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

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

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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.

地幔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摘要/摘要由于激酶抑制剂在癌症治疗中的应用增加，因此需要发展无创的耳朵检测方法以监测患者的治疗活性。我们旨在开发解决方法三个关键问题 - 1）早期发现肿瘤反应或对治疗的抵抗力，特别是通过无创成像技术，2）定义药物反应和抗性的详细机制，3）使用此信息克服耐药性。细胞信号通路的无创体内监测是不可行的，监测肿瘤体积的变化是一个晚期且通常具有误导性的响应指标。 FDG宠物，而肿瘤检测的理想选择不是反应预测，可能是因为它仅评估糖酵解途径，而肿瘤能够使用其他途径来处理其生长所需的营养。我们提出了一种新颖的替代方案 - 通过监视由由关键的代谢途径来检测反应激酶抑制剂。我们的基本前提是，肿瘤代谢的变化较早，更可靠镇定治疗反应的变化比肿瘤体积变化的变化。我们专注于布鲁顿的酪氨酸激酶（BTK）使用FDA批准的BTK抑制剂IBRUTINIB（IBR）以及两秒第二代In-的信号通路地幔细胞淋巴瘤（MCL）的吉其杆。我们建议使用全面的基因组/磷酸蛋白质组/代谢组方法描述了对BTK抑制的反应机理和抗性的机理。在初步研究我们已经评估了指数MCL细胞系，其中之一（MCL-RL）对IBR高度敏感另一个（Jeko-1）具有抵抗力。初步RNA-seq分析表明BTK调节了许多参与关键代谢途径的基因，包括糖酵解，五糖分流，TCA循环和GLU- 玉米粉蒸解。通过测量与IBR治疗之前和之后通过这些途径的代谢通量，我们将确定这些途径中的哪些对于响应和抵抗至关重要。我们发现在Jeko-1细胞中塔米氨基溶解对IBR耐药至关重要，可以通过谷氨酰胺酶抑制剂克服。我们已经发展了并验证了新颖的13C MRS和13C LC-MS方法，以通过肿瘤Metabo-的关键途径监测通量在体外和体内研究中使用这些方法在MCL模型上使用这些方法来定义Mecha- 对药物的反应和抵抗力。乳酸，丙氨酸和胆碱已成为潜在的元元 MCL细胞对BTK抑制的反应的生物标志物，可以通过1H MRS来监测其使用HAD- 我们开发的SEL-MQC脉冲序列。在AIM 1中，我们将对重新进行基因组和代谢组学研究在MCL患者中衍生出的细胞系和原代细胞中对BTK抑制的赞助和抗性。在AIM 2中，我们将利用体外1H MRS和13C MRS和LC-MS来验证和定量代谢通量的扰动在AIM 1中鉴定为BTK抑制的潜在成像生物标志物。最后，在AIM 3中，我们将利用 MCL的小鼠异种移植物中的1H，13C和31P MRS成像和LC-MS分析，以验证代谢BI- AIM 1和2中确定的BTK抑制作用的Omarkers。