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.
项目摘要/摘要
该提案将应用一种创新的代谢成像方法,即超极化(HP)1-13-C MRI,以解决
核因子-kB在肿瘤中的激活。核因子-kB是一种关键的促进生存的转录调节因子,它推动了多种
恶性肿瘤,其中之一是原发性中枢神经系统淋巴瘤(PCNSL),一种高度难治性的活化B细胞
(ABC)型大细胞淋巴瘤。ABC型大细胞淋巴瘤是与癌症相关的重要原因
全球范围内的死亡率。最近使用靶向药物阻断核因子-kB激活的试验显示,在
PCNSL和系统性ABC型淋巴瘤,但反应仅持续几个月,这表明替代方案
核因子-kB的激活途径被适应性地诱导来介导抗性。我们假设惠普1-13-C
MRI可能在检测PCNSL的临床反应、确定预后和靶点抑制方面具有特殊的实用价值
也可用于确定持久抑制核因子-kB激活的有效组合策略。在……里面
此外,我们预计,这种方法可能会在识别预测疗效的生物标志物方面产生影响。
免疫疗法。我们的团队最近首次证明了HP 1-13-C磁共振成像的可行性
恶性胶质瘤患者。这些研究支持Hp 1-13-C MRI识别代谢产物的潜力
产生影响PCNSL体内代谢过程的非侵入性生物标志物,包括耐药途径,
与标准MRI相比,敏感度和特异度显著提高。我们招募了一位才华横溢的,
多学科团队开展这一高度转化的项目,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)测试假设,超极化(HP)[1-13-C]代谢磁共振成像的基因定义,患者-
所建立的PCNSL原位模型可以无创性地评估联合应用核因子-kB的反应深度
靶向药物以及提供耐药出现的早期生物标志物。
2)验证HP[1-13-C]代谢磁共振指标可以作为非侵入性生物标志物开发的假设
同基因、免疫活性PCNSL模型中核因子-kB的激活和免疫抑制。
3)进行HP 13C MRI的初步患者研究,以确定HP的可行性和方法
[1-13C]丙酮酸盐MRI作为一种实时、非侵入性成像工具,用于评估PCNSL的反应。
我们将把肿瘤中核因子-kB激活的遗传标志与HP 13C MRI上的乳酸和在肿瘤中的乳酸相关联
脑脊液及其与无进展生存的关系。这些研究将构成以下方面的基础
HP13C代谢成像在PCNSL和ABC型淋巴瘤研究中的整合
提高检测、预测、识别耐药性,促进精准医疗。我们期待着这些
研究将确定可持久阻断核因子-kB的新组合和药物时间表,以便在
诊所。这些研究也可能为实现肿瘤乳酸作为一种新的生物标志物提供理论基础。
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Hp 13C MRI在PCNSL中的应用。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Myriam Marianne Chaumeil其他文献
Myriam Marianne Chaumeil的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Myriam Marianne Chaumeil', 18)}}的其他基金
Theranostic Metabolic Imaging of Oxidative Stress in Multiple Sclerosis.
多发性硬化症氧化应激的治疗诊断代谢成像。
- 批准号:
10666890 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Imaging cerebral metabolic impairment in AD using Deuterium MRI
使用氘 MRI 对 AD 中的脑代谢损伤进行成像
- 批准号:
10608908 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Imaging innate and adaptive immune response in MS using using [18F]F-AraG PET and hyperpolarized 13C MRSI
使用 [18F]F-AraG PET 和超极化 13C MRSI 对 MS 中的先天性和适应性免疫反应进行成像
- 批准号:
10040874 - 财政年份:2020
- 资助金额:
$ 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
- 批准号:
10177970 - 财政年份:2019
- 资助金额:
$ 58.41万 - 项目类别:
Development and validation of novel models for cerebral small vessel disease and vascular cognitive impairment
脑小血管疾病和血管性认知障碍新模型的开发和验证
- 批准号:
10471562 - 财政年份:2019
- 资助金额:
$ 58.41万 - 项目类别:
Development and validation of novel models for cerebral small vessel disease and vascular cognitive impairment
脑小血管疾病和血管性认知障碍新模型的开发和验证
- 批准号:
10684902 - 财政年份:2019
- 资助金额:
$ 58.41万 - 项目类别:
Development and validation of novel models for cerebral small vessel disease and vascular cognitive impairment
脑小血管疾病和血管性认知障碍新模型的开发和验证
- 批准号:
9894276 - 财政年份:2019
- 资助金额:
$ 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
- 批准号:
10651730 - 财政年份:2019
- 资助金额:
$ 58.41万 - 项目类别:
Understand and probing disrupted glucose metabolism in Alzheimer's disease
了解并探索阿尔茨海默病中葡萄糖代谢紊乱
- 批准号:
9802793 - 财政年份:2019
- 资助金额:
$ 58.41万 - 项目类别:
相似海外基金
Linking Epidermis and Mesophyll Signalling. Anatomy and Impact in Photosynthesis.
连接表皮和叶肉信号传导。
- 批准号:
EP/Z000882/1 - 财政年份:2024
- 资助金额:
$ 58.41万 - 项目类别:
Fellowship
Digging Deeper with AI: Canada-UK-US Partnership for Next-generation Plant Root Anatomy Segmentation
利用人工智能进行更深入的挖掘:加拿大、英国、美国合作开发下一代植物根部解剖分割
- 批准号:
BB/Y513908/1 - 财政年份:2024
- 资助金额:
$ 58.41万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Social and ecological influences on brain anatomy
博士论文研究:社会和生态对大脑解剖学的影响
- 批准号:
2235348 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Standard Grant
Simultaneous development of direct-view and video laryngoscopes based on the anatomy and physiology of the newborn
根据新生儿解剖生理同步开发直视喉镜和视频喉镜
- 批准号:
23K11917 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Computational comparative anatomy: Translating between species in neuroscience
计算比较解剖学:神经科学中物种之间的翻译
- 批准号:
BB/X013227/1 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Research Grant
computational models and analysis of the retinal anatomy and potentially physiology
视网膜解剖学和潜在生理学的计算模型和分析
- 批准号:
2825967 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Studentship
Genetics of Extreme Phenotypes of OSA and Associated Upper Airway Anatomy
OSA 极端表型的遗传学及相关上呼吸道解剖学
- 批准号:
10555809 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Development of a novel visualization, labeling, communication and tracking engine for human anatomy.
开发一种新颖的人体解剖学可视化、标签、通信和跟踪引擎。
- 批准号:
10761060 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Understanding the functional anatomy of nociceptive spinal output neurons
了解伤害性脊髓输出神经元的功能解剖结构
- 批准号:
10751126 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
The Anatomy of Online Reviews: Evidence from the Steam Store
在线评论剖析:来自 Steam 商店的证据
- 批准号:
2872725 - 财政年份:2023
- 资助金额:
$ 58.41万 - 项目类别:
Studentship














{{item.name}}会员




