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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

基本信息

批准号：
10560537
负责人：
Justin Taylor
金额：
$ 24.45万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10560537
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 Heterozygote 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 Proliferating 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 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 insight instructor knowledge base leukemia mouse model mutant novel nucleocytoplasmic transport overexpression precision medicine prognostication programs response targeted treatment therapeutic target tool translational study

项目摘要

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·泰勒是纪念斯隆·凯特琳癌症中心的医学讲师

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Therapy-selected clonal hematopoiesis and its role in myeloid neoplasms.

DOI：
10.1016/j.leukres.2023.107020
发表时间：
2023-01
期刊：
Leukemia research
影响因子：
2.7
作者：
J. Jahn;B. Diamond;J. Hsu;S. Montoya;T. Totiger;O. Landgren;F. Maura;Justin Taylor
通讯作者：
J. Jahn;B. Diamond;J. Hsu;S. Montoya;T. Totiger;O. Landgren;F. Maura;Justin Taylor

Treatment of Richter Transformation of Chronic Lymphocytic Leukemia in the Modern Era.

DOI：
10.3390/cancers15061857
发表时间：
2023-03-20
期刊：
Cancers
影响因子：
5.2
作者：
通讯作者：

Targeted Therapy Development in Acute Myeloid Leukemia.

DOI：
10.3390/biomedicines11020641
发表时间：
2023-02-20
期刊：
Biomedicines
影响因子：
4.7
作者：
通讯作者：

CD33 splice site genotype was not associated with outcomes of patients receiving the anti-CD33 drug conjugate SGN-CD33A.

CD33 剪接位点基因型与接受抗 CD33 药物缀合物 SGN-CD33A 的患者的结果无关。

DOI：
10.1186/s13045-019-0771-0
发表时间：
2019
期刊：
Journal of hematology & oncology
影响因子：
28.5
作者：
Stanchina,Michele;Pastore,Alessandro;Devlin,Sean;Famulare,Christopher;Stein,Eytan;Taylor,Justin
通讯作者：
Taylor,Justin

Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).