Leveraging Vulnerabilities Induced by STING Activation in Pancreatic Cancer

利用胰腺癌中 STING 激活引起的脆弱性

• 批准号: 10350646
• 负责人: Timothy R Donahue
• 金额: $ 60.28万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350646
• 关键词: ATR gene; Agonist; Biochemical Process; Cancer Etiology; Cell Line; Cells; Cellular Metabolic Process; Clinical; Clinical Trials; Combined Modality Therapy; Consumption; DNA Repair; DNA biosynthesis; Data; Data Analyses; Deoxyribonucleosides; Deoxyribonucleotides; Dependence; Disease; Family; Future; Gene Activation; Genetic; Genetic Models; Genetic Transcription; Goals; Immunocompetent; Impairment; In Vitro; Inflammatory; Interferon Type I; Interferons; Investigation; Knowledge; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Niacinamide; Nicotinamide adenine dinucleotide; Non-Malignant; Nucleotides; PARP9 gene; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phosphoric Monoester Hydrolases; Poly(ADP-ribose) Polymerases; Process; Production; Property; Proteins; Proteomics; Recycling; Resistance; Role; SAM Domain; Signal Pathway; Signal Transduction; Solid Neoplasm; Source; Stimulator of Interferon Genes; Stress Response Signaling; Testing; Therapeutic; Therapeutic Effect; Up-Regulation; anti-PD-1; anticancer treatment; antitumor effect; base; biological adaptation to stress; cancer cell; cancer therapy; cell growth; clinical translation; clinically translatable; cytokine; design; immune checkpoint blockade; immunoregulation; implantation; improved; in vivo; in vivo Model; inhibitor; member; metabolomics; mortality; mouse model; neoplastic cell; nicotinamide phosphoribosyltransferase; novel; novel therapeutic intervention; novel therapeutics; nucleotide metabolism; overexpression; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; patient derived xenograft model; phosphoproteomics; prevent; rational design; replication stress; repository; sensor; therapy design; tripolyphosphate; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Stimulator of interferon genes (STING) is an emerging target for the treatment of solid tumors. Investigations of the therapeutic relevance of STING agonists have primarily focused on the immunomodulatory effects mediated by STING-activation dependent induction of type I interferons (IFN) in the tumor microenvironment. However, how IFN signaling induced by STING agonists impacts malignant cell signaling and metabolism is poorly understood and, whether these effects can be therapeutically exploited has not been investigated. Data are presented showing that STING is highly over-expressed in pancreatic ductal adenocarcinoma (PDAC) and that its activation in PDAC malignant cells results in impaired tumor growth in an IFN-signaling dependent manner. Thus, elucidating the consequences of STING-driven IFN signaling is particularly relevant in PDAC which is the third-leading cause of cancer-related mortality in the U.S. with an overall survival of less than one year. Preliminary metabolomic and proteomic analyses point to two major interconnected biochemical processes impacted by IFN signaling in PDAC cells: (i) nucleotide metabolism, which is evidenced by the depletion of deoxyribonucleotide triphosphate (dNTP) and nicotinamide adenine dinucleotide (NAD) pools; and (ii) activation of the DNA replication stress response signaling pathway mediated by Ataxia Telangiectasia and Rad3-related protein (ATR). This proposal is designed to test the hypothesis that STING-driven dNTP and NAD depletion in malignant cells result from the transcriptional upregulation of SAM domain and HD domain- containing protein 1 (SAMHD1), a powerful dNTP phosphohydrolase, and of specific members of the poly- ADP-ribose-polymerase (PARP) family (PARP9/10/14) which increase NAD consumption, respectively. It will further test the hypothesis that malignant cells engage specific adaptive mechanisms to counteract these metabolic alterations and that their inhibition will synergize with STING agonists. Studies in Aim 1 will investigate the consequences of STING activation in orthotopic PDAC cell line and patient-derived xenograft models from a pre-existing repository and will investigate mechanistic links between STING activation and replication stress. Studies in Aim 2 will test rationally designed combination therapies that block two major co- dependencies elicited by STING activation in PDAC cells: (i) the ATR-regulated replication stress response and (ii) nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide recycling. Studies in Aim 3 will employ immunocompetent implantation and autochthonous PDAC models to test the concept of targeting co-dependencies identified in Aims 1 and 2 in the context provided by ongoing clinical trials in which STING agonists are combined with immune checkpoint blockade. Collectively, studies proposed in this application are designed to increase the understanding of the interplay between STING signaling, nucleotide/NAD metabolism and replication stress response in PDAC with the ultimate goal of uncovering critical vulnerabilities to be exploited by new therapeutic approaches against this extremely aggressive and difficult to treat malignancy.

项目概要/摘要 干扰素基因刺激物（STING）是治疗实体瘤的新兴靶点。调查 STING 激动剂的治疗相关性主要集中在免疫调节作用 由肿瘤微环境中 I 型干扰素 (IFN) 的 STING 激活依赖性诱导介导。 然而，STING 激动剂诱导的 IFN 信号传导如何影响恶性细胞信号传导和代谢尚不清楚。 人们对此知之甚少，并且尚未研究这些效应是否可以用于治疗。数据 表明 STING 在胰腺导管腺癌 (PDAC) 中高度过表达，并且 它在 PDAC 恶性细胞中的激活会导致 IFN 信号依赖性肿瘤生长受损 方式。因此，阐明 STING 驱动的 IFN 信号传导的后果在 PDAC 中尤其重要 这是美国癌症相关死亡的第三大原因，总体生存率不到一 年。初步代谢组学和蛋白质组学分析指出两个主要的相互关联的生物化学 PDAC 细胞中受 IFN 信号传导影响的过程：(i) 核苷酸代谢，这由 脱氧核糖核苷酸三磷酸 (dNTP) 和烟酰胺腺嘌呤二核苷酸 (NAD) 池的耗尽；和 (ii) 共济失调毛细血管扩张介导的 DNA 复制应激反应信号通路的激活和 Rad3 相关蛋白 (ATR)。该提案旨在测试 STING 驱动的 dNTP 和 恶性细胞中 NAD 的消耗是由于 SAM 结构域和 HD 结构域的转录上调造成的 含有蛋白质 1 (SAMHD1)，一种强大的 dNTP 磷酸水解酶，以及多聚体的特定成员 ADP-核糖聚合酶 (PARP) 家族 (PARP9/10/14) 分别增加 NAD 消耗。它会 进一步检验恶性细胞利用特定的适应性机制来抵消这些的假设 代谢改变及其抑制作用将与 STING 激动剂产生协同作用。目标 1 的研究将 研究原位 PDAC 细胞系和患者来源的异种移植物中 STING 激活的后果 来自预先存在的存储库的模型，并将研究 STING 激活和 复制压力。目标 2 的研究将测试合理设计的联合疗法，以阻断两种主要的联合疗法： PDAC 细胞中 STING 激活引起的依赖性：(i) ATR 调节的复制应激反应 (ii) 烟酰胺磷酸核糖转移酶 (NAMPT) 介导的烟酰胺回收。目标 3 的研究 将采用免疫活性植入和本地 PDAC 模型来测试靶向概念 在正在进行的临床试验提供的背景下，目标 1 和 2 中确定了相互依赖性，其中 STING 激动剂与免疫检查点阻断相结合。总的来说，本申请中提出的研究是 旨在加深对 STING 信号传导、核苷酸/NAD 代谢之间相互作用的理解 PDAC 中的复制压力响应，最终目标是发现关键漏洞 利用新的治疗方法来对抗这种极具侵袭性且难以治疗的恶性肿瘤。