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项目概要/摘要由于激酶抑制剂在癌症治疗中的应用越来越多，因此需要开发非侵入性耳我们的目标是开发方法来监测患者的治疗活动。三个关键问题 – 1) 早期检测肿瘤反应或对治疗的耐药性，特别是通过非侵入性方法成像技术，2）定义药物反应和耐药性的详细机制，3）使用这些信息克服耐药性的无创体内监测细胞信号通路是不可行的， FDG PET 监测肿瘤体积的变化是一个晚期且常常具有误导性的反应指标。肿瘤检测的理想方法不是反应预测，可能是因为它仅评估反应的前两个步骤糖酵解途径，而肿瘤能够使用其他途径来处理其生长所需的营养物质。我们提出了一种新颖的替代方案——通过监测受调节的关键代谢途径来检测反应我们的基本前提是肿瘤代谢的变化是更早、更可靠的指标。我们关注的是布鲁顿酪氨酸激酶（BTK），而不是肿瘤体积的变化。使用 FDA 批准的 BTK 抑制剂依鲁替尼 (IBR) 以及两种第二代药物的信号通路我们建议使用综合基因组/磷酸化抑制剂。蛋白质组学/代谢组学方法描述对 BTK 抑制的反应和抵抗机制。初步研究我们评估了索引 MCL 细胞系，其中之一 (MCL-RL) 对 IBR 高度敏感另一种 (JeKo-1) 具有抗性，初步 RNA-Seq 分析表明 BTK 调节的表达。许多基因参与关键代谢途径，包括糖酵解、戊糖分流、TCA 循环和葡萄糖通过测量 IBR 治疗前后这些途径的代谢通量，我们将确定这些途径中哪些对于反应和抵抗至关重要我们发现在 JeKo-1 细胞中 glu- 谷氨酰胺分解对于 IBR 耐药性至关重要，可以通过我们开发的谷氨酰胺酶抑制剂来克服。并验证了新颖的 13C MRS 和 13C LC-MS 方法来监测肿瘤代谢关键途径的通量 lism 并建议在体外和体内研究的 MCL 模型上使用这些方法来定义机制乳酸、丙氨酸和胆碱已成为潜在的代谢物 MCL 细胞对 BTK 抑制反应的代谢生物标志物，可以使用 Had-1H MRS 进行监测我们开发的 Sel-MQC 脉冲序列在目标 1 中，我们将进行基因组和代谢组学研究。在目标 2 中，我们研究了来自 MCL 患者的细胞系和原代细胞对 BTK 抑制的反应和抵抗。将利用体外 1H MRS 和 13C MRS 以及 LC-MS 来验证和定量体内代谢通量的扰动确定目标 1 中的途径作为 BTK 抑制的潜在成像生物标志物最后，在目标 3 中，我们将利用。对小鼠 MCL 异种移植物进行 1H、13C 和 31P MRS 成像和 LC-MS 分析，以验证代谢双目标 1 和 2 中确定的 BTK 抑制标记物。