Chronic Graft-Versus-Host Disease Biomarkers: Prediction of Resistance to Therapy
慢性移植物抗宿主病生物标志物:治疗耐药性的预测
基本信息
- 批准号:10751970
- 负责人:
- 金额:$ 22.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-23 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcademiaAcute Graft Versus Host DiseaseAddressAdoptedAftercareAllogenicAntibody AffinityAwardBiologicalBiological AssayBiological MarkersBiologyBloodBlood TestsBlood specimenBone Marrow TransplantationCXCL10 geneClinicalClinical Trials NetworkCollaborationsComplexComplicationDataDependenceDevelopmentDiseaseDisease PathwayDisease ResistanceEnzyme-Linked Immunosorbent AssayExposure toFutureHematologic NeoplasmsIRAK1 geneIn complete remissionIndividualInheritedInterleukinsJAK2 geneLeadLigandsMacrophage Colony-Stimulating Factor ReceptorMalignant - descriptorMeasuresMonitorPathologyPathway interactionsPatientsPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhase I/II TrialPhosphotransferasesPlasmaPlasma ProteinsPrognosisProgressive DiseaseProteinsProteomicsRefractoryResearchResistanceRiskRisk MarkerSamplingSensitivity and SpecificitySpecificitySteroidsStromelysin 1TestingTherapeuticTimeTransplant RecipientsValidationbiomarker panelcandidate identificationcandidate markerchemokinechronic graft versus host diseaseclinically relevantcohortcurative treatmentsdisorder riskexperienceexperimental studyhematopoietic cell transplantationinhibitorkinase inhibitormortalitynovelnovel therapeutic interventionpartial responsepersonalized medicinepredicting responsepredictive markerpredictive panelprognosticprognostic valueproteomic signaturereceptorresponserisk stratificationsecondary endpointspecific biomarkerssuccesstandem mass spectrometrytherapy resistanttreatment response
项目摘要
Major barriers to chronic graft-versus-host disease (cGVHD) research are the inability to predict the likelihood
of response to cGVHD therapy and subsequent patient survival. This absence of predictive biomarkers is partly
due to the complex pathology of cGVHD, which involves both soluble and cellular factors but mostly due to the
paucity, so far, of samples collected when specific cGVHD treatments are initiated, particularly as novel and
more targeted treatments for cGVHD are now available. Thus, major questions remaining in the field are: Can
we target more than one cGVHD pathway with a single drug? Can we detect biomarkers to predict future
resistance to treatment using already validated cGVHD biomarkers? Can we discover more specific markers
through a high throughput proteomics pipeline? Can we validate and utilize these predictive biomarkers to
provide strong support for FDA approval of these biomarkers? For this project, we will use samples (plasma
and PBMCs) collected during Dr. Pavletic trial testing Pacritanib, a multi-kinase inhibitor with specificity for
JAK2 and IRAK1, in patients with steroid-refractory/steroid-dependent (SR/D) cGVHD to analyze proteomic
signatures associated with prediction of cGVHD therapy nonresponse, and with prognosis of nonrelapse
mortality (NRM). Proposed markers are based on previous studies and will include other novel or hypothesized
factors. We will test the hypothesis that plasma proteomic panels measured prior to the start of cGVHD
treatment with pacritinib (PAC) will stratify HCT patients for prediction of resistance, and NRM at 1 year. We
will determine the thresholds of different biomarkers and panels that provide best sensitivity and specificity.
Our overarching hypothesis addresses gaps remaining by addressing two specific aims (SA): SA1: Are five
previously identified plasma cGVHD biomarkers [chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, matrix
metalloproteinase 3 (MMP3), Dickkopf-related protein 3 (DKK3), and Stimulation 2 (ST2; the interleukin (IL)-33
receptor)] predictive of resistance to PAC therapy? We will measure them using ELISA from fresh blood
samples collected during this award: ~35 samples pre-treatment and 3- and 6-months post-treatment. SA2:
Can additional plasma biomarkers that are key biologic drivers of cGVHD resistance be discovered through our
proteomics pipeline comparing responders vs. non responders? We will address this question using our well-
established proteomic workflow that can identify and quantify more than 2000 proteins. Upon completion, these
studies will result in biomarker panels that may facilitate prediction of response and resistance to therapy and
identify candidates for new therapeutic approaches.
