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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：
10358617
负责人：
Timothy R Donahue
金额：
$ 60.71万
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/10358617
关键词：
ADORA2A gene Adenosine Anabolism Animal Model Antigen Presentation Pathway Bioinformatics Biometry Biopsy CTLA4 gene CXCL1 gene Cancer Biology Catabolism Cell Culture Techniques Cell model Cells Clinical Clinical Trials Colorectal Cancer Combined Modality Therapy Consumption Data 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 Pharmaceutical Preparations Phase Ia/Ib Clinical Trial Positioning Attribute Pre-Clinical Model Preclinical Testing Production Progression-Free Survivals Property Proteomics Research Personnel Resistance Safety Signal Transduction Solid Neoplasm Stable Disease Technology Testing Therapeutic Translations Tumor Immunity Tumor-infiltrating immune cells anti-CTLA4 anti-PD-1 base cell type chemokine clinical development extracellular first-in-human human model 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 rational design receptor response response biomarker secondary endpoint stable isotope synergism targeted treatment therapy outcome transcriptomics 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.

项目总结激活KRAS突变，改变代谢，以及免疫抑制的肿瘤微环境都是胰腺导管癌(PDAC)的特征。最近KRASG12C的突破性发现特定的抑制剂重新燃起了直接靶向这种以前被认为是主导致癌基因的希望。 “无法下药”。然而，越来越清楚的是，突变的KRAS的治疗潜力 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。确定可操作的免疫调节和代谢事件由PDAC中KRASG12C抑制触发，转录组，蛋白质组和代谢组分析在人类和小鼠模型上进行了实验。KRASG12C在胰腺癌细胞中的抑制作用限制了其表达免疫抑制趋化因子，增加抗原递呈途径，减少营养(葡萄糖和谷氨酰胺)的消耗和免疫抑制代谢物(乳酸)的产生。这些研究提示KRASG12C抑制剂在PDAC中发挥免疫启动作用，并支持与免疫检查点阻断(ICB)代理。然而，这些免疫启动效应伴随着核苷酸代谢的改变和细胞外腺苷水平的升高。这一发现有很大的意义已知腺苷通过结合腺苷A2a/A2b抑制抗肿瘤免疫的潜在意义多种免疫细胞类型上的受体(A2aR/A2bR)。有待确定，如果这些 KRASG12C PDAC中的观察结果将被用于治疗目的，是(I)通过什么机制 KRASG12C抑制调节PDAC细胞的核苷酸代谢和腺苷水平，(Ii)必要的联合靶向KRASG12C和A2aR/A2bR的ICB组分(抗PD-1和/或抗CTLA-4) 模型，以及(Iii)靶向腺苷信号是否促进KRASG12C抑制和KRASG12C抑制之间的协同作用 KRASG12C PDAC患者的ICB检查。目标1中提出的研究将检验这样一个假设，即 KRASG12C抑制引起的腺苷水平反映了核苷酸代谢的变化，导致两者胰腺肿瘤细胞腺苷外流增加，腺苷摄取减少。目标2需要联合靶向KRASG12C、A2aR/A2bR和常规免疫的组合的机械测试 KRASG12C胰腺癌新的原位、转移和遗传小鼠模型中的检查点。目标3 由首个人类研究人员启动的IA/IB阶段临床试验组成，以测试该药的耐受性和有效性我们的联合疗法是胰腺癌患者的二线治疗方法。拟议的研究将建立一个 KRASG12C抑制、核苷酸代谢、腺苷信号和免疫抑制在PDAC小鼠模型和患者中都是如此。他们还将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，以及潜在的其他KRASG12C恶性肿瘤患者。