c-Myc modulation and its implications in EGFR-targeted cancer therapy
c-Myc 调节及其对 EGFR 靶向癌症治疗的影响
基本信息
- 批准号:10212350
- 负责人:
- 金额:$ 40.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-07 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal ModelApoptoticAreaBiochemicalBiologicalBiological AssayCancer PatientCancer cell lineCell LineCell ProliferationCell SurvivalChromosomal translocationClinicClinicalClinical TreatmentDataDevelopmentDisease ProgressionEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorErlotinibEventExonsFDA approvedFamily memberFutureGefitinibGene AmplificationGenerationsGenesGlutamineGoalsHumanHuman GenomeImmunityIn VitroInduction of ApoptosisKnowledgeLinkMYC geneMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMediatingMetabolismMethodsModelingMolecularMutationNon-Small-Cell Lung CarcinomaOutcome StudyPatientsPharmaceutical PreparationsPharmacologyPharmacotherapyPhysiological ProcessesPlayPoint MutationProteasome InhibitionProteinsRadiation therapyRegimenRegulationRelapseResistanceRoleSafetyScienceTestingTissuesTranslatingTreatment Efficacyc-myc Genescancer cellcell growthchemotherapyclinical translationcombinatorialgene cloningin vivoinhibitor/antagonistknock-downknockout genelung cancer cellmutantoverexpressionpre-clinicalresearch clinical testingresistance mechanismresponsesmall molecular inhibitortargeted cancer therapytargeted treatmenttherapeutic targettherapeutically effectivetranscription factortreatment comparisontumor
项目摘要
SUMMARY
An important milestone in the treatment of non-small cell lung cancer (NSCLC) is the discovery of
epidermal growth factor receptor (EGFR) activating mutations as an effective therapeutic target and the
successful development of EGFR tyrosine kinase inhibitors (EGFR-TKIs). AZD9291 (TAGRISSOTM or
osimertinib) represents a 3rd generation EGFR-TKI and an FDA-approved drug for patients with EGFR mutant
NSCLC that has become resistant to 1st generation EGFR-TKIs through the T790M mutation and for EGFR
mutation-positive advanced NSCLC as a front line treatment. Unfortunately, patients eventually relapse and
become resistant to AZD9291 in the clinic, resulting in disease progression. Thus, a better understanding of
the underlying mechanisms and development of effective strategies to overcome AZD9291 resistance is an
urgent and critical area of unmet need in the clinic. The C-MYC gene was the first Myc family member found in
the human genome and its product, c-Myc, functions as a transcription factor to regulate the expression of
many genes whose products are involved in the regulation of various physiological processes, such as cell
survival, proliferation, differentiation, metabolism and host immunity. MYC is genetically activated and/or
overexpressed in most types of human cancer including lung cancer and thus is a central driver of malignant
cellular growth and proliferation. c-Myc expression is associated with response or sensitivity of cancer cells to
chemotherapy or radiotherapy. However, no study has linked c-Myc to targeted therapy by third generation
EGFR-TKIs. Our strong preliminary data support the overall hypothesis that c-Myc modulation may play a
critical role in mediating therapeutic efficacy of AZD9291 against EGFRm NSCLC and the development of
acquired resistance to AZD9291; accordingly, targeting c-Myc will be an effective strategy to overcome
acquired resistance to AZD9291 and other EGFR-TKIs. This hypothesis will be tested by accomplishing the
following 3 specific aims: 1) To understand the mechanism(s) by which c-Myc is reduced in EGFR mutant
NSCLC cells by AZD9291 or other EGFR-TKIs; 2) To demonstrate the biological significance of c-Myc
suppression in EGFR-targeted therapy; and 3) To develop effective therapeutic regimens to overcome
acquired resistance to AZD9291 by targeting c-Myc. The objectives of this study are to understand the
mechanisms by which AZD9291 and other EGFR-TKIs decrease c-Myc levels, to demonstrate the biological
significance of c-Myc suppression during EGFR-targeted cancer therapy; and to develop effective strategies to
overcome acquired resistance to AZD9291 by targeting c-Myc. This proposal is of high scientific and
translational significance. The outcomes of this study can be immediately translated to the clinical treatment of
NSCLC patients with acquired resistance to AZD9291 or other EGFR-TKIs.
