JAK1/2 as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target
JAK1/2 as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target
批准号:
10736877
负责人:
David C Fajgenbaum
金额:
$80.75万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-06-15 至 2028-05-31
关键词:
Cell physiologyCellsChildhoodCirculationClinicalCritical IllnessCytokine SignalingCytotoxic ChemotherapyDataData DiscoveryDiagnosisDiseaseDisease ProgressionDisease remissionEtiologyFDA approvedFRAP1 geneFlareFunctional disorderFundingGoalsHematologyHumanHuman Herpesvirus 8HypersensitivityIRS1 geneImmuneIn VitroIn complete remissionIndividualInflammatoryInterferon Type IInterleukin-6InterruptionJAK1 geneJAK2 geneLinkLymphoproliferative DisordersMediatingMediatorMulticentric Angiofollicular Lymphoid HyperplasiaPI3K/AKTPIK3CG genePathogenesisPathologicPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhosphorylationProteomicsRare DiseasesRefractoryRelapseResearchRoleSTAT3 geneSamplingSerumSignal PathwaySignal TransductionSirolimusSymptomsT-Cell ActivationT-LymphocyteTherapeutic Effectbody systemcell typecytokineimprovedin vivoinflammatory markerlymph nodesmTOR inhibitionmonocytenew therapeutic targetnovelnovel therapeutic interventionpatient subsetsphenotypic biomarkersystemic inflammatory responsetreatment optimization
中文摘要
项目概要/摘要:
人类疱疹病毒(HHV)-8阴性,特发性多中心Castleman病(iMCD)是一种致命的血液病,
涉及多克隆淋巴细胞增生和多器官系统功能障碍的疾病。iMCD诊断为
美国每年约有1,500人,其中35%在5年内死亡。有限的选择存在于
对66%的siltuximab阻断白细胞介素-6(IL-6)难治性患者进行细胞毒性化疗;
复发是常见的。病因学、病理细胞类型和失调的信号传导通路是不好的
明白提高对疾病机制的理解对于确定新的治疗方法是必要的。
在上一个资助周期中,我们证明了iMCD患者显示mTOR信号增加,
淋巴结和循环中的活化T细胞。用西罗莫司抑制mTOR信号传导导致细胞凋亡减少。
活化的T细胞和患者亚群中的临床改善。然而,导致增加的信号
难治性患者中涉及的mTOR激活和替代途径仍然未知。我们
提出失调的细胞因子信号传导可能是免疫系统中mTOR信号传导增加的原因,
iMCD中的细胞和过度炎症。我们最近的初步数据表明,
缓解显示在用I型受体刺激后,pS 6表达增加,这是mTOR活化的读数
干扰素(IFN-I)和IL-6的水平。考虑到IFN-I和IL-6通过JAK 1和JAK 2发出信号,
我们假设JAK 1/2抑制可以消除IL-6和IFN-γ诱导的mTOR激活增加。
I.事实上,在iMCD患者T细胞中,ruxolitinib体外JAK 1/2抑制作用消除了mTOR激活的增加。
细胞基于这些体外结果和蛋白质组学数据,表明JAK-STAT 3信号转导在细胞内的富集。
在iMCD患者中,我们将鲁索利替尼给予高度治疗难治性和危重儿科iMCD患者,
她已经完全缓解了24个月,比她以前的平均缓解时间长20倍。
我们假设JAK 1/2信号是mTOR激活和iMCD的中心介导者,
发病机制,JAK介导的对细胞因子刺激的超敏反应是机制基础,
通过抑制JAK 1/2、T细胞活化和mTOR中断iMCD。在目的1中,我们将研究JAK 1/2的激活,
和爆发期间iMCD患者样品中的mTOR信号传导。在目标2中,我们将严格评估iMCD患者
T细胞在体外对IFN-1和IL-6的细胞因子刺激应答,并建立了IFN-1和IL-6之间的机制联系。
JAK 1/2和mTOR信号传导。基于我们的初步数据,我们假设IRS 1磷酸化
JAK 1/2下游的信号通路可导致PI 3 K/AKT和mTOR的激活。目标3概述了一个机制研究,
ruxolitinib在iMCD患者中研究体内JAK 1/2信号传导。拟议的研究将继续进行
了解iMCD中失调的信号通路和细胞类型,并可能导致新的治疗方法
iMCD和相关疾病的范例。使用临床和发现数据来揭示现有药物的新用途
药物对于确定95%的罕见疾病的治疗方法至关重要,这些疾病没有FDA批准的治疗方法。
英文摘要
Project Summary/Abstract:
Human herpesvirus(HHV)-8-negative, idiopathic multicentric Castleman disease (iMCD) is a deadly hematologic
illness involving polyclonal lymphoproliferation and multiple organ system dysfunction. iMCD is diagnosed in
approximately 1,500 individuals annually in the USA; 35% die within 5 years. Limited options exist beyond
cytotoxic chemotherapies for the 66% of patients refractory to interleukin-6 (IL-6) blockade with siltuximab;
relapse is common. The etiology, pathological cell types, and dysregulated signaling pathways are poorly
understood. Improved understanding of disease mechanisms is necessary to identify new treatments.
