Metabolic Imaging of Targeted Therapies in Cancer
癌症靶向治疗的代谢成像
基本信息
- 批准号:10551887
- 负责人:
- 金额:$ 59.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-17 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAftercareBiologicalBiological MarkersBiopsyCancer ModelCancer PatientCell LineCell TransplantationCell physiologyCellsCellular Metabolic ProcessChemicalsCitric Acid CycleClinicClinicalClinical TrialsCytostaticsDataDetectionDiagnosisDiseaseEnzymesEvaluationExhibitsFRAP1 geneFatty AcidsFutureGene ExpressionGene Expression ProfileGene Expression ProfilingGenesGenomicsGlycolysisGoalsHexokinase 2HourHyperactivityHypoxiaImageImaging TechniquesImmune systemIn VitroKnowledgeLactic acidLymphomaLymphoma cellMalignant NeoplasmsMeasurementMeasuresMetabolicMetabolic PathwayMetabolismMethodsMissionModelingMonitorMusNeoplasmsNon-Invasive DetectionOutcomePathway interactionsPatientsPentosephosphate PathwayPharmaceutical PreparationsPhosphorylationPhosphotransferasesPhysiologic pulsePositron-Emission TomographyPreclinical TestingProtein-Serine-Threonine KinasesProteinsProteomeProteomicsPublic HealthRadiationReportingResearchSDZ RADSerineSignal PathwaySignal TransductionSirolimusStagingStandardizationSterolsSystemTestingTherapeutic EffectTherapeutic InterventionTumor MarkersTumor VolumeUnited States National Institutes of HealthWorkXenograft ModelXenograft procedurebiomarker selectionbiomarker validationcancer cellcancer therapycancer typecandidate identificationcandidate markercell growthearly detection biomarkersfluorodeoxyglucose positron emission tomographygenome-wideimaging biomarkerimaging detectionimaging modalityin vivoin vivo Modelindexinginhibitorinhibitor therapyinsightkinase inhibitorlarge cell Diffuse non-Hodgkin&aposs lymphomamTOR InhibitormTOR inhibitionmetabolic abnormality assessmentmetabolic imagingmetabolomicsmouse modelneoplastic cellnon-invasive imagingnovelpatient responsepersonalized medicinephosphoproteomicspotential biomarkerpre-clinicalpreclinical studypredicting responsepredictive markerprotein expressionresearch clinical testingresponseresponse biomarkersmall moleculetargeted treatmenttranscriptome sequencingtranslational potentialtreatment responsetumortumor metabolism
项目摘要
Metabolic Imaging of Targeted Therapies in Cancer
PROJECT SUMMARY/ABSTRACT
Given the paradigm shift in cancer therapy including the ever-growing increase in the use of targeted
therapies, foremost small-molecule kinase inhibitors in cancer therapy, there is an urgent need to develop
reliable imaging techniques to detect and monitor the efficacy of such inhibitors in cancer patients. Because
direct evaluation of cell signaling is practically not feasible and changes in tumor volume occur late after
treatment initiation given the predominantly cytostatic effect of the inhibitors, we are proposing an alternative
approach to monitor changes in tumor metabolism induced by kinase inhibition. This will be achieved in three
stages: 1) analysis of gene expression/proteomic/phosphoproteomic to identify metabolic pathways perturbed
