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: 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
• 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

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：对靶向治疗的反应的代谢生物标志物 项目摘要/摘要 传播转移性黑色素瘤最初用V600E突变的BRAF激酶的抑制剂治疗A MAPK信号通路的组成部分控制着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，至少对其抑制作用有反应。但是，所有 有时会对这些抑制剂有抵抗力，必须通过替代疗法进行治疗 柱主要是免疫切除剂抑制剂。该项目的目的是开发一种成像方法 可以监测BRAF激酶抑制剂的有效性，并可以及时准确地检测到对 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 Nase信号传导在肿瘤代谢的变化是一个更快，更可靠的指标 阻力发作比肿瘤体积变化的变化，这可能需要数周到几个月才能变得可靠 显现。我们将使用13C MRS和液相色谱质谱法（LC-MS）来研究机制 BRAF代谢抑制作用，但这些方法不适用于人类体内检测-13C MRS不够灵敏，LC-MS具有侵入性。因此，我们的策略是确定合适的生物标志物 可以通过1H MRS或MRI监测的化学交换满意度来监测的代谢反应 转移（CEST），其灵敏度比1H MRS高约500倍，但需要高磁场仪器 在≥7T处运行。相比 我们可以在更多的医疗机构中。我们的第二个目标是描述Braf Inhi的生物标志物如何 为了更好地欣赏他们的能力和局限性。最后，我们自己的初步数据 实验室和其他实验室表明，对突变体BRAF抑制剂的抗性发作涉及 从依赖有氧糖酵解的肿瘤到对Ox-Phos和谷氨酸的依赖性更大的肿瘤 功。这导致了使用牛皮抑制剂（例如二甲双胍和苯甲甲型）的临床试验 延迟电阻的发作。作为我们的第三个目标，我们建议测试使用CB-839的可行性， 谷氨酰胺酶的Hibitor阻断向谷氨酰胺依赖性的过渡，作为抑制BRAF发作的方法 反抗。我们的具体目的是：AIM 1将决定MAPK的生化变化和有效性 黑色素瘤的鼠和人类模型中的途径抑制。 AIM 2将阐明对生物的底物限制 化学效应和生物标志物对微环境变化的反应。 AIM 3将验证提议的 在体内系统中的生物标志物，该系统使用谷氨酰胺酶抑制剂对治疗反应进行了修饰。 临床影响：该项目将使NMR MET-检测黑色素瘤对靶向治疗的反应 已经在常规1.5T和3T工具以及7T In-诊所实施的ODS 越来越普遍的条件。代谢组学研究将扩大我们的能力 在细胞，小鼠和人类模型以及最终在人类中的肿瘤代谢。