support and respond to these signaling and metabolic programs, both the tumor and stromal cell epigenomes are reprogrammed, leading to cellular heterogeneity and plasticity that restricts durable therapy responses. Each of these programs promote resistance to a broad range of therapeutics, including chemotherapies, targeted therapies, and immune checkpoint inhibitors. The central hypothesis of this program is that pancreatic cancer has co-opted an integrated network of epigenetic programs, paracrine signaling pathways, and metabolic adaptations to promote tumor survival and therapeutic resistance. Building upon the investigators’ complementary expertise in epigenetics, cell signaling, and metabolic adaptations, as well as common interests in pancreatic cancer, this program seeks to understand the interactions that hinder PDA therapeutic responses, with the ultimate goal of identifying vulnerabilities that can be exploited and targeted to overcome drug resistance. Importantly, the program will utilize advanced mono- and co-culture organoid systems, cutting-edge mouse models, novel therapeutics, single-cell approaches, and human clinical specimens to delineate the contributions of both tumor cells and their stromal support network to therapeutic resistance. Moreover, proposed cooperative and innovative approach will reveal how these resistance nodes are integrated and can be targeted to improve therapeutic outcomes in PDA.

项目概要——总体虽然许多癌症的死亡率正在下降，但胰腺导管腺癌（PDA）仍然是一个高度危险的癌症。不幸的是，目前常见恶性肿瘤中 5 年生存率最差。治疗对于 PDA 基本上无效，这一结果在很大程度上归因于治疗耐药。纤维化和血管化不良的肿瘤微环境（TME）限制了营养物质的可用性和药物传递，并提供促进生存和免疫抑制的线索，这些限制会产生能量压力。驱动代谢适应以支持肿瘤生长和治疗抵抗。肿瘤和基质细胞类型中的促生存和耐药途径的结合导致了综合耐药性这些通路的诱导是通过 TME 内的细胞间通信来协调的，包括异常糖基化 (CA-19-9) 以及免疫抑制和促生存旁分泌的分泌因子，例如来自癌症相关成纤维细胞 (CAF) 的白血病抑制因子 (LIF)。通过上调细胞类型特异性生存程序来适应缺氧、营养耗尽的 TME，包括最终，支持和响应这些信号传导和代谢程序，包括肿瘤和细胞。基质细胞表观基因组被重新编程，导致细胞异质性和可塑性，限制了持久性这些计划中的每一个都会促进对多种治疗方法的抵抗，包括化疗、靶向治疗和免疫检查点抑制剂。该计划的中心假设是胰腺癌已经选择了一个集成网络表观遗传程序、旁分泌信号通路和代谢适应促进肿瘤基于研究人员在表观遗传学方面的互补专业知识，该计划寻求细胞信号传导、代谢适应以及对胰腺癌的共同兴趣了解阻碍 PDA 治疗反应的相互作用，最终目标是确定重要的是，该计划将能够利用和瞄准克服耐药性的漏洞。利用先进的单一和共培养类器官系统、尖端的小鼠模型、新颖的疗法、单细胞方法和人类临床标本来描述肿瘤细胞及其贡献此外，所提出的合作和创新方法将支持基质网络。揭示这些耐药节点如何整合并有针对性地改善 PDA 的治疗结果。