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
基本信息
- 批准号:10437739
- 负责人:
- 金额:$ 58.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAnatomyB-Cell ActivationB-Cell LymphomasBiological MarkersBrainBrain NeoplasmsCancer EtiologyCentral Nervous System LymphomaCerebrospinal FluidCessation of lifeClinicClinicalClinical TrialsDetectionDiagnosisDiagnosticDiffusionDiseaseDoseEvaluationFoundationsFutureGadoliniumGeneticGenetic MarkersGenetic TranscriptionGliomaImageImaging DeviceImmunocompetentImmunosuppressionImmunotherapeutic agentImmunotherapyInhibition of NF-KB activationInvestigationLarge-Cell LymphomasLymphomaMagnetic Resonance ImagingMalignant GliomaMalignant NeoplasmsMalignant neoplasm of brainMeasurementMediatingMetabolicMetabolismMethodsMethotrexateModelingMonitorMulticenter TrialsMutationNF-kappa BNewly DiagnosedNon-Hodgkin&aposs LymphomaOutcomePathogenesisPathway interactionsPatientsPharmacologyPharmacotherapyPre-Clinical ModelPrognosisProgression-Free SurvivalsProtonsPyruvateRefractoryRegimenRelapseResearchResistanceRunningScheduleSensitivity and SpecificitySignal TransductionSpecimenTalentsTechniquesTestingTherapeuticTimeTreatment FailureValidationantagonistanti-PD-L1 therapybasecell typecombinatorialcontrast enhancedearly detection biomarkersgenetic approachhigh standardimaging approachimaging modalityimaging studyimmunotherapy trialsimprovedin vivoinnovationinsightmetabolic imagingmortalitymultidisciplinarynon-invasive imagingnovelnovel markerphase 1 studyprecision medicinepredictive markerprognosticationradiological imagingrecruitresistance mechanismresponsetargeted agenttemporal measurementtranslational studytumortumor-immune system interactions
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Myriam Marianne Chaumeil其他文献
Myriam Marianne Chaumeil的其他文献
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{{ truncateString('Myriam Marianne Chaumeil', 18)}}的其他基金
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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
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Development and validation of novel models for cerebral small vessel disease and vascular cognitive impairment
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- 批准号:
10684902 - 财政年份:2019
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$ 58.41万 - 项目类别:
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
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