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

• 批准号: 10115684
• 负责人: Ian Alexander Blair
• 金额: $ 47.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10115684
• 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/antagonist; 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

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，控制黑色素瘤细胞的复制。超过一半 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。然而，所有的 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 这些代理。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 显现。我们将使用 13C MRS 和液相色谱质谱法 (LC-MS) 来研究机械性能 BRAF代谢抑制的本质，但这些方法不适合人体体内检测 – 13C MRS 不够灵敏，LC-MS 是侵入性的。因此，我们的策略是寻找合适的生物标志物 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 运行在 ≥ 7T 的情况下。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 能够在更多的医疗机构。我们的第二个目标是描述 BRAF 的生物标志物如何抑制 进行工作，以便更好地了解他们的能力和局限性。最后是我们自己的初步数据 实验室和其他人的研究表明，对突变型 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 分解。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 延迟抵抗的发生。作为我们的第三个目标，我们建议测试使用 CB-839 的可行性，CB-839 是一种 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 反抗。我们的具体目标是： 目标 1 将确定 MAPK 的生化变化和有效性 小鼠和人类黑色素瘤模型中的途径抑制。目标 2 将阐明底物对生物的限制 化学效应和生物标志物对微环境变化的反应。目标 3 将验证提议的 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 越来越普遍的乐器。代谢组学研究将扩展我们定量分析的能力 促进细胞、小鼠和人类模型以及最终人类中的肿瘤代谢。