In the previous funding cycle, we demonstrated that iMCD patients display increased mTOR signaling in
lymph nodes and activated T cells in circulation. Inhibiting mTOR signaling with sirolimus led to a decrease in
activated T cells and clinical improvement in a subset of patients. However, the signals leading to increased
mTOR activation and alternative pathways involved in treatment-refractory patients remain unknown. We
propose that dysregulated cytokine signaling could be responsible for the increased mTOR signaling in immune
cells and hyperinflammation in iMCD. Our recent preliminary data suggest that T cells from iMCD patients in
remission display increased pS6 expression, a read-out of mTOR activation, upon stimulation with Type I
interferon (IFN-I) and IL-6 compared to healthy controls. Given that IFN-I and IL-6 signal through JAK1 and JAK2,
we hypothesized that JAK1/2 inhibition could abrogate the increased mTOR activation induced by IL-6 and IFN-
I. Indeed, in vitro JAK1/2 inhibition by ruxolitinib abrogated the increased mTOR activation in iMCD patient T
cells. Based on these in vitro results and proteomics data indicating enrichment of JAK-STAT3 signaling across
iMCD patients, we administered ruxolitinib to a highly treatment refractory and critically ill pediatric iMCD patient,
who has been in complete remission for 24 months, 20-fold longer than her previous average remission duration.
We hypothesize that JAK1/2 signaling is a central mediator of mTOR activation and iMCD
pathogenesis, JAK-mediated hypersensitivity to cytokine stimulation is the mechanistic basis, and ruxolitinib
interrupts iMCD by inhibiting JAK1/2, T cell activation, and mTOR. In Aim 1, we will study the activation of JAK1/2
and mTOR signaling in iMCD patient samples during flare. In Aim 2, we will rigorously evaluate how iMCD patient
T cells respond to cytokine stimulation with IFN-I and IL-6 in vitro and establish the mechanistic link between
JAK1/2 and mTOR signaling. Based on our preliminary data, we hypothesize that IRS1 phosphorylation
downstream of JAK1/2 can lead to PI3K/AKT and mTOR activation. Aim 3 outlines a mechanistic study of
ruxolitinib in iMCD patients to investigate JAK1/2 signaling in vivo. The proposed studies will advance
understanding of dysregulated signaling pathways and cell types in iMCD and may lead to a new treatment
paradigm for iMCD and related disorders. Using clinical and discovery data to uncover a novel use for an existing
drug is critical to identify therapies for the 95% of rare diseases with no FDA-approved therapy.
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DOI:
10.1038/s41467-022-34873-7
发表时间:
2022-11-24
期刊:
NATURE COMMUNICATIONS
影响因子:
16.6
作者:
[Pierson, Sheila K., Katz, Laura, Williams, Reece, Mumau, Melanie, Gonzalez, Michael, Guzman, Stacy, Rubenstein, Ayelet, Oromendia, Ana B., Beineke, Philip, Fossa, Alexander, van Rhee, Frits, Fajgenbaum, David C.]
通讯作者:
Fajgenbaum, David C.
DOI:
10.1111/bjh.18214
发表时间:
2022-07
期刊:
BRITISH JOURNAL OF HAEMATOLOGY
影响因子:
6.5
作者:
[Fajgenbaum, David C., Pierson, Sheila K., Kanhai, Karan, Bagg, Adam, Alapat, Daisy, Lim, Megan S., Lechowicz, Mary Jo, Srkalovic, Gordan, Uldrick, Thomas S., van Rhee, Frits]
通讯作者:
van Rhee, Frits
DOI:
10.1245/clin.1248-0124
发表时间:
2022-09-01
期刊:
CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY
影响因子:
1
作者:
[Brandstadter, Joshua D., Fajgenbaum, David C.]
通讯作者:
Fajgenbaum, David C.
DOI:
10.1056/nejmra2026131
发表时间:
2020-12-03
期刊:
The New England journal of medicine
影响因子:
--
作者:
[Fajgenbaum DC, June CH]
通讯作者:
June CH
DOI:
10.3389/fimmu.2022.919489
发表时间:
2022
期刊:
Frontiers in immunology
影响因子:
7.3
作者:
[Rossi JF, Chiang HC, Lu ZY, Levon K, van Rhee F, Kanhai K, Fajgenbaum DC, Klein B]
通讯作者:
Klein B
共 26 条
ACCELERATE: An Efficient and Innovative Natural History Study Addressing Unmet Needs in Castleman Disease
-
批准号:10573677
-
项目类别:
-
资助金额:$39.64万
-
财政年份:2022
-
负责人:David C Fajgenbaum
-
依托单位:
ACCELERATE: An Efficient and Innovative Natural History Study Addressing Unmet Needs in Castleman Disease
-
批准号:10701030
-
项目类别:
-
资助金额:$39.72万
-
财政年份:2022
-
负责人:David C Fajgenbaum
-
依托单位:
mTOR as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target
-
批准号:10179449
-
项目类别:
-
资助金额:$73.6万
-
财政年份:2018
-
负责人:David C Fajgenbaum
-
依托单位:
mTOR as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target
-
批准号:10415959
-
项目类别:
-
资助金额:$19.38万
-
财政年份:2018
-
负责人:David C Fajgenbaum
-
依托单位:
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