Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
基本信息
- 批准号:10402355
- 负责人:
- 金额:$ 34.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:ActivinsAdvanced Malignant NeoplasmAffectAntibodiesBindingBody Weight decreasedCachexiaCancer PatientCellsCessation of lifeComplicationDevelopmentDiagnosisDoseDrug TargetingDrug toxicityFBXO32 geneGDF8 geneGeneticGenetically Engineered MouseIncidenceKnowledgeLifeMalignant NeoplasmsMediatingMediator of activation proteinMedicineMesenchymal Stem CellsModelingMorbidity - disease rateMuscleMuscle ProteinsMuscle satellite cellMuscular AtrophyNeoplasm MetastasisPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPlayPredispositionPrognostic MarkerQuality of lifeRegimenReportingResistance developmentRoleSignal PathwaySignal TransductionSyndromeTestingTherapeuticTransforming Growth Factor betaTranslatingTumor-DerivedWasting Syndromeactivin Abasecancer cachexiacancer survivalchemotherapyclinically relevantcombatcombinatorialdesigndrug discoveryeffective therapyefficacy testingexperiencein vivoinnovationmembermortalitymouse modeloverexpressionpancreatic cancer modelpancreatic cancer patientspancreatic ductal adenocarcinoma modelprotein degradationreceptorsarcomaskeletalskeletal muscle wastingstem cell fatetranscription factortumortumor growthtumor progressionubiquitin ligase
项目摘要
PROJECT SUMMARY
Cancer cachexia is a debilitating syndrome that affects the vast majority of patients with advanced cancer
and accounts for nearly 30% of cancer-related deaths. The lack of prognostic markers to identify patient
susceptibility and effective treatment options represent major gaps in cancer cachexia knowledge. A key
feature of cancer cachexia is the progressive depletion of skeletal mass, which is mediated in part by two
secreted factors, Activin and Myostatin. Emerging studies have revealed that pharmacological inhibition of
Activin/Myostatin signaling is sufficient to suppress cachexia and extend survival in several mouse models of
cancer cachexia, raising the possibility that targeting this pathway might represent a promising strategy to
curb cachexia and attendant morbidity and mortality in cancer patients.
We have recently reported that overexpression of Twist1 in muscle progenitor cells causes severe
muscle loss akin to cancer cachexia. Using several genetic mouse models of pancreatic cancer, we detected
a massive increase in Twist1 expression in muscle undergoing cachexia. We also found that elevated levels
of muscle Twist1 are associated with severe cachexia in cancer patients. Inactivation of Twist1, either
genetically or pharmacologically, afforded substantial protection against cancer-mediated muscle cachexia,
which translated into meaningful survival benefits. From a mechanistic perspective, we present evidence that
tumor-derived Act-A induces expression of Twist1, which in turn drives expression of MuRF1 and Atrogin1,
leading to muscle protein degradation and attendant cachexia. Finally, we found that Twist1 also induces
Myostatin expression, further supporting its role in cancer-driven muscle cachexia.
Based on our findings, we hypothesize that Twist1 might function in Activin/Myostatin signaling to
coordinate a feed-forward loop to execute muscle cachexia during cancer progression. We also hypothesize
that developing combinatorial therapeutic strategies targeting both Twist1 and Activin/Myostatin could
mitigate potential drug toxicity by lowering the dose needed for each medicine and combat the development
of resistance. These overarching hypotheses will be tested in the following three Specific Aims:
Specific Aim 1: Investigate the role of Twist1 in cancer cachexia, focusing on its ability to mediate
Activin-induced muscle depletion.
Specific Aim 2: Explore the mechanisms by which Twist1 coordinates a feed-forward loop to sustain
Activin/Myostatin-driven muscle loss during cancer cachexia progression.
Specific Aim-3: Test the efficacy of combinatorial drugs regimens targeting both Twist1 and
Activin/Myostatin signaling pathway in cancer cachexia.
