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
项目总结/文摘:
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
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批准号:10573677
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项目类别:
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资助金额:$39.64万
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财政年份:2022
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负责人:David C Fajgenbaum
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依托单位:
ACCELERATE: An Efficient and Innovative Natural History Study Addressing Unmet Needs in Castleman Disease
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批准号:10701030
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资助金额:$39.72万
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财政年份:2022
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负责人:David C Fajgenbaum
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依托单位:
mTOR as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target
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批准号:10179449
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项目类别:
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资助金额:$73.6万
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财政年份:2018
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负责人:David C Fajgenbaum
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依托单位:
mTOR as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target
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批准号:10415959
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资助金额:$19.38万
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财政年份:2018
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负责人:David C Fajgenbaum
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