Molecular Pathogenesis and Therapy of Systemic Histiocytic Neoplasms

系统性组织细胞肿瘤的分子发病机制和治疗

• 批准号: 10185665
• 负责人: Eli Lous Diamond
• 金额: $ 55.1万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185665
• 关键词: Accounting; Adolescent; Adult; Alleles; BRAF gene; Biochemical; Biological; Biological Markers; Cells; Clinical; Clinical Trials; Collection; DNA Sequence Alteration; Data; Dependence; Disease; Eosinophilic Granuloma; Erdheim-Chester Disease; Exhibits; Feedback; Genes; Genomics; Grant; Heterogeneity; Histiocytosis; Hot Spot; Individual; Knowledge; MAP kinase activator; MAP2K1 gene; MEK inhibition; MEKs; Malignant Neoplasms; Measures; Medical Genetics; Medical center; Memorial Sloan-Kettering Cancer Center; Mitogen-Activated Protein Kinases; Molecular; Mutate; Mutation; Neoplasms; Pathogenesis; Pathway interactions; Patients; Phase II Clinical Trials; Phosphotransferases; Plasma; Plasma Cells; Property; Protein Isoforms; Publishing; RAS inhibition; Recurrence; Sampling; Signal Transduction; Sinus histiocytosis; Systemic Therapy; Testing; Therapeutic; Therapy trial; Time; United States; Work; base; biomedical referral center; cell free DNA; clinical practice; cohort; falls; gain of function; histiocyte; improved; inhibitor/antagonist; innovation; lipogranulomatosis; macrophage; man; monocyte; mutant; neoplastic cell; prospective; raf Kinases; rare cancer; resistance frequency; response; response biomarker; treatment response

Project Summary Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage that include Langerhans Cell Histiocytosis (LCH), Erdheim-Chester Disease (ECD), Juvenile Xanthogranuloma (JXG), and Rosai-Dorfman Disease (RDD). Although the pathogenesis of histiocytoses was previously obscure, it is now known that nearly every patient with these disorders has a mutation activating MAP kinase (MAPK) signaling, including BRAFV600E mutations in 50% of LCH and ECD cases. BRAF inhibition is efficacious for those patients with BRAFV600E-mutant disease and our clinical trial led to FDA approval of vemurafenib for BRAFV600E-mutant ECD in 2017. Correlative analyses from this study revealed that the allelic burden of mutant cell-free DNA in the plasma is a dynamic and reliable biomarker of therapeutic response in BRAFV600E-mutant histiocytosis. Prelim- inary data: More recently, a wide spectrum of genomic alterations in kinase signalling components were iden- tified in BRAFV600E-wildtype (WT) histiocytic neoplasms. Diverse mutations in MEK1/2 and ARAF are among the most common, accounting for >50% of BRAFV600 WT cases. Patients with BRAFV600-WT histiocytosis have also been treated with MEK inhibition, both within a phase 2 clinical trial (NCT02649972) and in clinical prac- tice. Knowledge gap: In contrast to the near-universal activity of BRAF inhibition for BRAFV600E-mutant histio- cytosis, patients with BRAFV600-WT histiocytosis exhibit heterogeneity in their responses to MEK inhibition, the basis of which remains unknown. Moreoever, many alterations in components of the MAPK pathway in histio- cytoses have not been functionally characterized. The hypothesis of this study is that tumor cell-intrinsic ge- netic alterations correlate with response to MEK inhibition in histiocytosis. This hypothesis will be tested by evaluating therapeutic responses to MEK inhibition in our cohort of BRAFV600-WT histiocytosis patients with diverse MAPK pathway mutations, and with innovative genomic analysis of plasma cell-free DNA to identify biomarkers of response. Memorial Sloan Kettering Cancer Center is the leading referral center in the U.S. for adults with histiocytosis—making it ideally suited to conduct this work. In parallel, the mechanistic and thera- peutic implications of mutations in MEK1/2 and ARAF (which represent the most commonly mutated genes in BRAFV600-WT patients) will be investigated. Although ARAF and MEK1/2 mutations are recurrent across many cancers, the unique enrichment of these mutations in histiocytoses provides an opportunity to functionally dis- sect mechanisms by which ARAF and MEK1/2 regulate MAPK signalling and drive cancer. Impact: This pro- ject will improve our understanding of histiocytosis pathogenesis, mechanisms of MAPK pathway activation, and determinants of response to MEK inhibition. Aim 1: Characterize the clinical and molecular response of histiocytosis to MEK inhibition in a prospectively treated patient cohort, including an ongoing phase 2 clinical trial. Aim 2. Understand the biochemical impact and therapeutic implications of MEK1/2 and ARAF mutations in patients with histiocytoses.

项目摘要 组织细胞肿瘤是包含兰格汉斯细胞的单核细胞/巨噬细胞谱系的克隆疾病 组织细胞增多症（LCH），Erdheim-Chester疾病（ECD），青少年黄果瘤（JXG）和Rosai-Dorfman 疾病（RDD）。尽管组织细胞的发病机理以前是晦涩的，但现在众所周知 几乎每个患有这些疾病的患者都有一个突变激活地图激酶（MAPK）信号，包括 LCH和ECD病例的50％的BRAFV600E突变。 BRAF抑制作用对于那些患者 BRAFV600E突变疾病和我们的临床试验导致FDA批准Vemurafenib brafv600e Mutant ECD 2017年。这项研究的相关分析表明，无突变细胞DNA的等位基因燃烧 等离子体是BRAFV600E突变的组织细胞增多症中热反应的动态且可靠的生物标志物。序 INARY数据：最近，激酶信号传导成分中的广泛基因组改变是偶然的 在BRAFV600E WILDTYPE（WT）组织肿瘤中进行了细胞。 MEK1/2和ARAF中的各种突变是 最常见的是，占BRAFV600 WT案件的50％。 BRAFV600-WT组织细胞增多症患者患有 在第二阶段临床试验（NCT02649972）和临床prac-中，还接受了MEK抑制作用治疗 Tice。知识差距：与BRAF抑制BRAFV600E-突变的组织 - 细胞增生，BRAFV600-WT组织细胞增多症患者在对MEK抑制的反应中表现出异质性， 其基础仍然未知。更重要的是，在组织中，MAPK途径的成分发生了许多变化 尚未在功能上表征细胞。这项研究的假设是肿瘤细胞中性ge- 网络改变与对组织细胞增多症中MEK抑制作用的反应相关。该假设将通过 在我们的BRAFV600-WT组织细胞增多症患者中，评估对MEK抑制的治疗反应 多种MAPK途径突变，并通过对浆细胞DNA进行创新的基因组分析以鉴定 反应的生物标志物。纪念斯隆·克特林癌症中心是美国领先的转诊中心 患有组织细胞增多症的成年人 - 非常适合进行这项工作。同时，机械和thera- MEK1/2和ARAF中突变的同性含义（代表最常见的突变基因 将研究BRAFV600-WT患者）。虽然ARAF和MEK1/2突变在许多方面反复出现 癌症，组织细胞剂中这些突变的独特富集为在功能上解散的机会提供了机会 ARAF和MEK1/2调节MAPK信号传导并驱动癌症的教派机制。影响：这个亲 JECT将提高我们对组织细胞增多症发病机理的理解，MAPK途径激活的机制， 并确定对MEK抑制的反应。 AIM 1：表征的临床和分子反应 前瞻性治疗的患者队列中的组织细胞增多症对MEK抑制作用，包括持续的2期临床 审判。目标2。了解MEK1/2和ARAF突变的生化影响和治疗含义 在组织细胞剂的患者中。