Cell-free DNA-Based Analysis for Diagnosis, Monitoring and Optimization of Therapy for Patients with Primary Central Nervous System Lymphomas

基于游离 DNA 的分析用于原发性中枢神经系统淋巴瘤患者的诊断、监测和治疗优化

• 批准号: 10420404
• 负责人: CHETAN BETTEGOWDA
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10420404
• 关键词: Address; Adverse effects; Agammaglobulinaemia tyrosine kinase; Age; Anatomy; Aneuploidy; Area; Autologous Stem Cell Transplantation; Biological; Biological Assay; Biological Markers; Biopsy; Brain; Cells; Central Nervous System Diseases; Central Nervous System Lymphoma; Central Nervous System Neoplasms; Cerebrospinal Fluid; Characteristics; Chemoresistance; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collection; Conduct Clinical Trials; Consolidation Therapy; Custom; Cytology; Cytopathology; DNA; Data; Detection; Development; Dexamethasone; Diagnosis; Diagnostic; Diagnostic Sensitivity; Disease; Disease Progression; Disease Surveillance; Disease remission; Dose; Enrollment; Etoposide; Extranodal; Failure; Flow Cytometry; Future; Genetic; Genotype; Goals; Gold; Hematologic Neoplasms; Hemorrhage; Image; Immunomodulators; Incidence; Knowledge; Lead; Lesion; Liposomal Doxorubicin; Location; Lymphoma; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Methods; Methotrexate; Modality; Molecular; Molecular Disease; Molecular Profiling; Monitor; Mutation; National Cancer Institute; Nervous System Trauma; Neuraxis; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Non-Malignant; Ommaya Reservoir; Outcome; Patient-Focused Outcomes; Patients; Plasma; Population; Prediction of Response to Therapy; Prognosis; Recurrence; Refractory; Regimen; Relapse; Residual Neoplasm; Sampling; Sensitivity and Specificity; Solid; Spinal Puncture; Systemic disease; Technology; Testing; Therapeutic; Therapy Clinical Trials; Time; Tissues; Translational Research; Tumor-Derived; Tyrosine Kinase Inhibitor; United States; United States National Institutes of Health; Visit; base; cancer invasiveness; cell free DNA; clinical care; clinical center; clinical practice; clinically relevant; contrast enhanced; design; detection assay; diagnostic strategy; effective therapy; exome sequencing; follow-up; genetic evolution; genetic information; genomic signature; high risk; improved; improved outcome; infection risk; lenalidomide; liquid biopsy; molecular marker; mutation assay; neurotoxicity; novel; novel strategies; older patient; patient prognosis; prospective; radiological imaging; response; rituximab; sample collection; specific biomarkers; targeted agent; targeted treatment; temozolomide; therapy resistant; treatment optimization; treatment response; tumor; tumor DNA

Project Summary Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma that involves the central nervous system (CNS) without systemic disease. Approximately 1400 cases of PCNSL are diagnosed in the United States annually, classically occurring between the ages of 45 and 65, but the incidence is rising in older patients who represent a population in need of effective therapies with limited adverse effect profiles[1, 2]. Standard frontline therapy consists of high-dose methotrexate (HD-MTX) with autologous stem cell transplant as consolidation therapy. However, these regimens are not tolerated by all patients due to significant neurotoxicity[3]. Even then, about a third of patients are refractory to first-line treatment, and up to 60% of the patients will eventually relapse[4]. Prognosis for patients who are refractory to or relapse after initial therapy is poor, with median survival of only about 1-year failure of upfront therapy[5]. Due to poor long term outcomes, there is a desperate need for improved diagnostic and therapeutic modalities. A considerable hurdle in conducting clinical trials to improve outcomes is the lack of available biomarkers that can be used reliably to diagnose and monitor disease. As such, the diagnosis of PCNSL frequently requires neurosurgical biopsies that are invasive and associated with risk of infection, bleeding and neurological injury. Many patients initially undergo a lumbar puncture (LP) for cerebrospinal fluid (CSF) that is analyzed by cytology and flow cytometry. These approaches, however, lack sensitivity, require large quantities (> 10 mL) of CSF, and are non-diagnostic in many cases. Contrast-enhanced MRI, the gold-standard test of disease monitoring, furthermore, cannot detect early recurrence or minimal residual disease (MRD) leading to an inability to detect chemo-resistance, complete remission, or recurrence. There exists an unmet need not only for better treatment options for patients with PCNSL, but also for biological biomarkers to aid in diagnosis and monitoring of therapeutic response. Such biomarkers would be of incredible importance in planning and executing future clinical trials in PCNSL and related diseases. Recently, several targeted therapies, including Bruton tyrosine kinase inhibitors (e.g., ibrutinib) as well as immunomodulatory agents (e.g., lenalidomide) have shown to dramatically decrease recurrence rate [6-9]. The molecular basis for treatment resistance to these novel targeted agents in PCNSL is largely unknown, uncharacterized and a critical area of translational research. Safe-SeqS and Real-SeqS, technologies that provide an opportunity to detect and quantify tumor DNA in CSF (CSF-tDNA), provide an opportunity to better characterize CNS disease. In this proposal, we aim to develop robust Safe-SeqS and Real-SeqS assays for detection of tumor-derived circulating free DNA (cf-tDNA) which will improve our ability to diagnose and genotype PCNSL, to longitudinally monitor disease status, and to perform whole-exome sequencing (WES) to identify molecular characteristics that can identify patients for targeted therapies based on genomic signatures of response. The knowledge gained from the completion of the proposed Aims would enable the development of cf-tDNA as the first biomarker in PNCSL, a much needed advance for a devastating malignancy.

