Targeting Oncogenic Pathways in Genetically Complex Sarcomas
靶向遗传复杂肉瘤的致癌途径
基本信息
- 批准号:10932623
- 负责人:
- 金额:$ 27.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectApoptosisCDK4 geneCell LineCellsClinical TrialsCollaborationsCombined Modality TherapyComplexDNA copy numberDataDedifferentiated LiposarcomasDevelopmentDiseaseDrug KineticsDrug TargetingDrug resistanceETV1 geneEffectivenessFRAP1 geneFeedbackG-QuartetsGenomicsGenotypeGoalsGrowthHumanIndividualInstitutionIntegrinsKnowledgeLettersMAP Kinase GeneMDM2 geneMEK inhibitionMEKsMalignant Fibrous HistiocytomaMeasuresMessenger RNAMethodsModelingMolecularMyxoid Malignant Fibrous HistiocytomaNTRK1 geneNeoplasm MetastasisOncogenicOutcomePIK3CG genePathway interactionsPatient-Focused OutcomesPatientsPharmacologic SubstancePhasePreclinical TestingPrimary NeoplasmPrognostic MarkerProliferatingProteinsRNA HelicaseRibosomesRoleSamplingSignal PathwaySignal TransductionTestingTherapeuticTissue SampleToxic effectTranslatingTranslational RegulationTranslationsUp-RegulationWorkXenograft ModelXenograft procedureclinical practiceclinical translationcommon treatmentdrug developmenteffective therapyefficacy evaluationimprovedimproved outcomein vitro activityin vivoinhibitorinhibitor therapyknock-downmRNA TranslationmTOR InhibitormTOR inhibitionnanomolarnew therapeutic targetnovel therapeuticsoverexpressionpatient derived xenograft modelprecision oncologypreventresponsesarcomatargeted treatmenttherapy resistanttranscriptometreatment strategytumortumor growthtumorigenesis
项目摘要
RP-3: Targeting oncogenic pathways in genetically complex sarcomas
ABSTRACT
Our overall goal is to find effective targeted therapies for two of the most common and aggressive types
of genetically complex sarcomas: myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma
(UPS). The development of new targeted therapies is urgent and vital for improving outcomes of these
patients. However, the complexity of alterations in these sarcomas has made it difficult to find the true
drivers of oncogenesis. We found that high expression of ITGA10 (integrin-α10) in MFS and UPS drives
sarcomagenesis by activating RAC/PAK and PI3K/mTOR signaling, and that 85% of MFS and UPS
harbor alterations that can activate the PI3K/mTOR signaling cascade. Signaling in this cascade
stimulates protein translation, and our preliminary results suggest that MFS and UPS, as well as
dedifferentiated liposarcoma (DDLS), rely on oncogenic translation enabled by the RNA helicase eIF4A.
We therefore hypothesize that most MFS/UPS will be dependent on PI3K/mTOR signaling and eIF4A
for growth and survival. First, we plan to define the role of the PI3K/mTOR and MAPK pathway
activation in sarcomagenesis and identify molecular alterations that associate with outcome. Second, we
plan to determine the efficacy of mTOR, PI3K, and MEK inhibitors in MFS/UPS cell lines, xenografts
and PDX models. In preliminary data the PI3K/mTOR inhibitors alone led to feedback upregulation of
the MAPK pathway, which could cause adaptive resistance to therapy. Therefore, we will test combining
each of the PI3K and mTOR inhibitors with a MEK inhibitor, to test whether the combination blocks the
adaptive response and leads to synergistic suppression of MFS/UPS. Third, we will determine the
efficacy and mechanism of action of a new eIF4A inhibitor, CR31B, in MFS, UPS, and DDLS cell lines and
xenografts. To discover which mRNAs require eIF4A for their translation in these cell lines, we will
perform ribosome footprinting on CR31B-treated cells. We expect that mTOR, PI3K, and eIF4A inhibitors
will be effective therapy in the majority of MFS and UPS. Clarification of the roles of the PI3K/mTOR
and oncogenic translation pathways will elucidate mechanisms of tumorigenesis and metastasis, identify
new drug targets, identify effective combination therapies, and enable precision oncology. We expect
that at least one of the treatment strategies investigated in this proposal will lead to clinical trials for
patients with MFS and UPS.
