Molecular understanding of leukemic bone marrow cytokine-Ras signals and metabolic dependence
白血病骨髓细胞因子-Ras 信号和代谢依赖性的分子理解
基本信息
- 批准号:10545014
- 负责人:
- 金额:$ 37.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:20 year oldAcute Lymphocytic LeukemiaAcute T Cell LeukemiaBar CodesBiochemicalBiologicalBone DiseasesBone MarrowBone Marrow DiseasesBone Marrow Stem CellCCL21 geneCRISPR interferenceCancer EtiologyCell LineCellsCellular Metabolic ProcessCessation of lifeCharacteristicsChildhoodChildhood Acute Lymphocytic LeukemiaChildhood Precursor T Lymphoblastic LeukemiaClinicClinicalCombined Modality TherapyDNA Sequence AlterationDataDependenceDevelopmentEpithelial CellsFRAP1 geneFlow CytometryGeneticGoalsGrantGuanosine TriphosphateHematopoiesisHematopoieticHematopoietic stem cellsHeterogeneityImmuneIn VitroKRASG12DLeadLeukemic CellMalignant NeoplasmsMeasurementMeasuresMetabolicMetabolismMethodsMissionModelingMolecularMusMutationNutrientOncogenicPathway interactionsPatientsPersonsPhenotypePhosphatidylinositide 3-Kinase InhibitorPhosphatidylinositolsPhosphotransferasesPoint MutationProgress ReportsProto-Oncogene Proteins c-aktRALGDS geneResearchResearch PersonnelResistanceResolutionRoleSamplingSignal TransductionT-Cell LeukemiaTestingTimeTubulinUnited States National Institutes of HealthVincristineacute T-cell lymphoblastic leukemia cellbiobankcancer typechemotherapycytokinedesignexperiencefitnessgenome-widehigh dimensionalityin vivoin vivo evaluationinhibitorinhibitor therapyinnovationinsightinterestkinase inhibitorleukemiamouse modelnew combination therapiesnoveloverexpressionpre-clinicalprecision medicinepreclinical trialprogramsral Guanine Nucleotide Exchange Factorsmall molecule inhibitorstemstem cellssynergismtechnology platform
项目摘要
PROJECT SUMMARY/ABSTRACT
Childhood Acute Lymphoblastic Leukemia (ALL) is a disease of the bone marrow with expansion of immature
cells and treated with non-specific chemotherapy. ALL remains one of the leading causes of cancer death in
persons <20 years old. The developmental origin of T cell ALL (T-ALL) is and profoundly impacts the clinic.
Genetic mutations pointed aberrant Ras signals with causal role in 50% of T-ALL, but how such aberrant
signals impact developmental trajectories in T-ALL is not known. Similarly, it is by and large unknown how to
effectively inhibit aberrant Ras signals.
During 1R01CA187318 we uncovered a new molecular paradigm in Ras signaling; Oncogenic Ras
mutations (KRasG12D) and overexpression of the Ras activator RasGRP1 drive two very distinctive leukemic
Ras signals. In the progress report with our new RoLoRiG/Mx1CRE mouse model, we show that these two
aberrant Ras signals both induce abnormal hematopoiesis, but with opposing stem cell features. Capitalizing
on our quantitative, multiplex flow cytometry platform we determined that Ras and RasGRP1 frequently
connect to PI3K (phosphoinositide 3-kinase)-AKT/mTOR signaling in T-ALL. Next, we performed four
extensive synthetic lethality screens with PI3K inhibitors to identify effective combination therapy in T-ALL. We
confirmed ten predicted combination therapies with small molecule inhibitors and the PI3K inhibitor GDC0941
with tubulin inhibitor Vincristine yields broad synergy in five cancer types and in our preclinical mouse trials in
vivo. The screens predict many metabolic targets, which remained unexplored.
