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）代表一种治疗顽固疾病，其生存率为5年 约10％。多次失败的临床试验强大了采用新方法的需求 针对PDAC肿瘤的关键遗传特征以及肿瘤的理性发展的疗法 微环境。从根本上讲，PDAC是KRAS驱动的肿瘤；但是，要针对Kras的方法 从遗传或药物上讲，已经意识到肿瘤可以发展机制以继续细胞 在这种干预措施的情况下进行分裂。结合无偏分析和衍生患者的组合 模型我们发现大多数肿瘤都会发展出解除抑制视网膜细胞瘤肿瘤的机制 （RB）限制靶向RAS或效应子途径的有效性（例如MEK抑制）的途径。 因此，RB的激活足以限制PDAC模型的增殖和肿瘤生长。 除了对增殖的影响外，我们还发现RB激活足以协调变化 对与PDAC和免疫基因的经典基因与基础亚型有关的基因影响的基因表达 表达程序（例如抗原表现和干扰素反应）。与细胞周期反应不同，这些 基因表达的变化更加异质，并且基本机制和关键调节 元素的理解仍然很差。在AIM 1中，我们将描述基因的RB调节和机制 PDAC模型中的表达调节。虽然RB状态显然对肿瘤细胞分裂有影响，但重要 RB - 气流激活的元素是与肿瘤微环境有关的效果。初步和出版 数据表明，RB激活对肿瘤基质和免疫环境具有广泛的影响。其中很多 研究采用了影响肿瘤和宿主的系统性策略。在初步数据中，我们 已经发现，在肿瘤内有选择性地激活RB足以改变成纤维细胞和 具有肿瘤的免疫细胞亚型，尽管不在同一系统治疗水平。我们会在这里 询问肿瘤与微环境之间的交集以及这些如何影响肿瘤静态 反应，可以通过免疫疗法方法利用。 AIM 2一起定义了RB-的影响 使用免疫胜任模型和临床的组合在肿瘤微环境上激活 标本。