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

• 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
• 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

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 胰腺导管腺癌（PDA）是一种毁灭性的疾病，其发病率的上升令人不安。穷人 PDA 的预后在很大程度上归因于对传统化疗和免疫治疗的固有抵抗 疗法。肿瘤内在和外在表观基因组程序的多因素贡献，一个精心设计的 肿瘤微环境（TME）内的细胞间通讯网络和复杂的代谢 适应性复合使 PDA 对当前的治疗方法无效。提议的实验用途 I 类组蛋白脱乙酰酶 (HDAC) 的药理学和遗传靶向，以确定 表观遗传编码程序对治疗耐药性的贡献。目标 1 扩展了实验室的发现 HDAC 抑制 (HDACi) 会导致 DNA 损伤反应途径基因的下调。能力 HDACi 使 PDA 的类器官和小鼠模型对 DNA 损伤剂敏感的实验通过使用 一种纳米颗粒递送系统，可规避体内 HDAC 抑制剂的全身毒性。初步给出 有证据表明 HDACi 上调自噬，这是一种已知的治疗耐药性介质， 测试了自噬抑制以增强对 HDACi（以及与 DNA 损伤剂的组合）的反应 与项目 3 合作。此外，对人类类器官库的询问将描绘出有何不同 突变谱影响对 HDACi 和 DNA 损伤的敏感性。目标 2 描述了 HDAC 的贡献- 癌症相关成纤维细胞（CAF）（TME 中的一种异质细胞类型）中受调控的表观遗传程序， PDA 结果。初步数据表明 HDAC1 是 CAF 响应的主要 HDAC 体外药理学 HDACi。在这里，采用遗传方法来确定成纤维细胞中 HDAC1 的丢失是如何发生的 影响 CAF 功能异质性、肿瘤生长和体内化疗耐药性。与以下机构的共同努力 项目 2 阐明 HDACi 如何通过以下方式影响肿瘤生长的基质支持和化疗耐药性： CAF 衍生的可溶性因子（包括 LIF）的改变。此外，HDACi 的分子机制 描述了特定 CAF 亚群中表观基因组的重新连接。最后，目标 3 基于初步发现 HDACi 使 PDA 小鼠模型对免疫检查点抑制 (ICI) 敏感。与项目 3 合作， HDACi 和自噬阻断通过收敛协同促进 ICI 反应的能力 测试了 MHC-I 的调节。通过诱导免疫细胞增强抗肿瘤免疫力的可能性 还探讨了 HDACi 和 DNA 损伤剂组合导致的死亡。与合作 项目 2，炎症性 CAF 群体中的 STAT 信号如何影响由 HDACi 和 ICI 已定义。最后，确定 HDACi 如何重新编程人类的免疫调节特征 PDA，通过数字空间分析结合 HDACi 和抗 PD-1 ICI 的已完成临床试验的活检样本 分析。总之，这些研究为治疗背后的表观遗传机制提供了重要的见解。 PDA 耐药性并探索有可能改善患者预后的新治疗策略。