Understanding CDK1 Function and Cancer Vulnerabilities
了解 CDK1 功能和癌症脆弱性
基本信息
- 批准号:10736617
- 负责人:
- 金额:$ 48.39万
- 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:2023-06-13 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAllelesAnimal ModelAnimalsBiochemicalBiological AssayBiologyBypassCDC2 geneCancer BiologyCell AgingCell CycleCell Cycle InhibitionCell Cycle RegulationCell DeathCell FractionCell ProliferationCell divisionCell physiologyCellsCessation of lifeChemicalsChromosome SegregationClinical TrialsCompensationCoupledCyclin BCyclin-Dependent Kinase InhibitorCyclin-Dependent KinasesDNA DamageDNA biosynthesisDevelopmentDisseminated Malignant NeoplasmEngineeringEpidermal Growth Factor ReceptorEukaryotic CellEventGenetic ModelsGrowthHomeostasisHumanImmunotherapyLeadLifeM cellMAP Kinase GeneMalignant NeoplasmsMammalian CellMapsMitosisMitoticModelingMole the mammalMorbidity - disease rateMusNeoplasm MetastasisNormal CellNormal tissue morphologyOncogenesOncogenicOutcomePathway interactionsPatientsPhasePhosphotransferasesPlayPrecision therapeuticsPrimary NeoplasmProliferatingProtein BiosynthesisProtein FamilyProtein KinaseProteinsPublishingRegulationResearchResearch PersonnelRoleSignal PathwaySignal TransductionTherapeuticTimeToxic effectTransgenic MiceTransgenic OrganismsTumor Tissueanalogcancer cellcancer therapycell transformationchemical geneticsclinical translationearly phase clinical trialepigenetic regulationgenetic approachin vivoin vivo evaluationinhibitorinnovationinterestkinase inhibitormodel organismmortalitymouse modelneoplastic cellnoveloverexpressionprogramsreceptorresponsesenescencesmall molecule inhibitorsynthetic lethal interactiontargeted cancer therapytargeted treatmenttherapeutic targettriple-negative invasive breast carcinomatumortumor growth
项目摘要
Project Summary/Abstract
Precision therapies for aggressive or metastatic cancers, while offering the promise of greater efficacy
and less toxicity, rarely achieve durable responses and only modestly extend a patient's life. The major
limitation to these approaches is that cancer cells evolve and alternate signaling pathways can compensate for
pathways blocked with targeted therapies, i.e. multiple alternative mechanisms to activate the
EGFR/RAS/MAPK pathway lead to a "whack-a-mole" approach with serial treatment with different kinase
inhibitors. Cyclin-dependent kinases (CDKs) are a conserved family of protein kinases that play a central role
in regulating the eukaryotic cell cycle. CDK1 in conjunction with its activating subunit, Cyclin B, plays a critical
role in permitting cells to enter mitosis, coordinates the events required for faithful mitotic progression and
chromosome segregation. To our knowledge, CDK1/B activity is essential for all cells to proliferate and there
are no alternative pathways to bypass the requirement for CDK1. We hypothesize that CDK1 is an ideal
therapeutic target in the context of specific oncogenic signaling pathways which result in an abortive cell cycle
program, such as cell death or senescence, while non-tumor cells are only transiently arrested. Until now,
specific inhibitors of CDK1 have not existed, limiting our ability to discover the underlying mechanisms of CDK1
inhibition as a cancer therapy. Our lab developed a novel engineered mouse, using a chemical-genetic
approach, that allows us to inhibit CDK1 selectively and reversibly in normal and oncogene transformed cells,
or in the context of transgenic tumor models. Our aims will define the mechanisms through which CDK1 elicits
growth arrest and senescence (Aim 1), regulates the unfolded protein response (Aim 2), and how CDK1
inhibition and other therapeutics can be best combined to block tumor growth (Aim 3). We bring together a
team with a track record of innovative research in oncogene signaling and cell cycle regulation (Andrei Goga);
expertise in chemical biology and analog-sensitive kinases (Kevan Shokat); in vivo studies of senescence (Anil
Bhushan) and expertise in mechanisms of regulation of the unfolded protein response (UPR). We hypothesize
that CDK1 controls previously unexplored cellular processes which can be exploited for tumor-specific
vulnerabilities. Such discoveries will hasten the clinical translation of CDK1 inhibitors for a broad variety of
human cancers.
