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: 10380788
• 负责人: Eli Lous Diamond
• 金额: $ 55.4万
• 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/10380788
• 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; 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.

项目总结