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.

项目摘要 原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见且具有侵略性的非疾病外霍奇金淋巴瘤 这涉及中枢神经系统（CNS）没有全身性疾病。大约1400例PCNSL是 每年在美国诊断，经典地发生在45至65岁之间，但发病率上升 代表需要有效疗法的人群的老年患者具有有限的不良反应谱[1，2]。标准 前线疗法由自体干细胞移植作为巩固的高剂量甲氨蝶呤（HD-MTX）组成 治疗。但是，由于明显的神经毒性，所有患者均未耐受这些方案[3]。即使那样，大约 三分之一的患者对一线治疗难治性，多达60％的患者最终会复发[4]。预后 初始治疗后难治或复发的患者较差，中位生存率仅为1年。 前期治疗[5]。由于长期结局不佳，迫切需要改善诊断和治疗性 方式。进行临床试验以改善预后的一个巨大障碍是缺乏可用的生物标志物 可靠地用于诊断和监测疾病。因此，PCNSL的诊断经常需要神经外科 具有侵入性且与感染风险，出血和神经​​系统损伤有关的活检。最初许多患者 通过细胞学和流式细胞仪分析的脑脊液（CSF）进行腰椎穿刺（LP）。这些 但是，方法缺乏灵敏度，需要大量的CSF（> 10 mL），并且在许多情况下是非诊断的。 对比增强的MRI，疾病监测的金标准测试，此外，无法检测到早期复发或 最小残留疾病（MRD）导致无法检测化学抗性，完全缓解或复发。那里 不仅需要为PCNSL患者提供更好的治疗选择，而且还需要生物生物标志物的更好的治疗选择 有助于诊断和监测治疗反应。这种生物标志物在计划中将非常重要 并在PCNSL和相关疾病中执行未来的临床试验。 最近，几种有针对性的疗法，包括布鲁顿酪氨酸激酶抑制剂（例如ibrutinib）以及 免疫调节剂（例如，列纳莱度胺）已显示出大幅降低复发率[6-9]。分子 对PCNSL中这些新型靶向剂的治疗耐药性的基础在很大程度上未知，未表征和关键 转化研究领域。安全性和实季，提供机会来检测和量化的技术 CSF（CSF-TDNA）中的肿瘤DNA为更好地表征CNS疾病提供了机会。在此提案中，我们的目标是 开发可靠的安全性和实性测定法，以检测肿瘤来源的循环自由DNA（CF-TDNA） 提高我们诊断和基因型PCNSL的能力，纵向监测疾病状态并执行全身疾病状态 测序（WES）以鉴定可以基于基因组鉴定靶向疗法的患者的分子特征 响应的签名。从提议的目标完成后获得的知识将使能够发展 CF-TDNA是PNCSL中的第一个生物标志物，这是毁灭性恶性肿瘤的急需进步。