慢性移植物抗宿主病(cGVHD)研究的主要障碍是无法预测其发生的可能性
对 cGVHD 治疗的反应和随后的患者生存率。缺乏预测性生物标志物的部分原因是
由于 cGVHD 的病理学复杂,涉及可溶性因素和细胞因素,但主要是由于
到目前为止,在开始特定的 cGVHD 治疗时收集的样本很少,特别是作为新的和
现在已有针对 cGVHD 更有针对性的治疗方法。因此,该领域剩下的主要问题是:
我们用一种药物针对多个 cGVHD 途径?我们可以检测生物标志物来预测未来吗
使用已经验证的 cGVHD 生物标志物对治疗产生耐药性?我们能否发现更具体的标记
通过高通量蛋白质组学管道?我们能否验证并利用这些预测生物标志物
为 FDA 批准这些生物标志物提供强有力的支持吗?对于这个项目,我们将使用样品(血浆
Pavletic 博士试验期间收集的 Pacritanib 是一种多激酶抑制剂,具有特异性
JAK2 和 IRAK1,在类固醇难治性/类固醇依赖性 (SR/D) cGVHD 患者中进行蛋白质组学分析
与 cGVHD 治疗无反应预测以及无复发预后相关的特征
死亡率(NRM)。提议的标记基于之前的研究,并将包括其他新颖或假设的标记
因素。我们将检验在 cGVHD 开始之前测量血浆蛋白质组组的假设
pacritinib (PAC) 治疗将对 HCT 患者进行分层,以预测 1 年时的耐药性和 NRM。我们
将确定提供最佳敏感性和特异性的不同生物标志物和组合的阈值。
我们的总体假设通过解决两个具体目标 (SA) 来解决剩余的差距: SA1:有 5 个
先前鉴定的血浆 cGVHD 生物标志物 [趋化因子(C-X-C 基序)配体 9 (CXCL9)、CXCL10、基质
金属蛋白酶 3 (MMP3)、Dickkopf 相关蛋白 3 (DKK3) 和刺激 2 (ST2;白细胞介素 (IL)-33
受体)]预测对 PAC 治疗的耐药性?我们将使用新鲜血液中的 ELISA 来测量它们
该奖项期间收集的样本:约 35 个处理前和处理后 3 个月和 6 个月的样本。 SA2:
能否通过我们的研究发现作为 cGVHD 耐药性关键生物驱动因素的其他血浆生物标志物?
比较响应者与非响应者的蛋白质组学管道?我们将利用我们的优势来解决这个问题
建立了可以识别和定量 2000 多种蛋白质的蛋白质组工作流程。完成后,这些
研究将产生生物标志物组,可促进预测治疗反应和耐药性
确定新治疗方法的候选者。
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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Sophie Paczesny其他文献
Sophie Paczesny的其他文献
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{{ truncateString('Sophie Paczesny', 18)}}的其他基金
IL-33 induced-lL-9 producing type 2 innate lymphoid cells in the regulation of acute lung injury after hematopoietic stem cell transplantation (HSCT) in pediatric patients
IL-33诱导产生IL-9的2型先天淋巴细胞在调节儿科患者造血干细胞移植(HSCT)后急性肺损伤中的作用
- 批准号:
10540768 - 财政年份:2022
- 资助金额:
$ 22.65万 - 项目类别:
IL-33 induced-lL-9 producing type 2 innate lymphoid cells in the regulation of acute lung injury after hematopoietic stem cell transplantation (HSCT) in pediatric patients
IL-33诱导产生IL-9的2型先天淋巴细胞在儿科患者造血干细胞移植(HSCT)后急性肺损伤的调节中
- 批准号:
10392134 - 财政年份:2022
- 资助金额:
$ 22.65万 - 项目类别:
Development of first-in-class ST2 inhibitors for treating graft-versus-host disease
开发用于治疗移植物抗宿主病的一流 ST2 抑制剂
- 批准号:
10093120 - 财政年份:2019
- 资助金额:
$ 22.65万 - 项目类别:
Development of first-in-class ST2 inhibitors for treating graft-versus-host disease
开发用于治疗移植物抗宿主病的一流 ST2 抑制剂
- 批准号:
10357753 - 财政年份:2019
- 资助金额:
$ 22.65万 - 项目类别:
Biomarkers for risk of chronic Graft-Versus-Host Disease occurrence
慢性移植物抗宿主病发生风险的生物标志物
- 批准号:
9433011 - 财政年份:2017
- 资助金额:
$ 22.65万 - 项目类别:
High Throughput Screening (HTS) to Discover Graft-Versus-Host Disease Inhibitors
高通量筛选 (HTS) 发现移植物抗宿主疾病抑制剂
- 批准号:
8649031 - 财政年份:2013
- 资助金额:
$ 22.65万 - 项目类别:
Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease
转化新型药物靶向生物标志物来治疗移植物抗宿主病
- 批准号:
8501916 - 财政年份:2013
- 资助金额:
$ 22.65万 - 项目类别:
High Throughput Screening (HTS) to Discover Graft-Versus-Host Disease Inhibitors
高通量筛选 (HTS) 发现移植物抗宿主疾病抑制剂
- 批准号:
8474927 - 财政年份:2013
- 资助金额:
$ 22.65万 - 项目类别:
Bridging Pediatric and Adult Biomarkers of Graft-Versus-Host-Disease
桥接儿童和成人移植物抗宿主疾病的生物标志物
- 批准号:
8842670 - 财政年份:2013
- 资助金额:
$ 22.65万 - 项目类别:
Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease
转化新型药物靶向生物标志物来治疗移植物抗宿主病
- 批准号:
8841692 - 财政年份:2013
- 资助金额:
$ 22.65万 - 项目类别:
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