by inhibition of the signaling pathway performed both in vitro and in vivo in the mouse xenotransplant models
using patient derived cultured and primary cells (PDX), 2) metabolomic and metabolic fluxomic analysis of
effect of kinase inhibition on metabolic pathways, also done in in vitro and in vivo settings, 3) analysis of
biomarkers of inhibitor response validated by the above “-omics” studies by imaging techniques, preferably
non-invasive, such as 1H MRS or chemical exchange saturation-transfer (CEST) with standard FDG PET
imaging serving as control. In these proof-of-principle studies, we will focus on mTOR, the serine/threonine
kinase hyperactive in the majority of cancer types, and employ direct and indirect inhibitors of mTOR,
rapamycin/rapalog and Torin2, respectively, as index kinase/kinase inhibitor system. We will use diffuse large
B-cell lymphoma (DLBCL) as experimental cancer model. In preliminary studies, we have demonstrated that
rapamycin decreased concentrations of lactic acid in patient-derived lymphoma cell lines, both cultured in vitro
and xenotransplanted into mice, as detected by unique 1H MRS imaging-based detection pulse sequences
developed by us and our collaborators. The rapamycin-induced decrease in glycolytic metabolism correlated
with and, importantly, markedly preceded inhibition of tumor cell growth, strongly supporting the notion that
image-based evaluation of the key metabolic response is predictive of biological tumor cell response to the
inhibition. The response also correlated with and, hence, was at least in part attributable to decreased
expression of hexokinase II, other glycolytic enzymes and enzymes from other key metabolic pathways
including phosphoribosyl-amidotransferase and other enzymes involved in glutaminolysis. Utilizing 13C MRS
and 13C LC-MS, we have confirmed mTOR control of glycolysis and also noted decreases in fatty acid and
sterol metabolism as well as inhibition of the pentose phosphate shunt and the TCA cycle. We anticipate that
the proposed studies will extend our knowledge of the impact of mTOR inhibition on malignant cell metabolism
and, ultimately, set the stage for future clinical evaluation of MRS or other imaging method(s) for monitoring
response to inhibitors of mTOR and other cell-signaling kinases in DLBCL and other types of cancer.
肿瘤靶向治疗的代谢成像
项目总结/摘要
鉴于癌症治疗的范式转变,包括靶向化疗的使用不断增加,
作为癌症治疗中最重要的小分子激酶抑制剂,迫切需要开发
可靠的成像技术来检测和监测这种抑制剂在癌症患者中的功效。因为
直接评估细胞信号传导实际上是不可行的,并且肿瘤体积的变化发生在
考虑到抑制剂的主要细胞抑制作用,我们提出了一种替代方案,
一种监测激酶抑制诱导的肿瘤代谢变化的方法。这将在三个
阶段:1)基因表达/蛋白质组学/磷酸蛋白质组学分析,以确定受干扰的代谢途径
通过抑制在小鼠异种移植模型中在体外和体内进行的信号传导途径
使用患者来源的培养细胞和原代细胞(PDX),2)代谢组学和代谢通量组学分析,
激酶抑制对代谢途径的影响,也在体外和体内环境中进行,3)分析
通过成像技术的上述“组学”研究验证的抑制剂应答的生物标志物,优选
非侵入性,如1H MRS或化学交换饱和转移(CEST)与标准FDG PET
成像作为对照。在这些原理验证研究中,我们将重点关注mTOR,即丝氨酸/苏氨酸
激酶在大多数癌症类型中过度活跃,并采用mTOR的直接和间接抑制剂,
分别使用雷帕霉素/雷帕霉素和Torin 2作为索引激酶/激酶抑制剂系统。我们将使用扩散大
B细胞淋巴瘤(DLBCL)作为实验癌症模型。在初步研究中,我们已经证明,
雷帕霉素降低了体外培养的患者源性淋巴瘤细胞系中的乳酸浓度
并异种移植到小鼠中,如通过独特的基于1H MRS成像的检测脉冲序列所检测的
由我们和我们的合作者开发。雷帕霉素诱导的糖酵解代谢减少与
