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.

项目总结/摘要 研究：毛细胞白血病（HCL）和系统性组织细胞病（SH）是唯一的， 造血系统恶性肿瘤，因为它们都在BRAFV 600 E和 MAP2K1.虽然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，并且疑似具有不同的谱系衍生。然而，精确 其发病机制差异的生物学基础知之甚少。此外，分子 非BRAFV 600 E突变变体HCL（vHCL）和SH对 促分裂原活化蛋白激酶（MAPK）途径抑制剂也未定义。最后，基因 最近在临床上描述的经典HCL（cHCL）患者中RAF抑制剂耐药的机制是 未知因此，本项目的主要目标是确定BRAFV 600 E、MAP 2K 1和其他 激酶的改变有助于不同的造血疾病的发病机制， 他们对MAPK通路抑制剂的临床反应。本提案将利用银行HCL和SH 患者样本和几种新开发的体外和体内小鼠模型来实现这一目标。我们 希望这些研究能为理解遗传相关性疾病的发病机制建立一个范例。 由于遗传和发育生物学的结合而在同一组织系统中出现的疾病 的观点，以及提供新的生物学和治疗的见解MAPK驱动的 造血系统肿瘤候选人：本杰明达勒姆博士是一名血液病理学家和分子遗传学家 病理学家，他目前在病理学系担任基因组病理学研究员， MSKCC。他的目标是成为一个独立的，终身的医生，科学家研究分子 通过基因组学、功能基因组学和 小鼠模型。达勒姆博士概述了一个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建模。该培训期将在林博士的指导下进行。 Omar Abdel-Wahab，造血系统恶性肿瘤功能基因组学的新兴领导者， 罗森是MAPK和PI 3 K-AKT信号转导方面的专家。达勒姆医生还组建了一个顾问委员会 由Charles Sawyers、James Fagin、Frédéric Geissmann、Marc Ladanyi和Christopher Park博士组成 指导他的训练和研究环境：MSKCC是世界上最古老，最大的私人 癌症中心，致力于超过130年的特殊病人护理，创新研究， 优秀的教育项目。MSKCC让学员接触到一个非常强大的学术 研究环境与强大的承诺和成功支持初级教师的跟踪记录 他们正在寻求独立的医学科学家的职业生涯。

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