Our renewal focuses on understanding the connection between aberrant Ras-PI3K signals and cell
metabolism with the goal of resolving the developmental origin of T-ALL and testing new combination
therapies. We will determine the connections between Ras-PI3K signals and cell metabolism in our panel of 10
T-ALL cell lines by investigating six nutrient transporters (SLCs), identified in our screens (Aim 1). We will
obtain mechanistic understanding of the signals, metabolic features, and hematopoietic composition and
trajectories, as a function of leukemic Ras-PI3K signals with unprecedented resolution. We will continue efforts
on RoLoRiG/Mx1CRE and KRasG12D/Mx1CRE mouse models that display completely opposite phenotypes in
bone marrow stem cells (Aim 2). Lastly, we will obtain a comprehensive characterization of developmental-,
biochemical- and metabolic- programs in pediatric T-ALL with single cell resolution. We will combine these
efforts with preclinical trial to test the in vivo efficacy of PI3Kγ- and δ- inhibition, inhibition of SLC13A2 and
SLC25A44, and combinations in our T-ALL/NGS platform (Aim 3). The synergistic aims, metabolic insights,
new mouse models, patient sample-NSG pipeline, and innovative, single cell-resolution technology platforms
(CyTOF, SCENITH, phospho-flow) will allow us to make significant contributions towards molecular
understanding of T-ALL and precision medicine in cancer.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JEROEN ROOSE其他文献
JEROEN ROOSE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JEROEN ROOSE', 18)}}的其他基金
Molecular understanding of cytokine-Ras signals in leukemic bone marrow
白血病骨髓中细胞因子-Ras 信号的分子理解
- 批准号:
9296107 - 财政年份:2015
- 资助金额:
$ 37.59万 - 项目类别:
Molecular understanding of cytokine-Ras signals in leukemic bone marrow
白血病骨髓中细胞因子-Ras 信号的分子理解
- 批准号:
9103012 - 财政年份:2015
- 资助金额:
$ 37.59万 - 项目类别:
Molecular understanding of leukemic bone marrow cytokine-Ras signals and metabolic dependence
白血病骨髓细胞因子-Ras 信号和代谢依赖性的分子理解
- 批准号:
10363571 - 财政年份:2015
- 资助金额:
$ 37.59万 - 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
- 批准号:
10396864 - 财政年份:2014
- 资助金额:
$ 37.59万 - 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
- 批准号:
8696061 - 财政年份:2014
- 资助金额:
$ 37.59万 - 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
- 批准号:
9237188 - 财政年份:2014
- 资助金额:
$ 37.59万 - 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
- 批准号:
8810642 - 财政年份:2014
- 资助金额:
$ 37.59万 - 项目类别:
Non-linear transduction of TCR signals leading to Ras activation
TCR 信号的非线性转导导致 Ras 激活
- 批准号:
8503586 - 财政年份:2013
- 资助金额:
$ 37.59万 - 项目类别:
相似海外基金
Understanding of the onset and recurrence pattern of intractable acute lymphocytic leukemia based on clone analysis
基于克隆分析了解难治性急性淋巴细胞白血病的发病和复发模式
- 批准号:
20K08723 - 财政年份:2020
- 资助金额:
$ 37.59万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Novel Inhibitors of Multi-Drug-Resistant Mutants of BCR-ABL for the Treatment of Chronic Myelogenous Leukemia (CML) and Ph Positive Acute Lymphocytic Leukemia (ALL).
BCR-ABL 多重耐药突变体的新型抑制剂,用于治疗慢性粒细胞白血病 (CML) 和 Ph 阳性急性淋巴细胞白血病 (ALL)。
- 批准号:
9047400 - 财政年份:2015
- 资助金额:
$ 37.59万 - 项目类别:
The Role of Genetic Variants in Sensitivity to Methotrexate in Acute Lymphocytic Leukemia Survivors
遗传变异在急性淋巴细胞白血病幸存者对甲氨蝶呤敏感性中的作用
- 批准号:
319114 - 财政年份:2014
- 资助金额:
$ 37.59万 - 项目类别:
Fellowship Programs
Targeting the Bone Marrow Microenvironment In Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的骨髓微环境
- 批准号:
8595788 - 财政年份:2013
- 资助金额:
$ 37.59万 - 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
- 批准号:
8023518 - 财政年份:2011
- 资助金额:
$ 37.59万 - 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
- 批准号:
8404025 - 财政年份:2011
- 资助金额:
$ 37.59万 - 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
- 批准号:
8220724 - 财政年份:2011
- 资助金额:
$ 37.59万 - 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
- 批准号:
8599754 - 财政年份:2011
- 资助金额:
$ 37.59万 - 项目类别:
INSULIN RESISTANCE IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA UNDERGOING INDUCT
正在接受治疗的急性淋巴细胞白血病儿童的胰岛素抵抗
- 批准号:
8356701 - 财政年份:2010
- 资助金额:
$ 37.59万 - 项目类别:
INSULIN RESISTANCE IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA UNDERGOING INDUCT
正在接受治疗的急性淋巴细胞白血病儿童的胰岛素抵抗
- 批准号:
8166720 - 财政年份:2009
- 资助金额:
$ 37.59万 - 项目类别:














{{item.name}}会员




