Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer.
项目 3:针对非小细胞肺癌治疗耐药的转录机制。
基本信息
- 批准号:9766096
- 负责人:
- 金额:$ 34.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal ModelBRAF geneCancer ModelCancer PatientCancer cell lineCell LineCell SurvivalCell modelChemistryClinicalClonal EvolutionComplexCyclin-Dependent Kinase GeneCyclin-Dependent Kinase InhibitorCyclin-Dependent KinasesDNA Sequence AlterationDataData AnalysesDependenceDevelopmentDrug TargetingDrug resistanceERBB2 geneEnhancersEnzymesEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpigenetic ProcessExhibitsFibroblast Growth Factor ReceptorsGeneticGenetic TranscriptionGenetically Engineered MouseGenomeGoalsIn VitroIndividualInformaticsKRAS2 geneLeadMEKsMalignant NeoplasmsMalignant neoplasm of lungMolecularMutationNon-Small-Cell Lung CarcinomaOutcomePathway interactionsPatient-Focused OutcomesPharmaceutical PreparationsPharmacologyPhosphotransferasesPopulationProcessPropertyProtein KinaseProteinsRegulatory ElementResidual stateResistanceResistance developmentSignal TransductionSpecificityStructural ChemistryStructureTestingTherapeuticTimeTranscriptTranscription ElongationTranscription InitiationTranscription Processcancer cellcancer therapyclinical translationdesigngenetic approachimprovedimproved outcomein vivoinhibitor/antagonistkinase inhibitormembermouse modelmultidisciplinarymutantnovelpatient subsetspreventresistance mechanismresponsesmall moleculestructural biologysynergismtargeted agenttargeted cancer therapytargeted treatmenttherapeutic targettherapy resistanttooltranscription factortranscriptomicstreatment responsetreatment strategy
项目摘要
The use of genomically targeted therapies has improved treatment response and clinical outcomes for
molecularly defined subsets of patients with non-small cell lung cancers. While responses to these therapies
can often be dramatic, they are rarely durable, and there is a significant need to improve the duration of
response and delay or prevent treatment resistance. Studies from our group and others have characterized the
properties of cancer cells which escape initial treatment with a targeted agent. Analyses of these data have
revealed transcriptional and epigenetic adaptation as a requirement for the survival of cells that persist in the
face of targeted therapy.
Working with Core A (Chemistry) and Core B (Structure), we have obtained Preliminary Data suggesting that
inhibitors of higher-order cyclin dependent kinases (CDKs), enzymes which perform key roles in transcriptional
initiation and elongation, display potent synergy with targeted kinase inhibitors in a diverse array of NSCLC
models both in vitro and in vivo. Specifically, we have identified THZ1, a covalent CDK7/12 inhibitor designed
by Core A leader Dr. Gray, as a tool compound which synergizes with inhibitors of EGFR (Project 1), MEK
(Project 2) as well as ALK, HER2, BRAF, FGFR and PI3K in genetically selected NSCLC models. In this
project, we will advance our efforts in targeting transcriptional adaptation to targeted therapies by using genetic
tools to define the key CDK/cyclin genes responsible for therapeutic synergy and using this information to
design more selective CDK inhibitors and selective degraders with improved specificity and in vivo
pharmacology as compared to THZ1. Further, we will use transcriptional and epigenetic analysis to define the
mechanisms governing therapeutic synergy among targeted therapies and CDK inhibitors. This project will be
amenable to clinical translation given the broad applicability of this approach and ongoing efforts to develop
transcriptional CDK inhibitors for clinical use.
基因组靶向治疗的使用改善了治疗反应和临床结果,
分子定义的非小细胞肺癌患者亚群。虽然对这些疗法的反应
通常可能是戏剧性的,它们很少持久,并且非常需要改善
反应和延迟或防止治疗抵抗。我们小组和其他人的研究表明,
癌细胞逃避靶向剂的初始治疗的特性。对这些数据的分析
揭示了转录和表观遗传适应作为细胞生存的必要条件,
面对靶向治疗。
通过核心A(化学)和核心B(结构),我们获得了初步数据,表明
高级细胞周期蛋白依赖性激酶(CDK)的抑制剂,所述CDK是在转录调控中起关键作用的酶,
在多种NSCLC中与靶向激酶抑制剂显示出有效协同作用
体外和体内模型。具体来说,我们已经鉴定了THZ 1,一种共价CDK 7/12抑制剂,
由核心A领导人Gray博士,作为与EGFR抑制剂协同作用的工具化合物(项目1),MEK
(项目2)以及ALK、HER 2、BRAF、FGFR和PI 3 K。在这
项目,我们将推进我们的努力,在靶向转录适应靶向治疗,通过使用遗传
定义负责治疗协同作用的关键CDK/细胞周期蛋白基因的工具,并使用此信息
设计更具选择性的CDK抑制剂和选择性降解剂,具有改善的特异性和体内
与THZ 1相比的药理学。此外,我们将使用转录和表观遗传分析来定义
靶向治疗和CDK抑制剂之间的治疗协同作用机制。该项目将
考虑到这种方法的广泛适用性和正在进行的努力,
转录CDK抑制剂的用途。
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)
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Peter S Hammerman其他文献
Peter S Hammerman的其他文献
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{{ truncateString('Peter S Hammerman', 18)}}的其他基金
Therapeutic approaches for LKB1-deficient non-small cell lung cancer
LKB1缺陷型非小细胞肺癌的治疗方法
- 批准号:
9082508 - 财政年份:2016
- 资助金额:
$ 34.82万 - 项目类别:
Therapeutic targeting of Fibroblast Growth Factor Receptors in Squamous Cancers
鳞状癌中成纤维细胞生长因子受体的治疗靶向
- 批准号:
8938887 - 财政年份:2015
- 资助金额:
$ 34.82万 - 项目类别:
Genomic Discovery and Targeted Therapeutics in Squamous Cell Lung Cancer
鳞状细胞肺癌的基因组发现和靶向治疗
- 批准号:
8716540 - 财政年份:2012
- 资助金额:
$ 34.82万 - 项目类别:
Genomic Discovery and Targeted Therapeutics in Squamous Cell Lung Cancer
鳞状细胞肺癌的基因组发现和靶向治疗
- 批准号:
8907920 - 财政年份:2012
- 资助金额:
$ 34.82万 - 项目类别:
Genomic Discovery and Targeted Therapeutics in Squamous Cell Lung Cancer
鳞状细胞肺癌的基因组发现和靶向治疗
- 批准号:
8531888 - 财政年份:2012
- 资助金额:
$ 34.82万 - 项目类别:
Genomic Discovery and Targeted Therapeutics in Squamous Cell Lung Cancer
鳞状细胞肺癌的基因组发现和靶向治疗
- 批准号:
8383327 - 财政年份:2012
- 资助金额:
$ 34.82万 - 项目类别:
Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer.
项目 3:针对非小细胞肺癌治疗耐药的转录机制。
- 批准号:
9553649 - 财政年份:
- 资助金额:
$ 34.82万 - 项目类别:
Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer.
项目 3:针对非小细胞肺癌治疗耐药的转录机制。
- 批准号:
9279636 - 财政年份:
- 资助金额:
$ 34.82万 - 项目类别:
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