JAK1/2 as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target

JAK1/2 作为 iMCD 发病机制和新治疗靶点的中央调节因子

• 批准号: 10736877
• 负责人: David C Fajgenbaum
• 金额: $ 80.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736877
• 关键词: Cell physiology; Cells; Childhood; Circulation; Clinical; Critical Illness; Cytokine Signaling; Cytotoxic Chemotherapy; Data; Data Discovery; Diagnosis; Disease; Disease Progression; Disease remission; Etiology; FDA approved; FRAP1 gene; Flare; Functional disorder; Funding; Goals; Hematology; Human; Human Herpesvirus 8; Hypersensitivity; IRS1 gene; Immune; In Vitro; In complete remission; Individual; Inflammatory; Interferon Type I; Interleukin-6; Interruption; JAK1 gene; JAK2 gene; Link; Lymphoproliferative Disorders; Mediating; Mediator; Multicentric Angiofollicular Lymphoid Hyperplasia; PI3K/AKT; PIK3CG gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Proteomics; Rare Diseases; Refractory; Relapse; Research; Role; STAT3 gene; Sampling; Serum; Signal Pathway; Signal Transduction; Sirolimus; Symptoms; T-Cell Activation; T-Lymphocyte; Therapeutic Effect; body system; cell type; cytokine; improved; in vivo; inflammatory marker; lymph nodes; mTOR inhibition; monocyte; new therapeutic target; novel; novel therapeutic intervention; patient subsets; phenotypic biomarker; systemic inflammatory response; treatment optimization

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.

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。

项目成果

CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.

• 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.

The disease course of Castleman disease patients with fatal outcomes in the ACCELERATE registry.

• 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

How We Manage Idiopathic Multicentric Castleman Disease

• 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.

Cytokine Storm.

• DOI: 10.1056/nejmra2026131
• 发表时间: 2020-12-03
• 期刊: The New England journal of medicine
• 作者: Fajgenbaum DC;June CH
• 通讯作者: June CH

Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.

• 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