项目概要/摘要
针对侵袭性或转移性癌症的精准治疗,同时有望提高疗效
毒性较小,很少能达到持久的反应,只能适度延长患者的生命。主要
这些方法的局限性在于癌细胞会进化,并且替代信号通路可以补偿
靶向治疗阻断途径,即激活多种替代机制
EGFR/RAS/MAPK 通路导致采用不同激酶进行连续治疗的“打地鼠”方法
抑制剂。细胞周期蛋白依赖性激酶 (CDK) 是一个保守的蛋白激酶家族,发挥着核心作用
调节真核细胞周期。 CDK1 与其激活亚基 Cyclin B 一起发挥着关键作用
在允许细胞进入有丝分裂中的作用,协调忠实有丝分裂进展所需的事件和
染色体分离。据我们所知,CDK1/B 活性对于所有细胞增殖至关重要,并且
没有其他途径可以绕过 CDK1 的要求。我们假设 CDK1 是一个理想的
在导致细胞周期失败的特定致癌信号通路背景下的治疗靶标
程序,例如细胞死亡或衰老,而非肿瘤细胞只是暂时停滞。到目前为止,
CDK1的特异性抑制剂尚不存在,限制了我们发现CDK1潜在机制的能力
抑制作为癌症治疗。我们的实验室利用化学遗传技术开发了一种新型工程小鼠
方法,使我们能够在正常细胞和癌基因转化细胞中选择性且可逆地抑制 CDK1,
或在转基因肿瘤模型的背景下。我们的目标将定义 CDK1 引发的机制
生长停滞和衰老(目标 1),调节未折叠蛋白反应(目标 2),以及 CDK1 如何
抑制和其他疗法最好结合起来阻止肿瘤生长(目标 3)。我们汇集了一个
团队在癌基因信号传导和细胞周期调控方面拥有创新研究记录(Andrei Goga);
化学生物学和类似物敏感激酶方面的专业知识(Kevan Shokat);衰老的体内研究(Anil
Bhushan)和未折叠蛋白反应(UPR)调节机制方面的专业知识。我们假设
CDK1 控制着以前未探索过的细胞过程,可用于肿瘤特异性
漏洞。这些发现将加速 CDK1 抑制剂在多种疾病中的临床转化
人类癌症。
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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ANDREI GOGA其他文献
ANDREI GOGA的其他文献
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{{ truncateString('ANDREI GOGA', 18)}}的其他基金
Understanding breast cancer progression as a defect in the mechanics of tissue self-organization
将乳腺癌进展理解为组织自组织机制的缺陷
- 批准号:
10395995 - 财政年份:2020
- 资助金额:
$ 48.39万 - 项目类别:
Understanding breast cancer progression as a defect in the mechanics of tissue self-organization
将乳腺癌进展理解为组织自组织机制的缺陷
- 批准号:
10613917 - 财政年份:2020
- 资助金额:
$ 48.39万 - 项目类别:
Uncovering Mechanisms of Regulation and Dependency on Fatty Acid Oxidation in MYC-Driven Tumors
揭示 MYC 驱动肿瘤中脂肪酸氧化的调节和依赖性机制
- 批准号:
10194413 - 财政年份:2018
- 资助金额:
$ 48.39万 - 项目类别:
Uncovering Mechanisms of Regulation and Dependency on Fatty Acid Oxidation in MYC-Driven Tumors
揭示 MYC 驱动肿瘤中脂肪酸氧化的调节和依赖性机制
- 批准号:
10436804 - 财政年份:2018
- 资助金额:
$ 48.39万 - 项目类别:
In Vivo Metabolic Catastrophe Is Induced By Acute Oncogene Inhibition (PQ #22)
体内代谢灾难是由急性癌基因抑制(PQ
- 批准号:
8513950 - 财政年份:2012
- 资助金额:
$ 48.39万 - 项目类别:
In Vivo Metabolic Catastrophe Is Induced By Acute Oncogene Inhibition (PQ #22)
体内代谢灾难是由急性癌基因抑制(PQ
- 批准号:
8676483 - 财政年份:2012
- 资助金额:
$ 48.39万 - 项目类别:
In Vivo Metabolic Catastrophe Is Induced By Acute Oncogene Inhibition (PQ #22)
体内代谢灾难是由急性癌基因抑制(PQ
- 批准号:
8384577 - 财政年份:2012
- 资助金额:
$ 48.39万 - 项目类别:
Targeting the MYC Oncogene with CDK Inhibitors
使用 CDK 抑制剂靶向 MYC 癌基因
- 批准号:
8063614 - 财政年份:2010
- 资助金额:
$ 48.39万 - 项目类别:
Targeting the MYC Oncogene with CDK Inhibitors
使用 CDK 抑制剂靶向 MYC 癌基因
- 批准号:
8458489 - 财政年份:2010
- 资助金额:
$ 48.39万 - 项目类别:
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