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

• 批准号: 10751970
• 负责人: Sophie Paczesny
• 金额: $ 22.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10751970
• 关键词: Academia; Acute Graft Versus Host Disease; Address; Adopted; Aftercare; Allogenic; Antibody Affinity; Award; Biological; Biological Assay; Biological Markers; Biology; Blood; Blood Tests; Blood specimen; Bone Marrow Transplantation; CXCL10 gene; Clinical; Clinical Trials Network; Collaborations; Complex; Complication; Data; Dependence; Development; Disease; Disease Pathway; Disease Resistance; Enzyme-Linked Immunosorbent Assay; Exposure to; Future; Hematologic Neoplasms; IRAK1 gene; In complete remission; Individual; Inherited; Interleukins; JAK2 gene; Lead; Ligands; Macrophage Colony-Stimulating Factor Receptor; Malignant - descriptor; Measures; Monitor; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase I/II Trial; Phosphotransferases; Plasma; Plasma Proteins; Prognosis; Progressive Disease; Proteins; Proteomics; Refractory; Research; Resistance; Risk; Risk Marker; Sampling; Sensitivity and Specificity; Specificity; Steroids; Stromelysin 1; Testing; Therapeutic; Time; Transplant Recipients; Validation; biomarker panel; candidate identification; candidate marker; chemokine; chronic graft versus host disease; clinically relevant; cohort; curative treatments; disorder risk; experience; experimental study; hematopoietic cell transplantation; inhibitor; kinase inhibitor; mortality; novel; novel therapeutic intervention; partial response; personalized medicine; predicting response; predictive marker; predictive panel; prognostic; prognostic value; proteomic signature; receptor; response; risk stratification; secondary endpoint; specific biomarkers; success; tandem mass spectrometry; therapy resistant; treatment response

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来 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非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 个治疗前样本以及治疗后 3 个月和 6 个月样本。 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流程？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合，有助于预测治疗反应和耐药性 确定新治疗方法的候选者。