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: 10437739
• 负责人: Myriam Marianne Chaumeil
• 金额: $ 58.41万
• 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/10437739
• 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; 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; antagonist; 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; prognostication; radiological imaging; 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.

项目总结/摘要 该提案将采用创新的代谢成像方法，超极化（HP）1-13-C MRI，以解决 癌症中的NF-kB活化。NF-kB是一个关键的促生存转录调节因子，可驱动多种植物的抗性 原发性中枢神经系统淋巴瘤（PCNSL）是一种高度难治性的活化B细胞淋巴瘤， （ABC）型大细胞淋巴瘤。ABC型大细胞淋巴瘤是引起恶性肿瘤的重要原因。 全世界的死亡率。最近使用阻断NF-kB活化的靶向药物的试验显示了在 PCNSL和系统性ABC型淋巴瘤，但反应仅持续几个月，这表明替代疗法 适应性诱导NF-κ B活化途径以介导抗性。我们假设HP 1-13-C MRI在检测PCNSL的临床反应、确定预后和靶点抑制方面可能具有特殊的实用性 并且还可以应用于鉴定持久抑制NF-κ B活化的有效组合策略。在 此外，我们设想这种方法可能在鉴定预测药物疗效的生物标志物方面具有影响力。 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鉴定代谢物的潜力， 产生PCNSL中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，其灵敏度和特异性显著提高。我们招募了一位才华横溢， 多学科团队致力于这个高度转化的项目，以通过以下方式解决PCNSL研究中的关键差距 追求以下具体目标： 1)检验超极化（HP）[1-13-C]-代谢MR成像对遗传定义的患者的假设， 衍生的PCNSL原位模型可以非侵入性地评估对NF-κ B组合的反应深度， 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指标可开发为以下非侵入性生物标志物的假设： 在PCNSL的同基因免疫活性模型中的NF-κ B活化和免疫抑制。 3)进行HP 13 C MRI的初步原理性患者研究证明，以确定HP的可行性和方法 [1- 13 C]丙酮酸盐MRI作为PCNSL缓解评估的真实的实时、非侵入性成像工具。 我们将把肿瘤中NF-κ B活化的遗传标记与HP 13 C MRI上的乳酸盐和肿瘤中的乳酸盐相关联。 脑脊液及其与无进展生存期的关系。这些研究将构成以下方面的基础： 在PCNSL和一般ABC型淋巴瘤的研究中整合HP 13 C代谢成像， 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的药物的新组合和时间表， 诊所这些研究也可能为将肿瘤乳酸盐作为一种新的生物标志物来治疗肿瘤提供理论基础。 免疫治疗试验最终，我们的研究可能会刺激多中心试验，以评估HP 13 C MRI在PCNSL中的作用。