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: 10549375
• 负责人: Timothy R Donahue
• 金额: $ 56.54万
• 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/10549375
• 关键词: ATR gene; Agonist; Anabolism; Biochemical Process; Cancer Etiology; Cell Line; Cell Reprogramming; Cells; Cellular Metabolic Process; Clinical; Clinical Trials; Combined Modality Therapy; Consumption; DNA Repair; DNA Replication Induction; DNA biosynthesis; Data; Data Analyses; Deoxyribonucleosides; Deoxyribonucleotides; Dependence; Disease; Endothelium; Enzymes; Family; Future; Gene Activation; Genetic; Genetic Models; Genetic Transcription; Goals; Immune; 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; NADP; 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 Induction; 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; biological adaptation to stress; cancer cell; cancer therapy; cell growth; clinical translation; cofactor; 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; synergism; 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.

项目摘要/摘要 干扰素基因（STING）的刺激剂是治疗实体瘤的新兴靶标。调查 刺痛激动剂的治疗相关性主要集中在免疫调节作用上 通过肿瘤微环境中I型干扰素（IFN）的刺激激活诱导介导的。 但是，刺痛激动剂引起的IFN信号如何影响恶性细胞信号传导和代谢是 尚未研究这些作用，并且尚未研究这些作用是否可以进行治疗。数据 提出表明刺激在胰腺导管腺癌（PDAC）和 它在PDAC恶性细胞中的激活导致IFN信号依赖性的肿瘤生长受损 方式。因此，阐明刺激驱动的IFN信号的后果在PDAC中特别相关 这是美国与癌症相关死亡率的第三个主要原因，总体生存率少于一个 年。初步代谢组和蛋白质组学分析指向两个主要的互连生化 PDAC细胞中IFN信号的影响的过程：（i）核苷酸代谢，这是由 脱氧核糖核苷酸三磷酸（DNTP）和烟酰胺腺苷二核苷酸（NAD）池的耗竭；和 （ii）激活由共济失调和毛taxia介导的DNA重复应力响应信号传导途径和 RAD3相关蛋白（ATR）。该提案旨在检验以下假设，即刺激驱动的DNTP和 恶性细胞中的NAD耗竭是由SAM结构域和HD结构域的转录上调引起的 含有蛋白1（SAMHD1），强大的DNTP磷酸化酶，以及多个蛋白质的特定成员 ADP-核糖 - 聚合酶（PARP）家族（PARP9/10/14），分别增加了NAD消耗量。会 进一步检验了恶性细胞参与特定自适应机制以抵消这些的假设 代谢改变，它们的抑制作用将与刺痛的激动剂协同作用。 AIM 1的研究将 研究原位PDAC细胞系和患者衍生异种移植物中刺激激活的后果 来自现有存储库的模型，将研究刺激激活与 复制应力。 AIM 2中的研究将测试合理设计的组合疗法，该疗法阻止了两个主要共同的共同辅助疗法 通过在PDAC细胞中激活引起的依赖项：（i）ATR调节的复制应力响应 （ii）烟酰胺磷酸贝糖基转移酶（NAMPT）介导的烟酰胺回收。 AIM 3的研究 将采用免疫能力的植入和自动PDAC模型来测试目标的概念 在持续的临床试验中，在目标1和2中确定的共同依赖性 激动剂与免疫检查点封锁结合使用。总的来说，在此应用中提出的研究是 旨在增加对刺激信号，核苷酸/NAD代谢之间相互作用的理解 PDAC中的复制应力反应，其最终目标是发现关键脆弱性 通过新的治疗方法利用这种极为激进且难以治疗恶性肿瘤。