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

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

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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.

项目摘要激活KRAS突变，代谢改变和免疫抑制性肿瘤微环境都是胰腺导管腺癌（PDAC）的标志。 KRASG12C最近的开创性发现特定的抑制剂已经重振了直接靶向这种主要驱动器癌基因的希望 “不可能”。但是，越来越清楚的是，突变体Kras的治疗潜力 PDAC和其他恶性肿瘤中的抑制剂只有在将其作为组成的组成部分时才能实现理性设计的组合疗法。确定可起作用的免疫调节和代谢事件由KRASG12C抑制在PDAC，转录组，蛋白质组学和代谢组分析中触发的是在人类和鼠模型中进行。胰腺癌细胞中的Krasg12c抑制限制了表达免疫抑制趋化因子，抗原表现途径增加，养分减少（葡萄糖和谷氨酰胺）的消耗，以及免疫抑制代谢产物（乳酸）的产生。这些研究表明KRASG12C抑制剂在PDAC中执行免疫促进作用，并支持与免疫检查点封锁（ICB）代理。但是，这些免疫促进作用是通过核肽代谢的改变和细胞外腺苷水平升高。这个发现很棒潜在的意义，因为已知腺苷通过参与腺苷A2A/A2B来减少抗肿瘤免疫力广泛的免疫细胞类型的受体（A2AR/A2BR）。仍有要确定，如果这些在KRASG12C PDAC中，应探索为治疗目的进行观察，是（i） KRASG12C抑制作用调节PDAC细胞中的核苷酸代谢和腺苷水平，（ii）必要的当在动物中共同定位KRASG12C和A2AR/A2BR时，ICB（抗PD-1和/或抗CTLA-4）的组件（抗PD-1和/或抗CTLA-4）模型，（iii）靶向腺苷信号传导是否促进Krasg12c抑制和 KRASG12C PDAC患者的ICB。 AIM 1提出的研究将检验以下假设。 KRASG12C抑制作用诱导的腺苷水平反映了核苷酸代谢的改变，这两者都导致增加胰腺肿瘤细胞腺苷外排，并改善腺苷摄取。目标2需要基于机械的组合测试共同靶向KRASG12C，A2AR/A2BR和常规免疫 KRASG12C胰腺癌的新型原位，转移和遗传鼠模型的检查点。目标3 由一个人类研究者发起的IA/IB临床试验组成，以测试可耐受性和效率我们作为胰腺癌患者的二线疗法的组合。拟议的研究将建立 KRASG12C抑制，核苷酸代谢之间相互关系的新机械框架， PDAC小鼠模型和患者的腺苷信号传导和免疫抑制。他们也会为前向和反向翻译研究提供基础，以改善免疫疗法反应 KRASG12C PDAC以及其他Krasg12c Malignancys患者。