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:
- 金额:$ 24.45万
- 依托单位:
- 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:
- 关键词:AddressAdvisory CommitteesAffectAmino AcidsAntineoplastic AgentsApoptosisApoptoticB Cell ProliferationB lymphoid malignancyB-Cell LymphomasBCL2 geneBindingBiologicalBreastCancerousCareer MobilityCell LineCell NucleusCell SurvivalCell physiologyCellsCharacteristicsChronic Lymphocytic LeukemiaClinicalCodeCytoplasmDataDevelopmentDevelopment PlansEnsureEnvironmentEvaluationFundingGene ExpressionGenerationsGenesGenetic DiseasesGenetic ModelsGenetically Engineered MouseGenomicsGlutamic AcidGoalsHead and Neck Squamous Cell CarcinomaHematologic NeoplasmsHematopoiesisHeterozygoteHodgkin DiseaseHomeostasisHospitalsImmunofluorescence ImmunologicIn VitroKnock-in MouseLaboratoriesLeadLearningLifeLungLysineMalignant - descriptorMalignant NeoplasmsMalignant lymphoid neoplasmMature B-LymphocyteMeasuresMediastinalMedicineMemorial Sloan-Kettering Cancer CenterMentorsMessenger RNAMitotic Cell CycleMolecularMutationNF-kappa BNamesNatureNuclearNuclear ExportOncogenicPathway interactionsPatientsPhase I/II Clinical TrialPoint MutationPre-Clinical ModelProcessProliferatingProtein Export PathwayProteinsRNARNA SplicingRecurrenceRegulationReporterResearchResearch Project GrantsRibosomal RNARoleServicesSignal TransductionSmall Nuclear RNASolidSolid NeoplasmSomatic MutationStrategic PlanningStudy modelsTRAF2 geneTestingThe Cancer Genome AtlasTrainingTranslationsWestern BlottingWorkcancer subtypescancer typecarcinogenesiscareer developmentcell transformationearly phase clinical trialexportin 1 proteinfunctional genomicsgain of functiongain of function mutationhuman tissueimprovedin vivoinhibitorinsightinstructorknowledge baseleukemiamouse modelmutantnovelnucleocytoplasmic transportoverexpressionprecision medicineprognosticationprogramsresponsetargeted treatmenttherapeutic targettooltranslational 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:
- 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:
- 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:
- 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:
- 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).
- DOI:10.3390/genes14122182
- 发表时间:2023-12-06
- 期刊:
- 影响因子:3.5
- 作者:
- 通讯作者:
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Justin Taylor其他文献
Justin Taylor的其他文献
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{{ truncateString('Justin Taylor', 18)}}的其他基金
The role of XPO1 in nuclear export of RNA
XPO1 在 RNA 核输出中的作用
- 批准号:
10714250 - 财政年份:2023
- 资助金额:
$ 24.45万 - 项目类别:
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:
10146153 - 财政年份:2018
- 资助金额:
$ 24.45万 - 项目类别:
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:
10333411 - 财政年份:2018
- 资助金额:
$ 24.45万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 24.45万 - 项目类别:
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