项目概要 原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见的侵袭性结外非霍奇金淋巴瘤 涉及中枢神经系统 (CNS)，但没有全身性疾病。大约有 1400 例 PCNSL 病例 在美国每年都会被诊断出来，通常发生在 45 岁至 65 岁之间，但发病率在 老年患者是需要有效治疗且不良反应有限的人群[1, 2]。标准 一线治疗包括大剂量甲氨蝶呤 (HD-MTX) 和自体干细胞移植作为巩固 治疗。然而，由于显着的神经毒性，并非所有患者都能耐受这些治疗方案[3]。即便如此，大约 三分之一的患者对一线治疗耐药，高达 60% 的患者最终会复发[4]。预后 初次治疗后难治或复发的患者效果较差，中位生存期仅为 1 年左右 前期治疗[5]。由于长期结果不佳，迫切需要改进诊断和治疗 方式。进行临床试验以改善结果的一个相当大的障碍是缺乏可用的生物标志物 可可靠地用于诊断和监测疾病。因此，PCNSL 的诊断通常需要神经外科手术 活检是侵入性的，与感染、出血和神经​​损伤的风险有关。很多患者一开始 进行腰椎穿刺（LP）以获取脑脊液（CSF），并通过细胞学和流式细胞术进行分析。这些 然而，这些方法缺乏敏感性，需要大量（> 10 mL）脑脊液，并且在许多情况下无法诊断。 此外，对比增强 MRI 是疾病监测的金标准测试，无法检测早期复发或 微小残留病 (MRD) 导致无法检测化疗耐药、完全缓解或复发。那里 不仅对 PCNSL 患者有更好的治疗选择，而且对生物标志物的需求也未得到满足。 帮助诊断和监测治疗反应。这些生物标志物在规划中具有极其重要的意义 并执行未来 PCNSL 及相关疾病的临床试验。 最近，几种靶向疗法，包括布鲁顿酪氨酸激酶抑制剂（例如依鲁替尼）以及 免疫调节剂（例如来那度胺）已被证明可以显着降低复发率[6-9]。分子 PCNSL 对这些新型靶向药物的治疗耐药性的基础在很大程度上是未知的、未表征的并且是一个关键的 转化研究领域。 Safe-SeqS 和 Real-SeqS，提供检测和量化机会的技术 CSF 中的肿瘤 DNA (CSF-tDNA) 为更好地表征 CNS 疾病提供了机会。在本提案中，我们的目标是 开发强大的 Safe-SeqS 和 Real-SeqS 检测方法来检测肿瘤来源的循环游离 DNA (cf-tDNA)，这将 提高我们诊断 PCNSL 和进行基因分型、纵向监测疾病状态以及进行全外显子组分析的能力 测序 (WES) 来识别分子特征，从而根据基因组识别患者进行靶向治疗 回复签名。从完成拟议目标中获得的知识将有助于开发 cf-tDNA 作为 PNCSL 的第一个生物标志物，这是毁灭性恶性肿瘤急需的进步。