同时,重要的是,明显地抑制了肿瘤细胞的生长,强烈支持了这样的观点,
关键代谢反应的基于图像的评估预测生物肿瘤细胞对代谢产物的反应。
抑制作用反应也与,因此,至少部分归因于减少
己糖激酶II、其他糖酵解酶和其他关键代谢途径的酶的表达
包括磷酸核糖基-酰胺基转移酶和其它参与β-氨基糖苷分解的酶。利用13 C MRS
和13 C LC-MS,我们已经证实了mTOR对糖酵解的控制,并且还注意到脂肪酸和
固醇代谢以及抑制戊糖磷酸分流和TCA循环。我们预计
这些研究将扩展我们对mTOR抑制对恶性细胞代谢影响的认识
并最终为MRS或其他用于监测的成像方法的未来临床评价奠定基础
DLBCL和其他类型癌症中对mTOR和其他细胞信号传导激酶抑制剂的反应。
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 }}
JERRY D GLICKSON其他文献
JERRY D GLICKSON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('JERRY D GLICKSON', 18)}}的其他基金
Metabolic Imaging of Targeted Therapies in Cancer
癌症靶向治疗的代谢成像
- 批准号:
10391657 - 财政年份:2022
- 资助金额:
$ 59.77万 - 项目类别:
Metabolic Biomarkers of Response of Mantle Cell Lymphoma to Bruton Tyrosine Kinase Inhibition
套细胞淋巴瘤对布鲁顿酪氨酸激酶抑制反应的代谢生物标志物
- 批准号:
10362649 - 财政年份:2020
- 资助金额:
$ 59.77万 - 项目类别:
Metabolic Biomarkers of Response of Mantle Cell Lymphoma to Bruton Tyrosine Kinase Inhibition
套细胞淋巴瘤对布鲁顿酪氨酸激酶抑制反应的代谢生物标志物
- 批准号:
10580590 - 财政年份:2020
- 资助金额:
$ 59.77万 - 项目类别:
NMR of Melanoma Acidification, Bioenergetics, Metabolism and Therapeutic Response
黑色素瘤酸化、生物能量学、代谢和治疗反应的 NMR
- 批准号:
7740882 - 财政年份:2009
- 资助金额:
$ 59.77万 - 项目类别:
Systemic Chemotherapy of Melanoma: NMR Studies of Lonidamine & N-Mustard Activity
黑色素瘤的全身化疗:洛尼达明的 NMR 研究
- 批准号:
8304740 - 财政年份:2009
- 资助金额:
$ 59.77万 - 项目类别:
相似海外基金
Life outside institutions: histories of mental health aftercare 1900 - 1960
机构外的生活:1900 - 1960 年心理健康善后护理的历史
- 批准号:
DP240100640 - 财政年份:2024
- 资助金额:
$ 59.77万 - 项目类别:
Discovery Projects
Development of a program to promote psychological independence support in the aftercare of children's homes
制定一项计划,促进儿童之家善后护理中的心理独立支持
- 批准号:
23K01889 - 财政年份:2023
- 资助金额:
$ 59.77万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Integrating Smoking Cessation in Tattoo Aftercare
将戒烟融入纹身后护理中
- 批准号:
10452217 - 财政年份:2022
- 资助金额:
$ 59.77万 - 项目类别:
Integrating Smoking Cessation in Tattoo Aftercare
将戒烟融入纹身后护理中
- 批准号:
10670838 - 财政年份:2022
- 资助金额:
$ 59.77万 - 项目类别:
Aftercare for young people: A sociological study of resource opportunities
年轻人的善后护理:资源机会的社会学研究
- 批准号:
DP200100492 - 财政年份:2020
- 资助金额:
$ 59.77万 - 项目类别:
Discovery Projects
Creating a National Aftercare Strategy for Survivors of Pediatric Cancer
为小儿癌症幸存者制定国家善后护理策略
- 批准号:
407264 - 财政年份:2019
- 资助金额:
$ 59.77万 - 项目类别:
Operating Grants
Aftercare of green infrastructure: creating algorithm for resolving human-bird conflicts
绿色基础设施的善后工作:创建解决人鸟冲突的算法
- 批准号:
18K18240 - 财政年份:2018
- 资助金额:
$ 59.77万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Development of an aftercare model for children who have experienced invasive procedures
为经历过侵入性手术的儿童开发善后护理模型
- 批准号:
17K12379 - 财政年份:2017
- 资助金额:
$ 59.77万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development of a Comprehensive Aftercare Program for children's self-reliance support facility
为儿童自力更生支持设施制定综合善后护理计划
- 批准号:
17K13937 - 财政年份:2017
- 资助金额:
$ 59.77万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Project#2 Extending Treatment Effects Through an Adaptive Aftercare Intervention
项目
- 批准号:
8742767 - 财政年份:2014
- 资助金额:
$ 59.77万 - 项目类别: