Molecular Pathogenesis and Therapy of Systemic Histiocytic Neoplasms

项目摘要 组织细胞肿瘤是包括朗格汉斯细胞在内的单核/巨噬细胞系的克隆性疾病 组织细胞增生症(LCH)、埃尔德海姆-切斯特病(ECD)、幼年黄色肉芽肿(JXG)和罗赛多夫曼(Rosai-Dorfman) 疾病(RDD)。尽管组织细胞增多症的发病机制以前并不清楚，但现在已经知道 几乎每个患有这些疾病的患者都有一个突变激活的MAPK信号，包括 50%的LCH和ECD患者存在BRAFV600E突变。抑制BRAF对以下患者有效 BRAFV600E突变疾病和我们的临床试验导致FDA批准维莫拉非尼用于BRAFV600E突变ECD 2017年。本研究的相关分析表明，突变的无细胞DNA的等位基因负担 血浆是BRAFV600E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。初审- 医学数据：最近，发现了一系列激酶信号成分的基因组变化。 在BRAFV600E-野生型(WT)组织细胞肿瘤中。MEK1/2和ARAF的不同突变是 最常见，占BRAFV600例WT病例的50%。BRAFV600-WT组织细胞增多症患者 在2期临床试验(NCT02649972)和临床实践中也使用MEK抑制治疗 蒂斯。知识鸿沟：与BRAF对BRAV600E突变体Histio-Go的几乎普遍的抑制活性相比， 细胞增多症，BRAFV600-WT组织细胞增多症患者对MEK抑制的反应不同， 其依据尚不清楚。此外，Histio-MAPK通路的许多成分发生了变化。 细胞质的功能特征还没有确定。这项研究的假设是肿瘤细胞固有的Ge-Ge-1。 磁性改变与组织细胞增多症中MEK抑制的反应有关。这一假设将通过以下方式检验 评估我们队列中BRAFV600-WT组织细胞增多症患者对MEK抑制的疗效 不同的MAPK途径突变，并用创新的基因组分析浆细胞无DNA来鉴定 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癌症转介中心 患有组织细胞增多症的成年人--使其非常适合进行这项工作。同时，机械论和哲学论-- MEK1/2和ARAF(代表人类最常见的突变基因)突变的临床意义 BRAFV600-WT患者)将接受调查。尽管ARAF和MEK1/2突变在许多 在癌症中，这些突变在组织细胞中的独特富集性为在功能上分化提供了机会。 ARAF和MEK1/2调节MAPK信号和驱动癌症的部分机制。影响：这一亲- 这将加深我们对组织细胞增多症的发病机制，MAPK通路激活机制， 以及对MEK抑制反应的决定因素。目的1：描述临床和分子反应的特征 前瞻性治疗患者队列中的组织细胞增多症对MEK抑制的影响，包括正在进行的2期临床研究 审判。目的2.了解MEK1/2和ARAF突变对生化的影响和治疗意义 在患有组织细胞增多症的患者中。

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.