Targeting KRAS and adenosine mediated immunosuppression in pancreatic cancer

靶向 KRAS 和腺苷介导的胰腺癌免疫抑制

基本信息

批准号：
10583537
负责人：
Timothy R Donahue
金额：
$ 59.01万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583537
关键词：
Adenosine Anabolism Animal Model Antigen Presentation Pathway Bioinformatics Biometry Biopsy CTLA4 gene CXCL1 gene Cancer Biology Catabolism Cell Culture Techniques Cell model Clinical Clinical Trials Colorectal Cancer Combined Modality Therapy Consumption Data Drug Combinations Evaluation Event Foundations Future Genetic Glucose Glutamine Goals IL8 gene Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunology Immunosuppression Immunotherapeutic agent Immunotherapy Inflammatory KRAS2 gene KRASG12D Liver MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mass Spectrum Analysis Measurement Measures Mediating Metabolic Metabolism Modeling Mutation Nivolumab Nucleosides Nucleotides Nutrient Oncogenes Oncogenic Organoids Pancreatic Ductal Adenocarcinoma Pathology Pathway interactions Patients Phase Ia/Ib Clinical Trial Positioning Attribute Pre-Clinical Model Preclinical Testing Production Progression-Free Survivals Property Proteomics Receptor Inhibition Receptor Signaling Research Personnel Resistance Safety Signal Transduction Solid Neoplasm Stable Disease Technology Testing Therapeutic Tumor Burden Tumor Immunity Tumor Promotion anti-CTLA4 anti-PD-1 cell type chemokine clinical development extracellular first-in-human human model immune cell infiltrate immune checkpoint immune checkpoint blockade immunoregulation improved inhibitor ipilimumab melanoma metabolomics mouse model mutant new combination therapies nucleotide metabolism objective response rate pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm primary endpoint programmed cell death protein 1 programs rational design receptor response response biomarker secondary endpoint stable isotope synergism targeted treatment therapy outcome transcriptomics translational study trial design tumor tumor microenvironment tumor-immune system interactions uptake

项目摘要

PROJECT SUMMARY Activating KRAS mutations, altered metabolism, and an immunosuppressive tumor microenvironment are all hallmarks of pancreatic ductal adenocarcinoma (PDAC). The recent groundbreaking discovery of KRASG12C specific inhibitors has reinvigorated hope for direct targeting of this dominant driver oncogene formerly deemed “undruggable”. However, it is becoming increasingly clear that the therapeutic potential of mutant KRAS inhibitors in PDAC and other malignancies will only be realized if they are administered as components of rationally designed combination therapies. To identify actionable immunomodulatory and metabolic events triggered by KRASG12C inhibition in PDAC, transcriptomic, proteomic, and metabolomic analyses were performed in human and murine models. KRASG12C inhibition in pancreatic cancer cells limited the expression of immunosuppressive chemokines, increased antigen presentation pathways, reduced nutrient (glucose and glutamine) consumption, and the production of immunosuppressive metabolites (lactate). These studies indicate that KRASG12C inhibitors exert immune-priming effects in PDAC and support combinations with immune checkpoint blockade (ICB) agents. However, these immune-priming effects were accompanied by alterations in nucleotide metabolism and by elevated extracellular adenosine levels. This finding has great potential significance since adenosine is known to curtail anti-tumor immunity by engaging adenosine A2a/A2b receptors (A2aR/A2bR) on a broad array of immune cell types. Remaining to be determined, if these observations are to be exploited for therapeutic purposes in KRASG12C PDAC, are (i) the mechanisms by which KRASG12C inhibition modulates nucleotide metabolism and adenosine levels in PDAC cells, (ii) the requisite components of ICB (anti-PD-1 and/or anti-CTLA-4) when co-targeting KRASG12C and A2aR/A2bR in animal models, and (iii) whether targeting adenosine signaling promotes synergy between KRASG12C inhibition and ICB in patients with KRASG12C PDAC. Studies proposed in Aim 1 will test the hypothesis that elevations in adenosine levels induced by KRASG12C inhibition reflect alterations in nucleotide metabolism, leading both to increased pancreatic tumor cell adenosine efflux and to decreased adenosine uptake. Aim 2 entails mechanistically-based testing of combinations co-targeting KRASG12C, A2aR/A2bR and conventional immune checkpoints in new orthotopic, metastatic and genetic murine models of KRASG12C pancreatic cancer. Aim 3 consists of a first-in-human investigator-initiated phase IA/IB clinical trial to test the tolerability and efficacy of our combinations as second-line therapies in patients with pancreatic cancer. Proposed studies will establish a new mechanistic framework of interrelationships between KRASG12C inhibition, nucleotide metabolism, adenosine signaling, and immunosuppression both in mouse models of PDAC and in patients. They will also provide the foundation for forward and reverse translation studies to improve immunotherapy responses in patients with KRASG12C PDAC and, potentially, in other KRASG12C malignancies.

项目概要激活 KRAS 突变、代谢改变和免疫抑制肿瘤微环境都是 KRASG12C 是胰腺导管腺癌 (PDAC) 的标志。特定的抑制剂重新燃起了直接靶向这种以前被认为是主要驱动癌基因的希望然而，突变型 KRAS 的治疗潜力越来越明显。 PDAC 和其他恶性肿瘤中的抑制剂只有作为合理设计的联合疗法。由 PDAC 中的 KRASG12C 抑制触发，进行转录组学、蛋白质组学和代谢组学分析在人类和小鼠模型中进行的 KRASG12C 抑制在胰腺癌细胞中限制了表达。免疫抑制趋化因子的增加，抗原呈递途径的增加，营养物质的减少（葡萄糖和谷氨酰胺）的消耗，以及免疫抑制代谢物（乳酸）的产生。表明 KRASG12C 抑制剂在 PDAC 中发挥免疫启动作用并支持与然而，这些免疫启动效应伴随着免疫检查点阻断（ICB）药物。核苷酸代谢的改变和细胞外腺苷水平的升高这一发现具有重大意义。潜在意义，因为已知腺苷可通过与腺苷 A2a/A2b 结合来削弱抗肿瘤免疫力多种免疫细胞类型上的受体（A2aR/A2bR）仍有待确定。观察结果将被用于 KRASG12C PDAC 的治疗目的，是 (i) 的机制 KRASG12C 抑制调节 PDAC 细胞中的核苷酸代谢和腺苷水平，(ii) 当在动物体内共同靶向 KRASG12C 和 A2aR/A2bR 时，ICB 成分（抗 PD-1 和/或抗 CTLA-4）模型，以及 (iii) 靶向腺苷信号传导是否促进 KRASG12C 抑制和目标 1 中提出的针对 KRASG12C PDAC 患者的 ICB 将检验以下假设： KRASG12C 抑制诱导的腺苷水平反映了核苷酸代谢的变化，从而导致目标 2 需要增加胰腺肿瘤细胞腺苷流出并减少腺苷摄取。对共同靶向 KRASG12C、A2aR/A2bR 和传统免疫的组合进行基于机制的测试 KRASG12C 胰腺癌新原位、转移和遗传小鼠模型中的检查点 Aim 3。包括一项由研究者发起的首次人体 IA/IB 期临床试验，以测试其耐受性和有效性我们的联合疗法作为胰腺癌患者的二线疗法。 KRASG12C 抑制、核苷酸代谢、 PDAC 小鼠模型和患者中的腺苷信号传导和免疫抑制也将发挥作用。为正向和反向翻译研究提供基础，以改善免疫治疗反应患有 KRASG12C PDAC 的患者以及可能患有其他 KRASG12C 恶性肿瘤的患者。