Cellular Origins, Molecular Pathogenesis, and Novel Therapeutic Strategies for MAP Kinase-Driven Hematological Malignancies

MAP 激酶驱动的血液恶性肿瘤的细胞起源、分子发病机制和新治疗策略

• 批准号: 10357896
• 负责人: Benjamin Heath Durham
• 金额: $ 20.87万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-13 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357896
• 关键词: Advisory Committees; Affect; Aftercare; BRAF gene; Behavior; Biological; Biological Assay; Biological Response Modifier Therapy; CD34 gene; Cancer Center; Cells; Clinical; Clinical Trials; Derivation procedure; Development; Developmental Biology; Disease; Disease model; Environment; Epithelial; Event; Exhibits; Faculty; Frequencies; Gene Mutation; Genetic; Genetic Transcription; Genomics; Goals; Hairy Cell Leukemia; Hairy Cell Leukemia Variant; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; In Vitro; Lesion; MAP2K1 gene; Malignant Neoplasms; Maps; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Mitogen-Activated Protein Kinases; Molecular; Molecular Genetics; Mus; Mutate; Mutation; Nature; Neoplasms; Oncogenic; Pathogenesis; Pathogenicity; Pathologic; Pathologist; Pathology; Pathway interactions; Patient Care; Patients; Phase; Phase II Clinical Trials; Phenotype; Phosphotransferases; Physicians; Population; Pre-Clinical Model; Privatization; Proto-Oncogene Proteins c-akt; Relapse; Reporting; Research; Research Proposals; Resistance; Resistance development; Role; Sampling; Scientist; Series; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Tissues; Training; Treatment Efficacy; Variant; Work; Xenograft Model; Xenograft procedure; career; disease phenotype; effective therapy; functional genomics; histiocyte; in vivo; inhibitor; inhibitor therapy; innovation; insight; kinase inhibitor; member; mouse model; mutant; novel therapeutic intervention; patient subsets; programs; response; skills; small molecule; targeted treatment; tenure track; therapeutic evaluation

PROJECT SUMMARY/ABSTRACT Research: Hairy cell leukemia (HCL) and the systemic histiocytoses (SH) are unique amongst hematopoietic malignancies in that they both harbor a high frequency of mutations in BRAFV600E and MAP2K1. Although these disorders share common molecular alterations, HCL and the SH have very distinct clinical behavior and are suspected to have different lineage derivations. However, the precise biological basis for the differences in their pathogenesis is poorly understood. In addition, the molecular pathogenesis and therapeutic responsiveness of non-BRAFV600E-mutated variant HCL (vHCL) and SH to mitogen activated protein kinase (MAPK) pathway inhibitors are also undefined. Finally, the genetic mechanisms for RAF inhibitor resistance recently described clinically in classic HCL (cHCL) patients are unknown. Thus, the primary goal of this project is to determine how BRAFV600E, MAP2K1, and other kinase alterations contribute to the pathogenesis of distinct hematopoietic disorders and affect their clinical responses to MAPK pathway inhibitors. This proposal will utilize banked HCL and SH patient samples and several newly developed in vitro and in vivo murine models to pursue this goal. We expect these studies to establish a paradigm for understanding the pathogenesis of genetically related disorders arising in the same tissue system by incorporating both genetic and developmental biology perspectives, as well as providing new biological and therapeutic insights into MAPK-driven hematopoietic neoplasms. Candidate: Dr. Benjamin Durham is a hematopathologist and molecular genetic pathologist who currently serves as a Genomic Pathology Research Fellow in the Department of Pathology at MSKCC. He aims to become an independent, tenure-track physician-scientist investigating the molecular pathogenesis of hematological malignancies through a combination of genomics, functional genomics, and murine modeling. Dr. Durham has outlined a five-year period of mentored training to strengthen his skills in functional genomics and disease modeling. This training period will be carried out under the mentorship of Dr. Omar Abdel-Wahab, a rising leader in the functional genomics of hematopoietic malignancies and Dr. Neal Rosen, an expert in MAPK and PI3K-AKT signaling. Dr. Durham has also assembled an advisory committee composed of Drs. Charles Sawyers, James Fagin, Frédéric Geissmann, Marc Ladanyi, and Christopher Park who will help guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.

项目概要/摘要 研究：毛细胞白血病 (HCL) 和系统性组织细胞增多症 (SH) 在 造血系统恶性肿瘤，因为它们都含有 BRAFV600E 和 BRAFV600E 的高频率突变 MAP2K1。尽管这些疾病有共同的分子改变，但 HCL 和 SH 具有非常大的差异。 不同的临床行为，并被怀疑具有不同的谱系衍生。然而，准确的 其发病机制差异的生物学基础尚不清楚。此外，分子 非 BRAFV600E 突变变体 HCL (vHCL) 和 SH 的发病机制和治疗反应 丝裂原激活蛋白激酶 (MAPK) 通路抑制剂也未定义。最后，遗传 最近在临床上描述的经典 HCL (cHCL) 患者的 RAF 抑制剂耐药机制是 未知。因此，该项目的主要目标是确定 BRAFV600E、MAP2K1 和其他 激酶改变有助于不同造血系统疾病的发病机制并影响 他们对 MAPK 通路抑制剂的临床反应。该提案将利用银行 HCL 和 SH 患者样本和几个新开发的体外和体内小鼠模型来实现这一目标。我们 期望这些研究能够建立一个范例来理解遗传相关的发病机制 通过结合遗传和发育生物学在同一组织系统中产生的疾病 观点，以及为 MAPK 驱动提供新的生物学和治疗见解 造血系统肿瘤。候选人：Benjamin Durham 博士是一名血液病理学家和分子遗传学家 病理学家，目前担任病理学系基因组病理学研究员 MSKCC。他的目标是成为一名独立的终身教授医师科学家，研究分子生物学 通过基因组学、功能基因组学的结合，研究血液恶性肿瘤的发病机制 小鼠模型。达勒姆博士概述了为期五年的指导培训，以加强他的技能 功能基因组学和疾病模型。本次培训将在博士的指导下进行。 Omar Abdel-Wahab，造血系统恶性肿瘤功能基因组学领域的新锐领导者和 Neal 博士 Rosen，MAPK 和 PI3K-AKT 信号传导专家。达勒姆博士还组建了一个咨询委员会 由博士组成。查尔斯·索耶斯、詹姆斯·费金、弗雷德里克·盖斯曼、马克·拉达尼和克里斯托弗·帕克 谁将帮助指导他的培训和研究。环境：MSKCC是世界上历史最悠久、规模最大的私立 癌症中心，130 多年来致力于卓越的患者护理、创新研究和 优秀的教育计划。 MSKCC 让学员接触到异常强大的学术知识 研究环境具有坚定的承诺和成功支持初级教师的记录 他们正在寻求作为独立医师科学家的职业。

项目成果

MAP-Kinase-Driven Hematopoietic Neoplasms: A Decade of Progress in the Molecular Age.

• DOI: 10.1101/cshperspect.a034892
• 发表时间: 2021-05-03
• 期刊: Cold Spring Harbor perspectives in medicine
• 影响因子: 5.4
• 作者: Chakraborty R;Abdel-Wahab O;Durham BH
• 通讯作者: Durham BH