1
摘要
非小细胞肺癌(NSCLC)治疗的一个重要里程碑是发现了
表皮生长因子受体(EGFR)激活突变作为有效的治疗靶点
成功开发了EGFR酪氨酸激酶抑制剂(EGFR-TKIs)。AZD9291(TAGRISSOTM或
Osimertinib)代表第三代EGFR-TKI,是FDA批准用于EGFR突变患者的药物
通过T790M突变和EGFR对第一代EGFR-TKIs产生耐药性的非小细胞肺癌
突变阳性的晚期非小细胞肺癌作为一线治疗。不幸的是,患者最终会复发并
在临床上对AZD9291产生抗药性,导致疾病进展。因此,更好地理解
克服AZD9291抗性的潜在机制和有效策略的发展是一种
诊所中未得到满足的紧急和关键需求领域。C-MYC基因是第一个发现的Myc家族成员
人类基因组及其产物c-Myc发挥转录因子的作用,调节
许多基因,其产物参与各种生理过程的调节,如细胞
生存、增殖、分化、新陈代谢和宿主免疫。MYC是基因激活的和/或
在包括肺癌在内的大多数类型的人类癌症中过度表达,因此是恶性的中心驱动因素
细胞的生长和增殖。C-Myc的表达与癌细胞对药物的反应或敏感性有关
化疗或放射治疗。然而,还没有研究将c-Myc与第三代靶向治疗联系起来。
EGFR-TKIs。我们强劲的初步数据支持c-Myc调制可能发挥作用的总体假设
AZD9291在介导EGFRm非小细胞肺癌疗效中的关键作用及进展
对AZD9291的获得性耐药;因此,靶向c-Myc将是克服
对AZD9291和其他EGFR-TKI的获得性耐药。这一假设将通过实现
目的:1)了解EGFR突变体中c-Myc降低的机制(S)
AZD9291或其他EGFR-TKI介导的非小细胞肺癌细胞;2)论证c-Myc的生物学意义
EGFR靶向治疗中的抑制;以及3)开发有效的治疗方案来克服
通过靶向c-Myc获得对AZD9291的抗性。这项研究的目的是了解
AZD9291和其他EGFR-TKI降低c-Myc水平的机制,以证明生物学
C-Myc抑制在EGFR靶向癌症治疗中的意义;并开发有效的策略来
通过靶向c-Myc克服对AZD9291的获得性耐药性。这项建议具有很高的科学性和科学性
翻译意义。这项研究的结果可以立即转化为临床治疗
对AZD9291或其他EGFR-TKIs有获得性耐药的非小细胞肺癌患者。
1
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 }}
Shi-Yong Sun其他文献
Shi-Yong Sun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('Shi-Yong Sun', 18)}}的其他基金
c-Myc modulation and its implications in EGFR-targeted cancer therapy
c-Myc 调节及其对 EGFR 靶向癌症治疗的影响
- 批准号:
10427217 - 财政年份:2020
- 资助金额:
$ 40.31万 - 项目类别:
c-Myc modulation and its implications in EGFR-targeted cancer therapy
c-Myc 调节及其对 EGFR 靶向癌症治疗的影响
- 批准号:
10649650 - 财政年份:2020
- 资助金额:
$ 40.31万 - 项目类别:
Modulation of death receptor 4 in EGFR-targeted cancer therapy
EGFR 靶向癌症治疗中死亡受体 4 的调节
- 批准号:
10006518 - 财政年份:2018
- 资助金额:
$ 40.31万 - 项目类别:
Modulation of death receptor 4 in EGFR-targeted cancer therapy
EGFR 靶向癌症治疗中死亡受体 4 的调节
- 批准号:
10524101 - 财政年份:2018
- 资助金额:
$ 40.31万 - 项目类别:
Modulation of death receptor 4 in EGFR-targeted cancer therapy
EGFR 靶向癌症治疗中死亡受体 4 的调节
- 批准号:
10653881 - 财政年份:2018
- 资助金额:
$ 40.31万 - 项目类别:
Modulation of death receptor 4 in EGFR-targeted cancer therapy
EGFR 靶向癌症治疗中死亡受体 4 的调节
- 批准号:
10206047 - 财政年份:2018
- 资助金额:
$ 40.31万 - 项目类别:
Modulation of death receptor 4 in EGFR-targeted cancer therapy
EGFR 靶向癌症治疗中死亡受体 4 的调节
- 批准号:
10428557 - 财政年份:2018
- 资助金额:
$ 40.31万 - 项目类别:
Therapeutic potential of mTOR kinase inhibitors in lung cancer
mTOR 激酶抑制剂在肺癌中的治疗潜力
- 批准号:
8624748 - 财政年份:2012
- 资助金额:
$ 40.31万 - 项目类别:
Therapeutic potential of mTOR kinase inhibitors in lung cancer
mTOR 激酶抑制剂在肺癌中的治疗潜力
- 批准号:
8639500 - 财政年份:2012
- 资助金额:
$ 40.31万 - 项目类别:
Therapeutic potential of mTOR kinase inhibitors in lung cancer
mTOR 激酶抑制剂在肺癌中的治疗潜力
- 批准号:
8825457 - 财政年份:2012
- 资助金额:
$ 40.31万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 40.31万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




