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Metabolic Biomarkers of Response of Mantle Cell Lymphoma to Bruton Tyrosine Kinase Inhibition

套细胞淋巴瘤对布鲁顿酪氨酸激酶抑制反应的代谢生物标志物

基本信息

批准号：
10580590
负责人：
JERRY D GLICKSON
金额：
$ 49.22万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-09 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580590
关键词：
Address Adjuvant Therapy Aerobic Aftercare Agammaglobulinaemia tyrosine kinase Alanine Biochemical Pathway Biological Markers Biological Models Biopsy Specimen Bioreactors Cancer Patient Cell Line Cells Chemicals Choline Chronic Lymphocytic Leukemia Citric Acid Cycle Critical Pathways Cytostatics Data Data Analyses Detection Drug resistance Early Diagnosis Enzymes FDA approved Foundations Future Gene Expression Profiling Generations Genes Genomics Glutaminase Glycolysis Glycolysis Inhibition Goals Growth Human Hypoxia Image Imaging Techniques In Vitro Infiltration Institution Lactic acid Lymphoma Lymphoma cell Magnetic Resonance Imaging Malignant Neoplasms Mantle Cell Lymphoma Measures Messenger RNA Metabolic Metabolic Pathway Metabolism Methods Modeling Monitor Mus NMR Spectroscopy Non-Invasive Detection Nutritional Requirements Pathway Analysis Pathway interactions Patients Pentosephosphate Pathway Perfusion Pharmaceutical Preparations Phospholipid Metabolism Phosphoproteins Phosphorylation Physiologic pulse Process Proteins Proteomics Resistance Signal Pathway Signal Transduction Site Spectrum Analysis Techniques Testing Therapeutic Agents Tissues Tumor Volume Tyrosine Kinase Inhibitor X-Ray Computed Tomography Xenograft procedure cancer cell cancer imaging cancer therapy cell growth clinical application cytotoxic detection method fluorodeoxyglucose positron emission tomography genome-wide glucose monitor glucose uptake hexokinase imaging biomarker immunosuppressed in vivo in vivo Model in vivo monitoring indexing inhibitor inhibitor therapy innovation instrument kinase inhibitor metabolomics neoplastic cell non-invasive imaging novel novel drug class novel strategies phosphoproteomics potential biomarker preclinical study quantum response response biomarker therapy resistant tissue culture transcriptome sequencing treatment response tumor tumor growth tumor metabolism tumor xenograft

项目摘要

Metabolic Biomarkers of Response of Mantle Cell Lymphoma to Bruton Tyrosine Kinase Inhibition Project Summary/Abstract Due to increased application of kinase inhibitors to cancer therapy, there is a need to develop noninvasive ear- ly detection methods to monitor the activity of treatment in patients. We aim to develop methods to address three critical issues – 1) early detection of tumor response or resistance to therapy, particularly by noninvasive imaging techniques, 2) defining detailed mechanisms of drug response and resistance, and 3) using this infor- mation to overcome drug resistance. Noninvasive in vivo monitoring of cell signaling pathways is not feasible, and monitoring of changes in tumor volume is a late and often misleading response indicator. FDG PET, while ideal for tumor detection is not response predictive, likely because it evaluates only the first two steps of the glycolytic pathway, while tumors are able to use other pathways to process nutrients required for their growth. We propose a novel alternative – to detect response by monitoring the key metabolic pathways regulated by the kinase inhibitor. Our basic premise is that changes in tumor metabolism are earlier and more reliable indi- cators of therapeutic response than changes in tumor volume. We focus on the Bruton's tyrosine kinase (BTK) signaling pathway using an FDA-approved BTK inhibitor, ibrutinib (IBR), as well as two second-generation in- hibitors of mantle cell lymphoma (MCL). We propose to use a comprehensive genomic/phospho- proteomic/metabolomic approach to delineate the mechanism of response and resistance to BTK inhibition. In preliminary studies we have evaluated index MCL cell lines, one of which (MCL-RL) is highly sensitive to IBR and another (JeKo-1) is resistant. Preliminary RNA-Seq analysis indicates that BTK modulates expression of many genes involved in key metabolic pathways including glycolysis, the pentose shunt, TCA cycle and glu- taminolysis. By measuring metabolic flux through these pathways before and after treatment with IBR, we will determine which of these pathways are critical to response and resistance. We found that in JeKo-1 cells glu- taminolysis is critical to IBR resistance and can be overcome with glutaminase inhibitors. We have developed and validated novel 13C MRS and 13C LC-MS methods to monitor flux through key pathways of tumor metabo- lism and propose to use these methods on the MCL models in in vitro and in vivo studies to define the mecha- nism of response and resistance to the drug. Lactic acid, alanine and choline have emerged as potential meta- bolic biomarkers of response of MCL cells to BTK inhibition that can be monitored by 1H MRS using the Had- Sel-MQC pulse sequence developed by us. In Aim 1, we will perform genomic and metabolomic studies of re- sponse and resistance to BTK inhibition in cell lines and primary cells derived from MCL patients. In Aim 2, we will utilize in vitro 1H MRS and 13C MRS and LC-MS to verify and quantitate perturbations of metabolic fluxes in pathways identified in Aim 1 as potential imaging biomarkers of BTK inhibition. Finally, in Aim 3 we will utilize 1H, 13C & 31P MRS imaging and LC-MS analysis in mouse xenografts of MCL to validate the metabolic bi- omarkers of BTK inhibition identified in Aims 1 & 2.

套细胞淋巴瘤对布鲁顿酪氨酸激酶抑制反应的代谢生物标志物