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.

项目概要/摘要 该提案将应用创新的代谢成像方法，超极化 (HP) 1-13-C MRI 来解决 癌症中的 NF-kB 激活。 NF-kB 是一种关键的促生存转录调节因子，可驱动多种耐药性 恶性肿瘤，其中之一是原发性中枢神经系统淋巴瘤 (PCNSL)，这是一种高度难治性的活化 B 细胞形式 (ABC)型大细胞淋巴瘤。 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 激活的靶向药物进行的试验已显示出以下活性： PCNSL 和系统性 ABC 型淋巴瘤，但反应仅持续几个月，这表明替代方案 NF-kB 激活途径被适应性诱导以介导耐药性。我们假设 HP 1-13-C MRI 在检测 PCNSL 的临床反应、确定预后和目标抑制方面可能具有特殊用途 也可用于确定持久抑制 NF-kB 激活的有效组合策略。在 此外，我们预计这种方法可能会对识别预测疗效的生物标志物产生影响。 免疫疗法。我们的团队最近首次证明了 HP 1-13-C MRI 成像的可行性 恶性胶质瘤患者。这些研究支持 HP 1-13-C MRI 识别代谢物的潜力 产生 PCNSL 体内代谢过程的有影响力的非侵入性生物标志物，包括耐药途径， 与标准 MRI 相比，灵敏度和特异性显着提高。我们招募了一批才华横溢、 多学科团队致力于开展这一高度转化的项目，通过以下方式解决 PCNSL 研究的关键差距 追求以下具体目标： 1) 检验以下假设：基因定义的超极化 (HP) [1-13-C]-代谢 MR 成像、患者- PCNSL 衍生的原位模型可以无创地评估对 NF-kB 组合的反应深度 靶向剂并提供耐药性出现的早期生物标志物。 2) 检验 HP [1-13-C] 代谢 MR 指标可以开发为非侵入性生物标志物的假设 PCNSL 同基因、免疫功能正常模型中的 NF-kB 激活和免疫抑制。 3) 进行 HP 13C MRI 原则患者研究的初步证明，以确定 HP 的可行性和方法 [1-13C] 丙酮酸 MRI 作为实时、非侵入性成像工具，用于 PCNSL 反应评估。 我们将把肿瘤中 NF-kB 激活的遗传标记与 HP 13C MRI 上的乳酸和 脑脊液及其与无进展生存期的关系。这些研究将构成基础 将 HP13C 代谢成像整合到 PCNSL 和一般 ABC 型淋巴瘤的研究中， 改善检测、预测、识别耐药性并促进精准医疗。我们预计这些 研究将确定持久阻断 NF-kB 的新药物组合和方案，并在 诊所。这些研究还可能为肿瘤乳酸作为一种新型生物标志物的实施提供理论依据。 免疫治疗试验。最终，我们的研究可能会刺激多中心试验来评估 PCNSL 中的 HP 13C MRI。