Molecular Pathogenesis and Therapy of Systemic Histiocytic Neoplasms

项目摘要 组织细胞肿瘤是单核细胞/巨噬细胞谱系的克隆性疾病，包括朗格汉斯细胞 组织细胞增多症（LCH）、Erdheim-Chester病（ECD）、幼年黄色肉芽肿（JXG）和Rosai-Dorfman 疾病（RDD）。虽然组织细胞病的发病机制以前不清楚，但现在已知， 几乎所有患有这些疾病的患者都有激活MAP激酶（MAPK）信号传导的突变，包括 50%的LCH和ECD病例中存在BRAFV 600 E突变。BRAF抑制对那些患有以下疾病的患者有效： BRAFV 600 E突变型疾病和我们的临床试验导致FDA批准维罗非尼用于BRAFV 600 E突变型ECD 2017年这项研究的相关分析表明，突变型细胞游离DNA的等位基因负荷在 血浆是BRAFV 600 E突变型组织细胞增多症治疗反应的动态和可靠的生物标志物。- 初步数据：最近，在激酶信号传导组分中发现了广泛的基因组改变， 在BRAFV 600 E-野生型（WT）组织细胞肿瘤中得到证实。MEK 1/2和ARAF中的各种突变是 最常见，占BRAFV 600 WT病例的>50%。BRAFV 600-WT组织细胞增多症患者 在2期临床试验（NCT 02649972）和临床实践中， Tice。知识差距：与BRAF抑制BRAFV 600 E突变组织的几乎普遍活性相反， BRAFV 600-WT组织细胞增多症患者对MEK抑制的反应表现出异质性， 其依据仍然未知。此外，组织中MAPK通路组分的许多改变， 胞质酶还没有功能上的特征。本研究的假设是肿瘤细胞内在的基因， 在组织细胞增多症中，遗传学改变与对MEK抑制的反应相关。这一假设将由以下人员进行检验： 在我们的BRAFV 600-WT组织细胞增生症患者队列中评估对MEK抑制的治疗反应， 不同的MAPK途径突变，并与创新的基因组分析血浆细胞游离DNA，以确定 反应的生物标志物。纪念斯隆凯特琳癌症中心是美国领先的转诊中心， 组织细胞增多症的成年人，使其非常适合进行这项工作。与此同时，机械和治疗- MEK 1/2和ARAF突变的潜在意义（这两个基因代表了人类中最常见的突变基因， BRAFV 600-WT患者）。尽管ARAF和MEK 1/2突变在许多疾病中反复发生， 癌症，这些突变在组织细胞病中的独特富集提供了一个机会， ARAF和MEK 1/2调节MAPK信号传导和驱动癌症的机制。影响：这个亲- 本课题将提高我们对组织细胞增生症发病机制，MAPK通路激活机制， 和对MEK抑制反应的决定因素。目的1：表征以下药物的临床和分子反应： 前瞻性治疗患者队列中的组织细胞增多症至MEK抑制，包括正在进行的II期临床试验 审判目标2.了解MEK 1/2和ARAF突变的生化影响和治疗意义 在组织细胞病患者中。

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.