Comprehensive characterization of this newly discovered cachexia driver will likely open up new angles to the
cachexia field, both in terms of understanding its mechanistic paradigms and in terms of drug discovery.
项目摘要
癌症恶病质是一种使人衰弱的综合征,影响绝大多数晚期癌症患者
占癌症相关死亡人数的近30%。缺乏识别患者的预后标志物
易感性和有效的治疗选择代表了癌症恶病质知识的主要差距。一个关键
癌症恶病质的特征是骨骼质量的进行性消耗,其部分由两种
分泌因子,激活素和肌肉生长抑制素。新的研究表明,药理学抑制
激活素/肌生长抑制素信号传导足以抑制恶病质并延长几种小鼠模型中的存活。
癌症恶病质,提高了靶向这一途径可能是一个有前途的战略,
抑制癌症患者的恶病质和伴随的发病率和死亡率。
我们最近报道,肌肉祖细胞中Twist 1的过度表达导致严重的
类似于癌症恶病质的肌肉损失。使用几种胰腺癌遗传小鼠模型,我们检测到
在经历恶病质的肌肉中Twist 1表达的大量增加。我们还发现,
肌肉扭曲1与癌症患者的严重恶病质有关。Twist 1的失活,
基因或免疫学上,对癌症介导的肌肉恶病质提供了实质性的保护,
这转化为有意义的生存福利。从机械的角度来看,我们提出的证据表明,
肿瘤来源的Act-A诱导Twist 1的表达,Twist 1又驱动MuRF 1和Atrogin 1的表达,
导致肌肉蛋白质降解和伴随的恶病质。最后,我们发现Twist 1也诱导了
肌生长抑制素表达,进一步支持其在癌症驱动的肌肉恶病质中的作用。
基于我们的发现,我们假设Twist 1可能在激活素/肌生长抑制素信号传导中起作用,
协调前馈回路以在癌症进展期间执行肌肉恶病质。我们还假设
开发针对Twist 1和Activin/Myostatin的组合治疗策略,
通过降低每种药物所需的剂量来减轻潜在的药物毒性,
抗战将在以下三个具体目标中检验这些总体假设:
具体目标1:研究Twist 1在癌症恶病质中的作用,重点是其介导癌症恶病质的能力。
激活素引起的肌肉衰竭。
具体目标2:探索Twist 1协调前馈回路以维持
癌症恶病质进展期间激活素/肌生长抑制素驱动的肌肉损失。
具体目标-3:测试靶向Twist 1和Twist 2的组合药物方案的功效。
癌症恶病质中的激活素/肌生长抑制素信号通路。
对这一新发现的恶病质驱动因素的全面表征可能会为研究恶病质提供新的视角。
恶病质领域,无论是在理解其机制范式和药物发现方面。
项目成果
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{{ truncateString('Azeddine Atfi', 18)}}的其他基金
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10442384 - 财政年份:2020
- 资助金额:
$ 34.8万 - 项目类别:
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10174890 - 财政年份:2020
- 资助金额:
$ 34.8万 - 项目类别:
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10032715 - 财政年份:2020
- 资助金额:
$ 34.8万 - 项目类别:
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10641967 - 财政年份:2020
- 资助金额:
$ 34.8万 - 项目类别:
Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
- 批准号:
9927610 - 财政年份:2019
- 资助金额:
$ 34.8万 - 项目类别:
Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
- 批准号:
10203885 - 财政年份:2019
- 资助金额:
$ 34.8万 - 项目类别:
Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
- 批准号:
10629446 - 财政年份:2019
- 资助金额:
$ 34.8万 - 项目类别:
Targeting the TGIF/Twist1 network in osteosarcoma
靶向骨肉瘤中的 TGIF/Twist1 网络
- 批准号:
9311684 - 财政年份:2017
- 资助金额:
$ 34.8万 - 项目类别: