Circulating biomarkers of ALK+ anaplastic large cell lymphoma

ALK 间变性大细胞淋巴瘤的循环生物标志物

• 批准号: 10470371
• 负责人: Megan S. Lim
• 金额: --
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2022-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470371
• 关键词: ALK gene; Accounting; Address; Autoantibodies; Biological Assay; Biological Markers; Biology; Blood; Child; Childhood; Childhood Lymphoma; Chromosome abnormality; Clinical; Clinical Trials; Detection; Development; Disease; Disease Progression; Early identification; Enrollment; Future; Genetic; Goals; Human; Immune response; Inflammatory Pseudotumor; Ki-1 Large-Cell Lymphoma; Lead; Lesion; Lymphoma; Malignant Neoplasms; Malignant neoplasm of lung; Mature T-Lymphocyte; Mediating; Methods; Modeling; Molecular; Monitor; Mutation; NPM1 gene; Neuroblastoma; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Patients; Pediatric Oncology Group; Plasma; Play; Population; Prognosis; Prognostic Marker; Prophase; Protein Tyrosine Kinase; Randomized; Receptor Protein-Tyrosine Kinases; Recurrence; Relapse; Research; Research Personnel; Residual Neoplasm; Residual Tumors; Resources; Risk; Role; Sampling; Subgroup; T-Cell Lymphoma; Therapeutic Agents; Time; Toxic effect; Transcript; anaplastic lymphoma kinase; base; chemotherapy; circulating biomarkers; cohort; crizotinib; digital; experience; high risk; minimally invasive; multidisciplinary; novel; novel therapeutics; peripheral blood; personalized diagnostics; phase 2 study; prognostic; prognostic significance; prognostic value; prognostication; relapse risk; response; specific biomarkers; t(2; 5)(p23; q35); targeted treatment; treatment response; tumorigenesis

Project Summary Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the ALK gene located on 5q35. Structural alterations including translocations, copy number gains and activating mutations targeting ALK occur in many types of human cancer, including lung cancer, non- Hodgkin lymphomas, Spitzoid melanocytic lesions, neuroblastoma and inflammatory myofibroblastic tumor. In over 80% of pediatric anaplastic large cell lymphoma (ALCL), the most common form of mature T cell lymphoma in this population, the chromosomal aberration t(2;5)(p23;q35) results in the expression of the constitutively active tyrosine kinase NPM-ALK. NPM-ALK positive lymphoma has served as a model for understanding ALK-mediated oncogenesis and development of targeted therapies, thus NPM-ALK related studies carry profound implications for the cancer field in general. Unfortunately, even with current intensive combined chemotherapy, approximately 30% of patients experiences disease progression or recurrence within two years of treatment. However, clinical or genetic factors that cause ALCL relapse are not known. Furthermore, prognostic biomarkers that can be easily obtained using non-invasive methods have not been clearly defined in patients receiving targeted therapies in ALCL. Our central hypothesis is that sensitive and specific quantitative assessment of circulating NPM-ALK transcript using digital droplet (dd)PCR in conjunction with plasma levels of ALK auto- antibody will serve as unique disease-specific biomarkers that will provide an opportunity for assessment of response to therapy and lead to prognostic biomarkers that may identify patients with high risk for relapse. Using plasma samples from uniformly treated patients enrolled in a Children's Oncology Group (COG) Phase II study of Brentuximab Vedotin and Crizotinib with newly diagnosed ALCL, we address our hypothesis through the following specific aims: 1) Determine the utility of ddPCR for minimal disease detection and disease monitoring in ALK+ ALCL, 2) Determine the prognostic utility of anti-ALK immune response in ALK+ ALCL 3) Investigate the prognostic significance of a multivariate model combining ddPCR and immune response to ALK in patients with ALK+ ALCL. The development of sensitive and precise assessment of minimal disseminated disease and/or minimal residual disease will play an important role in management of patients with ALK+ ALCL and facilitate decisions about discontinuation of treatment and identifying patients at risk of relapse/progression.

项目摘要 肿瘤淋巴瘤激酶（ALK）是由位于5q35上的ALK基因编码的受体酪氨酸激酶。 结构性改变，包括易位，拷贝数的收益和靶向ALK的激活突变 发生在许多类型的人类癌症中，包括肺癌，非霍奇金淋巴瘤，spitzoid 黑素细胞病变，神经母细胞瘤和炎症性肌纤维细胞肿瘤。超过80％的小儿 纳普斯大细胞淋巴瘤（ALCL），这是该人群中最常见的成熟T细胞淋巴瘤形式， 染色体畸变t（2; 5）（p23; q35）导致组成性活性酪氨酸的表达 激酶NPM-alk。 NPM-Alk阳性淋巴瘤已成为理解ALK介导的模型 靶向疗法的肿瘤发生和发展，因此NPM-Alk相关研究具有深刻的 一般来说，对癌症领域的影响。不幸的是，即使当前密集型 化学疗法，大约30％的患者经历了两种疾病的进展或复发 多年治疗。但是，尚不清楚引起ALCL复发的临床或遗传因素。 此外，可以轻松地使用非侵入性方法获得的预后生物标志物尚未 在接受ALCL的靶向疗法的患者中明确定义。我们的中心假设是敏感和 使用数字液滴（DD）PCR对循环NPM-ALK转录本进行特定的定量评估 与血浆水平的ALK自动抗体的结合将成为独特的特异性生物标志物 将为评估治疗的反应提供机会，并导致预后的生物标志物 可能识别出高复发风险的患者。使用统一治疗的患者的血浆样品 参加了Brentuximab vedotin和Crizotinib的儿童肿瘤学组（COG）II期研究 新诊断的ALCL，我们通过以下特定目的解决了我们的假设：1）确定 DDPCR在ALK+ ALCL中对最小疾病检测和疾病监测的效用，2）确定 抗Alk+ Alcl中抗ALM免疫反应的预后效用3）研究A的预后意义 ALK+ ALCL患者中DDPCR和对ALK的免疫反应组合的多元模型。这 开发对最小传播疾病和/或最小残留的敏感和精确评估 疾病将在ALK+ ALCL患者的管理中发挥重要作用，并促进有关 中断治疗并识别有复发/进展风险的患者。