Defining the Biological and Mechanistic Implications of XPO1 Mutations in Hematologic Malignancies

定义 XPO1 突变在血液系统恶性肿瘤中的生物学和机制意义

• 批准号: 10245306
• 负责人: Justin Taylor
• 金额: $ 21.31万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245306
• 关键词: Address; Advisory Committees; Affect; Amino Acids; Antineoplastic Agents; Apoptosis; Apoptotic; B Cell Proliferation; B lymphoid malignancy; B-Cell Lymphomas; BCL2 gene; Binding; Biological; Breast; Cancerous; Career Mobility; Cell Line; Cell Nucleus; Cell Survival; Cell physiology; Cells; Characteristics; Chronic Lymphocytic Leukemia; Clinical; Code; Cytoplasm; Data; Development; Development Plans; Ensure; Environment; Evaluation; Funding; Gene Expression; Generations; Genes; Genetic Diseases; Genetic Models; Genetically Engineered Mouse; Genomics; Glutamic Acid; Goals; Head and Neck Squamous Cell Carcinoma; Hematologic Neoplasms; Hematopoiesis; Hodgkin Disease; Homeostasis; Hospitals; Immunofluorescence Immunologic; In Vitro; Knock-in Mouse; Laboratories; Lead; Learning; Life; Lung; Lysine; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mature B-Lymphocyte; Measures; Mediastinal; Medicine; Memorial Sloan-Kettering Cancer Center; Mentors; Messenger RNA; Mitotic Cell Cycle; Molecular; Mutation; NF-kappa B; Names; Nature; Nuclear; Nuclear Export; Oncogenic; Pathway interactions; Patients; Phase I/II Clinical Trial; Point Mutation; Pre-Clinical Model; Process; Protein Export Pathway; Proteins; RNA; RNA Splicing; Recurrence; Regulation; Reporter; Research; Research Project Grants; Ribosomal RNA; Role; Services; Signal Transduction; Small Nuclear RNA; Solid; Solid Neoplasm; Somatic Mutation; Strategic Planning; Study models; TRAF2 gene; Testing; The Cancer Genome Atlas; Training; Translations; Western Blotting; Work; cancer genetics; cancer subtypes; cancer type; carcinogenesis; career development; cell transformation; early phase clinical trial; exportin 1 protein; functional genomics; gain of function; gain of function mutation; human tissue; improved; in vivo; inhibitor/antagonist; insight; instructor; knowledge base; leukemia; mouse model; mutant; novel; nucleocytoplasmic transport; overexpression; precision medicine; prognostic; programs; response; targeted treatment; therapeutic target; tool; translational study

Candidate: Justin Taylor is an Instructor in Medicine at Memorial Sloan Kettering Cancer Center and Attending on the Leukemia Service at Memorial Hospital. He has been working with his proposed K08 mentor, Dr. Omar Abdel-Wahab, to learn about targeting splicing factor mutant leukemias in translational preclinical models and now has begun independent work to discover the role of XPO1 hotspot mutations in hematologic malignancies as a potential therapeutic target. His goal is to develop an independent research program over the next 5 years and have an independent laboratory doing translational hematologic malignancies research. Career Development Plan: Dr. Taylor has strategically planned to address the necessary training and mentoring that will be required for his successful career transition to independence over the next few years through select coursework and a robust mentoring plan. He has also organized an advisory committee composed not only of leaders in the field but also those able to directly impact his career advancement. This will not only ensure that Dr. Taylor's research project progresses as planned, but also that his progress is recognized by promotion and support in garnering independent research funding. He has a very exciting research project that is sufficiently different from his mentor's research to avoid competition or overlap. Research Plan: Large discovery sequencing projects of cancer sub-types, such as The Cancer Genome Atlas, have identified a multitude of novel recurrent mutations in protein coding genes. The ultimate goal of these sequencing efforts is to lead to improved therapies for patients with cancer and will require understanding how these mutations mechanistically contribute to carcinogenesis. However, even when the function of a gene is known, the biological effect of the mutation cannot always be inferred from the coding sequence. In this proposal, we plan to discover the biological relevance of somatic mutations in the nuclear transport protein XPO1. Somatic mutations in XPO1 have been demonstrated in solid and hematologic malignancies, including ~10% of cases of chronic lymphocytic leukemia and 25% of cases of primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. Selective inhibition of nuclear export by inhibiting XPO1 has been utilized as an antineoplastic agent in current Phase I/II clinical trials. Yet, despite recognition of XPO1 as a potential driver of cancer, there has been no direct demonstration of the oncogenic potential of somatic mutations in XPO1. We plan to explore the effects of these mutations by using isogenic cell lines, genetically engineered mouse models and human tissues. Furthermore, since XPO1 is a nuclear exporter, we will study the effect of these genetic alterations on protein subcellular localization. Lastly, we aim to determine the effects of XPO1 mutations on response to XPO1 inhibitors currently in development. The end goal of this research will be to discover the biological and mechanistic implications of XPO1 mutations in order to develop rational and informed targeted therapies to treat these cancers for which there is still clinical need.

候选人：贾斯汀·泰勒（Justin Taylor）是纪念斯隆·克特林癌症中心医学的教练 参加纪念医院的白血病服务。他一直在与提议的K08导师合作， Omar Abdel-Wahab博士，了解靶向剪接因子突变体白血病 现在已经开始独立工作，以发现XPO1热点突变在血液学中的作用 恶性肿瘤是潜在的治疗靶点。他的目标是制定一个独立的研究计划 接下来的5年，并拥有一个独立的实验室进行翻译血液学恶性研究。 职业发展计划：泰勒博士已战略计划解决必要的培训和 在未来几年内成功过渡到独立的事业过渡将需要指导 通过选择课程和强大的指导计划。他还组织了一个咨询委员会 不仅由该领域的领导人组成，而且由能够直接影响他职业发展的人组成。这 不仅将确保泰勒博士的研究项目按计划进行，而且他的进步是 通过获得独立研究资金的晋升和支持认可。他非常令人兴奋 研究项目与他的导师的研究完全不同，以避免竞争或重叠。 研究计划：癌症亚型的大发现测序项目，例如癌症基因组 地图集已经鉴定出蛋白质编码基因中的许多新型复发突变。最终目标 这些测序努力是为癌症患者改善疗法，并需要 了解这些突变如何机械上有助于致癌。但是，即使 已知基因的功能，突变的生物学效应不能总是从编码中推断出来 顺序。在该提议中，我们计划发现核突变的生物学相关性 转运蛋白XPO1。 XPO1中的体细胞突变已在固体和血液学中得到证明 恶性肿瘤，包括约10％的慢性淋巴细胞性白血病病例和25％的原发性病例 纵隔B细胞淋巴瘤和经典霍奇金淋巴瘤。选择性抑制核出口 在当前I/II期临床试验中，抑制XPO1已被用作抗肿瘤剂。但是，尽管如此 识别XPO1是癌症的潜在驱动力，没有直接证明致癌性 XPO1中体突变的潜力。我们计划通过使用同源性探索这些突变的影响 细胞系，基因工程的小鼠模型和人体组织。此外，由于XPO1是核 出口商，我们将研究这些遗传改变对蛋白质亚细胞定位的影响。最后，我们的目标 确定XPO1突变对当前正在开发的XPO1抑制剂反应的影响。结尾 这项研究的目标是发现XPO1突变的生物学和机械含义 开发理性且知情的有针对性疗法来治疗这些仍然需要临床需求的癌症。