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/文摘