Targeting MTOR signaling in pancreatic cancer

靶向胰腺癌中的 MTOR 信号传导

• 批准号: 10617656
• 负责人: BRIAN C LEWIS
• 金额: $ 55.24万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-04 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617656
• 关键词: Ablation; Acute; American; Biological Models; Cancer Etiology; Cancer cell line; Cell Line; Cell Survival; Cessation of life; Combined Modality Therapy; Complex; Credentialing; Critical Pathways; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Gene Expression; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; Impairment; K-ras mouse model; KRAS2 gene; KRASG12D; Knock-out; Laboratories; Lesion; MEK inhibition; MEKs; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular; Mutation; Organoids; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Phenotype; Phosphotransferases; Play; Proteomics; Public Health; Publishing; Regimen; Resistance; Role; Signal Pathway; Signal Transduction; Therapeutic; Treatment Efficacy; United States; Work; aurora B kinase; data integration; gemcitabine; in vivo; knock-down; mTOR Inhibitor; mTOR inhibition; mouse model; mutant; novel; novel therapeutic intervention; overexpression; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; pancreatic tumorigenesis; recombinase; resistance mechanism; single-cell RNA sequencing; small molecule inhibitor; statistics; therapeutic target; tumor; tumor microenvironment

Abstract Pancreatic cancer is a leading cause of cancer-related deaths in the United States with an estimated 48,000 deaths in 2021. Prior work has identified several commonly occurring genetic alterations, including activating KRAS mutations in approximately 95% of pancreatic ductal adenocarcinoma (PDAC) cases and these alterations are believed to be initiating lesions in the disease. Studies in inducible KRAS mouse models, as well as in human cancer cell lines, indicate that KRAS is an important therapeutic target in this disease. Yet, small molecule inhibitors of the most common KRAS mutants in PDAC are lacking. Therefore, other therapeutic strategies that target critical downstream molecules are required. Prior published work from our laboratory indicated that the kinase MTOR may be one such target. MTOR exists in two distinct signaling complexes – MTORC1 and MTORC2. Genetic ablation of the essential MTORC2 component Rictor impaired the development and progression of precursor PanIN lesions. Moreover, Rictor deletion extended survival in a genetically engineered mouse model (GEMM) of invasive PDAC. These observations raise the question of whether the inactivation of MTORC2 signaling in established invasive PDAC will impair their progression and/or stimulate their regression. The published observations also indicate that a deeper understanding of the signaling pathways regulated by the MTOR signaling complexes, and the resulting proteomic and gene expression changes, is required to effectively target this axis and to predict potential resistance mechanisms. This application therefore seeks to elucidate the roles of MTOR signaling in PDAC in vivo; to identify the proteomic and gene expression changes induced downstream of MTOR; and to investigate the efficacy of novel MTOR inhibitor-based combination therapeutic approaches. To achieve these goals, three specific aims are proposed. Using elegant and novel dual recombinase mouse models, studies in Aim 1 will investigate whether genetic inactivation of MTORC2 impairs the progression of established PDAC in vivo. Using single cell RNA sequencing after the acute genetic inactivation of MTORC2, the molecular consequences of impairing this signaling complex in vivo will be uncovered. The proposed studies in Aim 2 will identify the gene expression and proteomic changes induced following the inhibition of MTORC1, MTORC2 or both complexes in human PDAC cell lines. Computational integration of these datasets will lead to the identification of critical pathways and transcription regulators, which will then be functionally validated in human PDAC cell lines. Finally, studies in Aim 3 will interrogate the efficacy of novel combination therapy strategies based on MTOR inhibitors in human tumor organoids and credentialed GEMMs. The successful execution of the proposed studies will enhance the understanding of the role played by MTOR signaling during pancreatic tumorigenesis and enhance our ability to effectively target this pathway for PDAC therapy.

摘要 胰腺癌是美国癌症相关死亡的主要原因， 2021年死亡。先前的工作已经确定了几种常见的遗传改变，包括激活 约95%的胰腺导管腺癌（PDAC）病例中存在KRAS突变， 这些改变被认为是疾病中的起始病变。诱导型KRAS小鼠模型的研究，如 以及在人癌细胞系中的表达，表明KRAS是这种疾病的重要治疗靶点。然而， 缺乏PDAC中最常见的KRAS突变体的小分子抑制剂。因此，其他 需要靶向关键下游分子的治疗策略。我们之前发表的作品 实验室表明，激酶MTOR可能是这样的靶点之一。MTOR存在于两种不同的信令中 复合物-MTORC 1和MTORC 2。MTORC 2重要组分Rictor受损的基因消除 前体PanIN病变的发展和进展。此外，Rictor缺失延长了 侵袭性PDAC的基因工程小鼠模型（GEMM）。这些意见提出了一个问题， 在已建立的侵袭性PDAC中MTORC 2信号转导的失活是否会损害其进展 和/或刺激它们的退化。发表的观察结果还表明， 由MTOR信号复合物调节的信号通路，以及由此产生的蛋白质组和基因 表达变化，需要有效地靶向该轴并预测潜在的抗性机制。 因此，本申请试图阐明MTOR信号传导在体内PDAC中的作用;鉴定MTOR信号传导在PDAC中的作用。 MTOR下游诱导的蛋白质组学和基因表达变化;并研究 新的基于MTOR通道的组合治疗方法。 为了实现这些目标，提出了三个具体目标。使用优雅新颖的双重组酶小鼠 模型，目标1中的研究将调查MTORC 2的遗传失活是否会损害 体内建立PDAC。在MTORC 2急性遗传失活后使用单细胞RNA测序， 将揭示在体内损害这种信号复合物的分子后果。拟议 目标2中的研究将鉴定在抑制细胞凋亡后诱导的基因表达和蛋白质组学变化。 MTORC 1、MTORC 2或两种复合物在人PDAC细胞系中的表达。这些数据集的计算集成 将导致识别关键途径和转录调节因子，然后将功能 在人PDAC细胞系中验证。最后，目标3中的研究将询问新组合的疗效 基于人类肿瘤类器官中的MTOR抑制剂的治疗策略和经认证的GEMM。 拟议研究的成功实施将增进对MTOR所发挥作用的理解 胰腺肿瘤发生过程中的信号传导，并增强我们有效靶向该途径进行PDAC的能力 疗法