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Project 1: Overcoming therapeutic resistance in pancreatic cancer through epigenetic reprogramming

项目1：通过表观遗传重编程克服胰腺癌的治疗耐药性

基本信息

批准号：
10629063
负责人：
RONALD M EVANS
金额：
$ 50.89万
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/10629063
关键词：
Affect Antigen Presentation Antineoplastic Agents Autophagocytosis Biopsy Cancer Cell Growth Cell Communication Cell Compartmentation Cell Death Cell Proliferation Cells Chemoresistance Chromatin Clinical Clinical Trials Collaborations Complex Cytotoxic T-Lymphocytes DNA Damage DNA Repair Data Disease Disease Progression Dose Down-Regulation Drug Delivery Systems Epigenetic Process Exhibits Extracellular Matrix Fibroblasts Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription HDAC1 gene Heterogeneity Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Human I-antigen Immune Immunologics Immunotherapy In Vitro Incidence Induction of Apoptosis Inflammatory Intercellular Fluid LIF gene Laboratory Finding Malignant Neoplasms Malignant neoplasm of pancreas Maps Mediating Mediator Metabolic Molecular Mus Mutation Organoids Outcome Pancreatic Ductal Adenocarcinoma Pathway interactions Patient-Focused Outcomes Patients Phenotype Population Production Prognosis Refractory Regulation Resistance Role Signal Transduction Stromal Cells System T-Lymphocyte Testing Therapeutic Tissues Toxic effect Treatment Efficacy Tumor Burden Tumor Immunity Tumor Promotion Work anti-PD-1 anti-PD1 therapy anti-tumor immune response cell growth cell type checkpoint inhibition cytokine digital drug sensitivity efficacy testing epigenome epigenomics experimental study genetic approach immunogenic immunoregulation improved in vivo inhibition of autophagy inhibitor insight mouse model nano-string nanoparticle nanoparticle delivery neoplastic cell novel novel therapeutics pancreatic cancer cells pancreatic ductal adenocarcinoma model pharmacologic prevent programs reconstitution response synergism targeted treatment therapy resistant transcriptional reprogramming treatment response treatment strategy tumor tumor growth tumor microenvironment tumorigenic

项目摘要

PROJECT SUMMARY – Project 1: Epigenetics Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a disturbing rise in incidence. The poor prognosis of PDA is attributed, in large part, to inherent resistance to conventional chemo- and immuno- therapies. Multifactorial contributions from tumor intrinsic and extrinsic epigenomic programs, an elaborate network of cell-cell communications within the tumor microenvironment (TME), and complex metabolic adaptations compound to make PDA refractory to the current arsenal of therapies. Proposed experiments use both pharmacological and genetic targeting of Class I histone deacetylases (HDACs) to determine the contributions of epigenetically encoded programs to therapeutic resistance. Aim 1 expands on the lab’s finding that HDAC inhibition (HDACi) leads to a downregulation of DNA damage response pathway genes. The ability of HDACi to sensitize both organoid and mouse models of PDA to DNA damaging agents is tested by employing a nanoparticle delivery system that circumvents systemic HDAC inhibitor toxicities in vivo. Given preliminary evidence that HDACi upregulates autophagy, a known mediator of therapeutic resistance, the ability of autophagy inhibition to potentiate responses to HDACi (and combinations with DNA damaging agents) is tested in collaboration with Project 3. Moreover, interrogation of a human organoid bank will delineate how different mutational profiles impact sensitivities to HDACi and DNA damage. Aim 2 delineates the contribution of HDAC- regulated epigenetic programs in cancer-associated fibroblasts (CAFs), a heterogenous cell type within the TME, to PDA outcomes. Preliminary data identifies HDAC1 as the primary HDAC underlying CAF responses to pharmacological HDACi in vitro. Here, a genetic approach is taken to determine how HDAC1 loss in fibroblasts impacts CAF functional heterogeneity, tumor growth, and chemoresistance in vivo. Collaborative efforts with Project 2 elucidate how HDACi influences stromal support of tumor growth and chemoresistance through alterations in CAF-derived soluble factors, including LIF. In addition, the molecular mechanisms by which HDACi rewires the epigenome in specific CAF subpopulations is delineated. Lastly, Aim 3 builds on preliminary findings that HDACi sensitizes PDA mouse models to immune checkpoint inhibition (ICI). In collaboration with Project 3, the ability of HDACi and autophagy blockade to synergize in promoting ICI responses through convergent regulation of MHC-I is tested. The possibility of enhancing anti-tumor immunity by inducing immunological cell death through the combination of HDACi and DNA damaging agents is also explored. In collaboration with Project 2, how STAT signaling in inflammatory CAF populations influences anti-tumor immunity elicited by HDACi and ICI is defined. Finally, to determine how HDACi reprograms immunomodulatory features in human PDA, biopsies from a completed clinical trial combining HDACi and anti-PD-1 ICI are analyzed via digital spatial profiling. Together, these studies provide critical insight into the epigenetic mechanisms underlying therapeutic resistance in PDA and explore novel treatment strategies with the potential to improve patient outcomes.

项目摘要-项目1：表观遗传学