Impact of RB activation on the pancreatic cancer epigenome and tumor microenvironment

RB激活对胰腺癌表观基因组和肿瘤微环境的影响

• 批准号: 10673462
• 负责人: Erik Knudsen
• 金额: $ 50.52万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673462
• 关键词: Antigen Presentation; Automobile Driving; Biochemical; CDK4 gene; Cancer Etiology; Cell Cycle; Cell division; Cells; Cessation of life; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Complement; Complex; Correlative Study; Coupled; Cytostatics; Data; Disease; Effectiveness; Elements; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genetic; Growth; Immune response; Immune system; Immunocompetent; Immunologics; Immunotherapy; Interferons; Intervention; KRAS2 gene; MEK inhibition; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Population; Pre-Clinical Model; Prognosis; Proliferating; Publishing; Regulation; Regulatory Element; Resistance; Specimen; Survival Rate; Therapeutic; Tissues; Tumor Biology; United States; Work; epigenome; immunoengineering; improved outcome; inhibitor; neoplastic cell; novel strategies; pancreatic ductal adenocarcinoma model; programs; response; retinoblastoma tumor suppressor; targeted treatment; therapy development; therapy resistant; treatment response; tumor; tumor microenvironment; tumorigenesis; tumorigenic

Pancreatic ductal adenocarcinoma (PDAC) represents a therapy recalcitrant disease with 5-year survival rate of approximately 10%. Multiple failed clinical trials reinforce the need for new approaches to treatment that employ rationally developed therapies targeting key genetic features of PDAC tumors as well as the tumor microenvironment. Fundamentally PDAC is a KRAS-driven tumor; however, approaches to target KRAS either genetically or pharmaceutically have led to the realization that tumors can evolve mechanisms to continue cell division in the presence of such interventions. Using a combination of unbiased analyses and patient derived models we find that most tumors have evolved mechanisms to deregulate the retinoblastoma tumors suppressor (RB) pathway that limits the effectiveness of targeting RAS or effector pathways (e.g. MEK inhibition). Consequently, the activation of RB is sufficient to limit the proliferation and tumorigenic growth of PDAC models. In addition to effects on the proliferation, we have found that RB activation is sufficient to coordinate changes in gene expression that impact on genes related to classical vs. basal subtypes of PDAC and immunological gene expression programs (e.g. antigen presentation and interferon response). Unlike cell cycle responses, these changes in gene expression are more heterogeneous and the underlying mechanisms and key regulatory elements remain poorly understood. In Aim 1 we will delineate the RB regulation and mechanisms of gene expression regulation in PDAC models. While RB status clearly has effects on tumor cell division, an important element of RB-pathway activation are effects related to the tumor microenvironment. Preliminary and published data indicate that RB activation has broad effects on the tumor stroma and immunological milieu. Much of these studies have employed systemic strategies that impact on both the tumor and the host. In preliminary data, we have found that activation of RB selectively within the tumor is sufficient to change the fibroblastic and immunological cell subtypes with the tumor, albeit not at the same level of systemic treatments. Here we will interrogate the intersection between the tumor and the microenvironment and how these impact tumor-static response and can be exploited by immunotherapy approaches. Together, Aim 2 will define the impact of RB- activation on the tumor microenvironment using a combination of immune competent models and clinical specimens.

胰腺导管腺癌（PDAC）是一种治疗难治性疾病，5年生存率为 大约10%。多个失败的临床试验加强了对新的治疗方法的需求， 针对PDAC肿瘤的关键遗传特征以及肿瘤的合理开发的疗法 微环境PDAC基本上是KRAS驱动的肿瘤;然而，靶向KRAS的方法 基因或药学上的研究已经使人们认识到，肿瘤可以进化出一种机制， 在这种干预下，分裂。使用无偏分析和患者衍生的组合 我们发现，大多数肿瘤已经进化出了一种机制，使视网膜母细胞瘤肿瘤抑制因子 (RB)限制靶向RAS或效应器途径有效性的途径（例如MEK抑制）。 因此，RB的活化足以限制PDAC模型的增殖和致瘤生长。 除了对增殖的影响外，我们发现RB激活足以协调细胞增殖的变化。 影响与PDAC的经典与基础亚型相关的基因和免疫基因的基因表达 表达程序（例如抗原呈递和干扰素应答）。与细胞周期反应不同， 基因表达的变化是更加异质性和潜在的机制和关键的调控 元素仍然知之甚少。在目的1中，我们将描述RB的调控和基因机制， PDAC模型中的表达调控。虽然RB状态对肿瘤细胞分裂有明显影响，但重要的 RB通路激活的主要因素是与肿瘤微环境相关的效应。初步和公布 数据表明RB活化对肿瘤基质和免疫环境具有广泛的影响。多的这些 研究采用了影响肿瘤和宿主的系统策略。根据初步数据，我们 已经发现RB在肿瘤内的选择性激活足以改变成纤维细胞， 免疫细胞亚型与肿瘤，虽然不是在同一水平的全身治疗。这里我们将 询问肿瘤和微环境之间的交叉点，以及这些如何影响肿瘤静态 反应，并可以利用免疫疗法的方法。目标2将共同界定经常预算的影响， 使用免疫活性模型和临床模型的组合对肿瘤微环境进行活化 标本