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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：
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.

项目总结