RP-3:靶向基因复杂肉瘤的致癌途径
摘要
我们的总体目标是为两种最常见和最具侵袭性的类型找到有效的靶向疗法
基因复杂的肉瘤:粘液纤维肉瘤(MFS)和未分化多形性肉瘤
(UPS)。开发新的靶向疗法对于改善这些疾病的结果是紧迫和至关重要的。
病人。然而,这些肉瘤变化的复杂性使人们很难找到真正的
肿瘤发生的驱动因素。我们发现整合素ITGA10(整合素-α10)在MFS和UPS驱动器中高表达
通过激活RAC/PAK和PI3K/mTOR信号通路发生肉瘤,85%的MFS和UPS
可以激活PI3K/mTOR信号级联的港口改变。此级联中的信令
刺激蛋白质翻译,我们的初步结果表明,MFS和UPS,以及
去分化脂肪肉瘤(DDLS),依赖于RNA解旋酶eIF4A实现的致癌翻译。
因此,我们假设大多数MFS/UPS将依赖于PI3K/mTOR信令和eIF4A
为了成长和生存。首先,我们计划确定PI3K/mTOR和MAPK通路的作用
在肉瘤发生中的激活,并确定与结果相关的分子变化。第二,我们
计划确定mTOR、PI3K和MEK抑制剂在MFS/UPS细胞系、异种移植瘤中的疗效
和PDX型号。在初步数据中,PI3K/mTOR抑制剂单独导致反馈上调
MAPK通路,这可能导致适应性抵抗治疗。因此,我们将测试组合
每种PI3K和mTOR抑制剂与一种MEK抑制剂一起使用,以测试组合是否阻止
适应性反应,导致对MFS/UPS的协同抑制。第三,我们将确定
一种新的eIF4A抑制剂CR31B对MFS、UPS和DDLS细胞株的疗效和作用机制
异种移植物。为了发现哪些mRNAs需要eIF4A在这些细胞系中进行翻译,我们将
在CR31B处理的细胞上执行核糖体足迹。我们预计mTOR、PI3K和eIF4A抑制剂
将是治疗大多数MFS和UPS的有效方法。澄清PI3K/mTOR的作用
而癌基因翻译途径将阐明肿瘤发生和转移的机制,识别
新的药物靶点,确定有效的联合疗法,并使精确肿瘤学成为可能。我们预计
本提案中调查的至少一种治疗策略将导致临床试验
MFS和UPS患者。
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 }}
SAMUEL SINGER其他文献
SAMUEL SINGER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('SAMUEL SINGER', 18)}}的其他基金
Targeting Oncogenic Pathways in Genetically Complex Sarcomas
靶向遗传复杂肉瘤的致癌途径
- 批准号:
10247699 - 财政年份:2018
- 资助金额:
$ 27.56万 - 项目类别:
Targeting Oncogenic Pathways in Genetically Complex Sarcomas
靶向遗传复杂肉瘤的致癌途径
- 批准号:
10016098 - 财政年份:2018
- 资助金额:
$ 27.56万 - 项目类别:
Targeting Oncogenic Pathways in Genetically Complex Sarcomas
靶向遗传复杂肉瘤的致癌途径
- 批准号:
10468964 - 财政年份:2018
- 资助金额:
$ 27.56万 - 项目类别:
相似国自然基金
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
- 批准号:LBY21H010001
- 批准年份:2020
- 资助金额:0.0 万元
- 项目类别:省市级项目
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
- 批准号:81703335
- 批准年份:2017
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
- 批准号:81670594
- 批准年份:2016
- 资助金额:58.0 万元
- 项目类别:面上项目
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
- 批准号:81470791
- 批准年份:2014
- 资助金额:73.0 万元
- 项目类别:面上项目
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
- 批准号:81301123
- 批准年份:2013
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
- 批准号:81101529
- 批准年份:2011
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
- 批准号:39500043
- 批准年份:1995
- 资助金额:9.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response
乳脂肪球-EGF因子8与肝细胞凋亡诱导的肝脏创面愈合反应
- 批准号:
10585802 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
Development of an apoptosis biosensor for monitoring of breast cancer
开发用于监测乳腺癌的细胞凋亡生物传感器
- 批准号:
10719415 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
Interrogating the Fgl2-FcγRIIB axis on CD8+ T cells: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
询问 CD8 T 细胞上的 Fgl2-FcγRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10605856 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
Novel targeted therapy for FGFR inhibitor-resistant urothelial cancer and apoptosis based therapy for urothelial cancer
FGFR抑制剂耐药性尿路上皮癌的新型靶向治疗和基于细胞凋亡的尿路上皮癌治疗
- 批准号:
23K08773 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Mechanistic analysis of apoptosis induction by HDAC inhibitors in head and neck cancer
HDAC抑制剂诱导头颈癌凋亡的机制分析
- 批准号:
23K15866 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
探究 Fgl2-FcgRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10743485 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
Investigating the role of apoptosis-resistance and the tumor environment on development and maintenance of sacrococcygeal teratomas
研究细胞凋亡抗性和肿瘤环境对骶尾部畸胎瘤发生和维持的作用
- 批准号:
10749797 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
The effects of glucose on immune cell apoptosis and mitochondrial membrane potential and the analysis of its mechanism by which glucose might modulate the immune functions.
葡萄糖对免疫细胞凋亡和线粒体膜电位的影响及其调节免疫功能的机制分析。
- 批准号:
22K09076 - 财政年份:2022
- 资助金额:
$ 27.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION
P53 信号传导、细胞凋亡和肿瘤抑制中的 XAF1
- 批准号:
10583516 - 财政年份:2022
- 资助金额:
$ 27.56万 - 项目类别:
Role of Thioredoxin system in regulation of autophagy-apoptosis cross talk in neurons: Uncovering Novel Molecular Interactions.
硫氧还蛋白系统在神经元自噬-凋亡串扰调节中的作用:揭示新的分子相互作用。
- 批准号:
RGPIN-2019-05371 - 财政年份:2022
- 资助金额:
$ 27.56万 - 项目类别:
Discovery Grants Program - Individual