Melanoma: Metabolic Biomarkers of Response to Targeted Therapy

黑色素瘤：靶向治疗反应的代谢生物标志物

基本信息

批准号：
10337249
负责人：
Ian Alexander Blair
金额：
$ 47.03万
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：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10337249
关键词：
Alanine BRAF gene Biochemical Biochemical Pathway Biochemical Reaction Biochemistry Biological Markers Biological Models Cell Culture Techniques Cells Chemicals Citric Acid Cycle Clinic Clinical Clinical Trials Data Dependence Detection Drug resistance Effectiveness Elements Genetically Engineered Mouse Glucose Glutamates Glutaminase Glutamine Goals Human Image Immune checkpoint inhibitor Immunocompetent Institution Knowledge MAP Kinase Gene MAP3K1 gene MAPK Signaling Pathway Pathway MEKs MEL Gene Magnetic Resonance Imaging Medical Melanoma Cell Metabolic Metabolic Pathway Metabolism Metastatic Melanoma Metformin Methods Modeling Monitor Mus Mutate Mutation Oxygen Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phenformin Phosphotransferases Physiologic pulse Proliferating Proto-Oncogene Proteins B-raf Recurrence Resistance Signal Transduction Signaling Protein System Techniques Time Tissue Survival Toxic effect Translations Treatment Protocols Tumor Volume Variant Work aerobic glycolysis analog base early detection biomarkers effective therapy experience feasibility testing human model imaging modality immunogenic immunosuppressed improved in vivo inhibitor inhibitor therapy instrument kinase inhibitor liquid chromatography mass spectrometry magnetic field melanoma metabolic phenotype metabolomics mouse model mutant neoplastic cell non-invasive imaging patient response precision medicine research clinical testing response response biomarker targeted treatment translation to humans treatment response tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

Melanoma: Metabolic Biomarkers of Response to Targeted Therapy Project Summary/Abstract Disseminated metastatic melanoma is initially treated with inhibitors of the V600E mutated BRAF kinase, a component of the MAPK signaling pathway that controls the replication of melanoma cells. More than half of melanoma patients express this mutation and are at least initially responsive to its inhibition. However, all pa- tients eventually become resistant to these inhibitors and have to be treated with alternate therapy, which con- sists primarily of immune checkpoint inhibitors. The goal of this project is to develop an imaging method that could monitor the effectiveness of BRAF kinase inhibitors and can promptly and accurately detect resistance to these agents. Our strategy for achieving this goal is to study the detailed biochemical mechanism of BRAF ki- nase signaling on the premise that a change in tumor metabolism is a quicker and more reliable indicator of the onset of resistance than a change in tumor volume, which can require weeks to months to become reliably manifest. We will use 13C MRS and liquid chromatography mass-spectrometry (LC-MS) to study the mecha- nism of BRAF metabolic inhibition, but these methods are not suitable for in vivo detection in humans – 13C MRS is not sensitive enough and LC-MS is invasive. Therefore, our strategy is to identify suitable biomarkers of metabolic response that can be monitored by 1H MRS or MRI monitored chemical exchange saturation transfer (CEST), which is about 500 times more sensitive than 1H MRS but requires high magnetic field instru- ments operating at ≥ 7T. In contrast, 1H MRS can be monitored at 1.5T or 3T, for which instruments are avail- able at many more medical institutions. Our second objective is to delineate how the biomarkers of BRAF inhi- bition work in order to better appreciate their capabilities and limitations. Finally, preliminary data from our own lab and from others indicates that the onset of resistance to mutant BRAF inhibitors involves a transition of the tumor from dependence on aerobic glycolysis to substantially greater dependence on ox-phos and on glutami- nolysis. This has led to clinical trials of the use of inhibitors of ox-phos such as metformin and phenformin to delay the onset of resistance. As our third objective, we propose to test the feasibility of using CB-839, an in- hibitor of glutaminase to block the transition to glutamine-dependence as a method to inhibit the onset of BRAF resistance. Our Specific Aims are: Aim 1 will determine biochemical changes and effectiveness of MAPK pathway inhibition in murine and human models of melanoma. Aim 2 will elucidate substrate limitations on bio- chemical effects and biomarker response to changes in microenvironment. Aim 3 will validate the proposed biomarkers in an in vivo system where the treatment response is modified using a glutaminase inhibitor. Clinical Impact: This project will enable detection of melanoma response to targeted therapy by NMR meth- ods that have already been implemented in the clinic on conventional 1.5T and 3T instruments and on 7T in- struments that are becoming progressively more common. Metabolomic studies will expand our ability to quan- tify tumor metabolism in cells, in mouse and human models, and eventually in humans.

黑色素瘤：靶向治疗反应的代谢生物标志物项目概要/摘要播散性转移性黑色素瘤最初使用 V600E 突变 BRAF 激酶（一种 MAPK 信号通路的组成部分，控制一半以上的黑色素瘤细胞的复制。黑色素瘤患者表达这种突变，并且至少在最初对其抑制有反应。患者最终会对这些抑制剂产生耐药性，必须采用替代疗法进行治疗，这需要主要由免疫检查点抑制剂组成，该项目的目标是开发一种成像方法。可监测BRAF激酶抑制剂的有效性，并能及时、准确地检测耐药性我们实现这一目标的策略是研究 BRAF ki- 的详细生化机制。鼻信号传导的前提是肿瘤代谢的变化是一个更快、更可靠的指标耐药性的发生多于肿瘤体积的变化，这可能需要数周至数月才能变得可靠我们将使用 13C MRS 和液相色谱质谱 (LC-MS) 来研究其机理。 BRAF代谢抑制，但这些方法不适合人体体内检测 – 13C MRS 不够灵敏，LC-MS 具有侵入性，因此我们的策略是识别合适的生物标志物。可以通过 1H MRS 或 MRI 监测的化学交换饱和度来监测代谢反应传输（CEST），它比1H MRS灵敏约500倍，但需要高磁场仪器相比之下，1H MRS 可以在 1.5T 或 3T 下进行监测，为此可以使用仪器。我们的第二个目标是描述 BRAF 的生物标志物如何抑制最后，我们自己的初步数据。实验室和其他人表明，对突变 BRAF 抑制剂产生耐药性涉及到肿瘤从依赖有氧糖酵解转向对氧化磷和谷氨酰胺的更大依赖这导致了使用二甲双胍和苯乙双胍等氧化磷抑制剂的临床试验。延迟耐药性的出现作为我们的第三个目标，我们建议测试使用 CB-839 的可行性。谷氨酰胺酶抑制剂可阻止向谷氨酰胺依赖性的转变，作为抑制 BRAF 发作的方法我们的具体目标是：目标 1 将确定 MAPK 的生化变化和有效性。目标 2 将阐明小鼠和人类黑色素瘤模型中的底物限制。目标 3 将验证所提出的化学效应和生物标志物对微环境变化的反应。体内系统中的生物标志物，其中使用谷氨酰胺酶抑制剂改变治疗反应。临床影响：该项目将能够通过核磁共振方法检测黑色素瘤对靶向治疗的反应 ods 已在临床上在传统 1.5T 和 3T 仪器以及 7T 仪器上实施代谢组学研究变得越来越普遍，这将扩大我们的定量能力。促进细胞、小鼠和人类模型以及最终人类中的肿瘤代谢。