Application of Hyperpolarized 13C Magnetic Resonance Imaging to Detect Target Inhibition of NF-kB Activation and Response in Primary CNS Lymphoma

应用超极化13C磁共振成像检测原发性中枢神经系统淋巴瘤中NF-kB激活和反应的靶点抑制

• 批准号: 10177970
• 负责人: Myriam Marianne Chaumeil
• 金额: $ 61.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177970
• 关键词: Address; Anatomy; B-Cell Activation; B-Cell Lymphomas; Biological Markers; Brain; Brain Neoplasms; Cancer Etiology; Central Nervous System Lymphoma; Cerebrospinal Fluid; Cessation of life; Clinic; Clinical; Clinical Trials; Detection; Diagnosis; Diagnostic; Diagnostic radiologic examination; Diffusion; Disease; Dose; Evaluation; Foundations; Future; Gadolinium; Genetic; Genetic Markers; Genetic Transcription; Glioma; Image; Imaging Device; Immunocompetent; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inhibition of NF-KB activation; Investigation; Large-Cell Lymphomas; Lymphoma; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Mediating; Metabolic; Metabolism; Methods; Methotrexate; Modeling; Monitor; Multicenter Trials; Mutation; NF-kappa B; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Pre-Clinical Model; Prognosis; Progression-Free Survivals; Protons; Pyruvate; Refractory; Regimen; Relapse; Research; Resistance; Running; Schedule; Sensitivity and Specificity; Signal Transduction; Specimen; Talents; Techniques; Testing; Therapeutic; Time; Treatment Failure; Validation; anti-PD-L1 therapy; base; cell type; combinatorial; contrast enhanced; early detection biomarkers; genetic approach; high standard; imaging approach; imaging modality; imaging study; immunotherapy trials; improved; in vivo; innovation; insight; metabolic imaging; mortality; multidisciplinary; non-invasive imaging; novel; novel marker; phase 1 study; precision medicine; predictive marker; prognostic; recruit; resistance mechanism; response; targeted agent; temporal measurement; translational study; tumor; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT This proposal will apply an innovative metabolic imaging approach, hyperpolarized (HP) 1-13-C MRI to address NF-kB activation in cancer. NF-kB is a key pro-survival transcriptional regulator that drives resistance in a variety of malignancies, one of which is primary CNS lymphoma (PCNSL) a highly refractory form of activated B-cell (ABC)-type large cell lymphoma. ABC-type large cell lymphomas are an important cause of cancer-related mortality worldwide. Recent trials using targeted agents that block NF-kB activation have shown activity in PCNSL and systemic ABC-type lymphoma, yet responses last only a few months, suggesting that alternative pathways of NF-kB activation are adaptively induced to mediate resistance. We hypothesize that HP 1-13-C MRI may have particular utility in detecting clinical response, defining prognosis and target inhibition in PCNSL and can also be applied to identify effective combinatorial strategies that durably suppress NF-kB activation. In addition, we envision that this approach may be impactful in identifying biomarkers that predict efficacy of immunotherapy. Our team recently demonstrated for the first time the feasibility of HP 1-13-C MRI to image malignant glioma in patients. These studies support the potential of HP 1-13-C MRI to identify metabolites that yield impactful non-invasive biomarkers of in vivo metabolic processes in PCNSL, including resistance pathways, with markedly improved sensitivity and specificity compared to standard MRI. We have recruited a talented, multidisciplinary team to pursue this highly translational project to address key gaps in PCNSL research through pursuit of the following specific Aims: 1) Test the hypothesis that hyperpolarized (HP) [1-13-C]-metabolic MR imaging of genetically-defined, patient- derived orthotopic models of PCNSL can non-invasively evaluate depth of response to combinations of NF-kB targeting agents as well as provide an early biomarker of the emergence of resistance. 2) Test the hypothesis that HP [1-13-C] metabolic MR metrics can be developed as non-invasive biomarkers of NF-kB-activation and immunosuppression in a syngeneic, immunocompetent model of PCNSL. 3) Perform the initial proof of principle patient studies of HP 13C MRI to determine feasibility and methods of HP [1-13C] pyruvate MRI as a real time, non-invasive imaging tool for response assessment in PCNSL. We will correlate genetic markers of NF-kB activation in tumors with lactate on HP 13C MRI and lactate in cerebrospinal fluid and their relationship to progression-free survival. These studies will constitute a basis for integration of HP13C metabolic imaging in the research of PCNSL, and of ABC-type lymphomas in general, to improve detection, prognostication, identify resistance, and facilitate precision medicine. We anticipate these studies will identify novel combinations and schedules of agents that durably block NF-kB, to be tested in the clinic. These studies may also provide a rationale for implementation of tumor lactate as a novel biomarker for immunotherapy trials. Ultimately our studies may stimulate multicenter trials to evaluate HP 13C MRI in PCNSL.

项目摘要/摘要 该建议将采用创新的代谢成像方法，超极化（HP）1-13-C MRI来解决 NF-KB激活癌症。 NF-KB是一个关键的促生存性转录调节器，可在各种各样的抗性中驱动阻力 恶性肿瘤，其中之一是原发性中枢神经系统淋巴瘤（PCNSL）一种高度难治的活化B细胞形式 （ABC） - 大细胞淋巴瘤。 ABC型大细胞淋巴瘤是癌症相关的重要原因 全球死亡率。最近使用阻断NF-KB激活的靶向剂的试验显示了活性 PCNSL和全身性ABC型淋巴瘤，但反应仅持续几个月，这表明替代方案 NF-KB激活的途径被自适应诱导介导电阻。我们假设HP 1-13-C MRI可能在检测临床反应，定义PCNSL的预后和靶向抑制方面具有特殊效用 还可以应用于确定持久抑制NF-KB激活的有效组合策略。在 此外，我们设想这种方法可能会影响到预测功效的生物标志物 免疫疗法。我们的团队最近首次证明了HP 1-13-C MRI的可行性 患者的恶性神经瘤。这些研究支持HP 1-13-C MRI的潜力，以鉴定代谢物 在PCNSL中产生体内代谢过程的有影响力的非侵入性生物标志物，包括抗性途径， 与标准MRI相比，灵敏度和特异性明显提高。我们已经招募了一个才华横溢的人， 多学科团队追求这个高度转化的项目，以解决PCNSL研究中的关键差距 追求以下特定目标： 1）检验以下假设：超极化（HP）[1-13-C] - 代谢MR成像的遗传定义，患者 - PCNSL的派生的原位模型可以非侵入性评估对NF-KB组合的响应深度 靶向剂以及提供抗性出现的早期生物标志物。 2）检验HP [1-13-C]代谢MR指标可以作为非侵入性生物标志物的假设 NF-KB激活和免疫抑制在PCNSL的合成性，免疫能力模型中。 3）执行HP 13C MRI的主要患者研究的初始证明，以确定HP的可行性和方法 [1-13C]丙酮酸MRI作为实时的无创成像工具，用于PCNSL中的响应评估。 我们将在HP 13C MRI和乳酸上的乳酸肿瘤中NF-KB激活的遗传标志物相关联 脑脊液及其与无进展生存的关系。这些研究将构成 HP13C代谢成像的整合在PCNSL的研究和ABC型淋巴瘤的研究中 改善检测，预后，识别抗药性并促进精确药物。我们期待这些 研究将确定持久阻止NF-KB的药物的新型组合和时间表 诊所。这些研究还可能为实施肿瘤乳酸作为一种新型生物标志物提供基本原理 免疫疗法试验。最终，我们的研究可能会刺激多中心试验，以评估PCNSL中的HP 13C MRI。