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.

抽象的 胰腺癌是美国与癌症相关死亡的主要原因，估计为48,000 2021年的死亡。先前的工作已经确定了几种常见的遗传改变，包括激活 大约95％的胰腺导管腺癌（PDAC）病例中的KRAS突变和这些病例 据信改变是该疾病的病变。在诱导KRAS小鼠模型中的研究 以及在人类癌细胞系中，表明KRAS是该疾病中重要的治疗靶点。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 需要针对关键下游分子的治疗策略。我们的事先发表的工作 实验室表示激酶MTOR可能是这样的靶标。 MTOR存在于两个不同的信号中 复合物 - MTORC1和MTORC2。基本MTORC2成分Rictor的遗传消融受损 前体Panin病变的发展和进展。此外，rictor删除延长了生存 Invasive PDAC的基因工程小鼠模型（GEMM）。这些观察提出了一个问题 已建立的入侵PDAC中MTORC2信号传导的失活是否会损害其进展 和/或刺激其回归。已发表的观察结果还表明，对 由MTOR信号复合物调节的信号通路以及所得的蛋白质组学和基因 需要表达变化，以有效地瞄准该轴并预测潜在的电阻机制。 因此，该应用程序旨在阐明MTOR信号在体内PDAC中的作用；识别 蛋白质组学和基因表达变化MTOR下游诱导；并调查效率 新型MTOR抑制剂基于组合疗法的方法。 为了实现这些目标，提出了三个具体目标。使用优雅而新颖的双重重组酶鼠标 模型，AIM 1中的研究将研究MTORC2的遗传失活是否会损害 在体内建立的PDAC。 MTORC2的急性遗传失活后，使用单细胞RNA测序 将发现损害体内信号传导复合物的分子后果。提议 AIM 2中的研究将确定抑制后引起的基因表达和蛋白质组学变化 人PDAC细胞系中的mTORC1，mTORC2或两个复合物。这些数据集的计算集成 将导致识别关键途径和转录调节剂，然后在功能上是 在人PDAC细胞系中进行了验证。最后，AIM 3中的研究将询问新型组合的效率 基于人类肿瘤类器官和凭证宝石的MTOR抑制剂的治疗策略。 拟议研究的成功执行将增强对MTOR所起的作用的理解 胰腺肿瘤发生过程中的信号传导，并增强了我们有效靶向PDAC的能力 治疗。