Overcoming mechanisms of therapeutic resistance in pancreatic ductal adenocarcinoma

克服胰腺导管腺癌的治疗耐药机制

• 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
• 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

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.

项目概述-整体