Systematic identification of oncogenic KRAS synthetic lethal interactions
系统鉴定致癌 KRAS 合成致死相互作用
基本信息
- 批准号:9330127
- 负责人:
- 金额:$ 80.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-25 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdverse effectsAllelesAnimal ModelAnimalsBiological AssayBiological ModelsBiological ProcessCRISPR libraryCRISPR screenCRISPR/Cas technologyCancer ModelCancer cell lineCell CountCell DeathCell LineCellsCessation of lifeClinicClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsColon CarcinomaDependencyDevelopmentDiagnosisDose-LimitingEssential GenesExhibitsExperimental ModelsFoundationsGene ExpressionGenerationsGenesGeneticGenetic EngineeringGoalsHumanIn VitroKRAS2 geneMAP Kinase GeneMEK inhibitionMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMediatingMethodsMitogen-Activated Protein Kinase InhibitorMusMutateMutationOncogenesOncogenicOrganoidsPathogenesisPathway interactionsPatientsPharmacologyPhenotypeProcessProtein-Serine-Threonine KinasesProteinsRALGDS geneRNA InterferenceRecurrenceSignal PathwaySignal TransductionSystemTANK-binding kinase 1TBK1 geneTechnologyTherapeutic AgentsToxic effectTumorigenicityWorkXenograft procedurebasecurative treatmentseffective therapyexperimental studygene productgenetic analysisgenome editinggenome-widein vivoin vivo Modelinhibitor/antagonistinnovationinsightloss of functionmouse modelmutantnovelnovel therapeutic interventionnovel therapeuticspre-clinicalpreventpublic health relevanceresistance mechanismtargeted treatmenttranslational studytumortumor growthtumor microenvironmenttumor progression
项目摘要
DESCRIPTION (provided by applicant): Activating mutations of KRAS are among the most common mutations found in human cancers, and cancers that harbor KRAS clearly depend on the activity of this oncogene for tumor maintenance. However, despite considerable effort, direct targeting of KRAS or known KRAS effector pathways has not yet led to effective therapies in cancers that harbor mutant KRAS. An alternative approach to direct targeting of known cancer alleles is to exploit the genetic concept of synthetic lethality, in which gene products are identified that, when suppressed or inhibited, result in cell death only in the presence of another
non-lethal mutation. Synthetic phenotype screens in model organisms have provided insights into a broad spectrum of biological processes and in principle; this strategy provides a means to target currently "undruggable" proteins while simultaneously reducing the potential for side effects. Over the past several years, we and others have used RNAi-mediated suppression of gene expression to identify genes whose expression is required in cell lines that depend on mutant KRAS for survival. Inhibitors to some of these synthetic lethal candidates are now the subject of clinical trials in KRAS-driven cancers. However, these early studies used different cells and experimental systems and were limited by scale, technological issues or context. In addition, the discovery and development of new gene manipulation technologies such as Cas9-CRISPR, and methods to isolate and propagate human tumors now provide the opportunity to comprehensively identify novel genes and pathways that are required for the survival of KRAS-dependent cancers. In this application, we propose to use new genome scale gene manipulation technologies, potentially more relevant human and murine experimental models and advanced analytical approaches in an integrated approach to systematically identify KRAS synthetic lethal relationships in cell, organoid and animal models. Specifically, we will performed
genome scale CRISPR mediated loss of function experiments to identify KRAS co-dependencies in both in vitro and in vivo model systems and identify genes and pathways that when inhibited synergize with known KRAS effector pathways to induce tumor regression in KRAS driven cancers. These studies will permit us to define the signaling network perturbed by oncogenic KRAS necessary for tumor maintenance and progression. Targets identified by these approaches will form the basis of translational studies to develop novel therapeutic approaches.
描述(由申请人提供):KRAS的激活突变是人类癌症中发现的最常见突变之一,携带KRAS的癌症显然依赖于该癌基因的活性来维持肿瘤。然而,尽管付出了相当大的努力,但直接靶向KRAS或已知的KRAS效应子途径尚未导致对携带突变KRAS的癌症的有效治疗。一种直接靶向已知癌症等位基因的替代方法是利用合成致死性的遗传概念,其中基因产物被鉴定为,当被抑制或抑制时,仅在另一个等位基因存在时才导致细胞死亡。
非致命突变模式生物中的合成表型筛选提供了对广泛的生物过程的见解,并且在原则上;这种策略提供了一种靶向当前“不可用药”蛋白质的方法,同时降低了副作用的可能性。在过去的几年里,我们和其他人已经使用RNAi介导的基因表达抑制来鉴定依赖突变KRAS生存的细胞系中需要表达的基因。这些合成致命候选物中的一些的抑制剂现在是KRAS驱动的癌症的临床试验的主题。然而,这些早期研究使用不同的细胞和实验系统,并受到规模,技术问题或背景的限制。此外,Cas9-CRISPR等新基因操作技术的发现和开发,以及分离和繁殖人类肿瘤的方法,现在为全面鉴定KRAS依赖性癌症生存所需的新基因和途径提供了机会。在本申请中,我们建议使用新的基因组规模的基因操作技术,潜在的更相关的人类和小鼠实验模型和先进的分析方法,在一个综合的方法,系统地确定KRAS合成致死的关系,细胞,类器官和动物模型。具体来说,我们将执行
基因组规模CRISPR介导的功能丧失实验,以鉴定体外和体内模型系统中的KRAS共依赖性,并鉴定当被抑制时与已知的KRAS效应子途径协同作用以在KRAS驱动的癌症中诱导肿瘤消退的基因和途径。这些研究将使我们能够确定肿瘤维持和进展所必需的致癌KRAS干扰的信号网络。通过这些方法确定的靶点将形成转化研究的基础,以开发新的治疗方法。
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 }}
William C. Hahn其他文献
SV40 small T antigen and PP2A phosphatase in cell transformation
- DOI:
10.1007/s10555-008-9116-0 - 发表时间:
2008-01-23 - 期刊:
- 影响因子:8.700
- 作者:
Anna A. Sablina;William C. Hahn - 通讯作者:
William C. Hahn
A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer
人类癌症中与扩增相关的敏感性增益基因纲要
- DOI:
10.1038/s41467-025-56301-2 - 发表时间:
2025-01-27 - 期刊:
- 影响因子:15.700
- 作者:
Veronica Rendo;Michael Schubert;Nicholas Khuu;Maria F. Suarez Peredo Rodriguez;Declan Whyte;Xiao Ling;Anouk van den Brink;Kaimeng Huang;Michelle Swift;Yizhou He;Johanna Zerbib;Ross Smith;Jonne Raaijmakers;Pratiti Bandopadhayay;Lillian M. Guenther;Justin H. Hwang;Amanda Iniguez;Susan Moody;Ji-Heui Seo;Elizabeth H. Stover;Levi Garraway;William C. Hahn;Kimberly Stegmaier;René H. Medema;Dipanjan Chowdhury;Maria Colomé-Tatché;Uri Ben-David;Rameen Beroukhim;Floris Foijer - 通讯作者:
Floris Foijer
The present and future of the Cancer Dependency Map
癌症依赖图谱的现在与未来
- DOI:
10.1038/s41568-024-00763-x - 发表时间:
2024-10-28 - 期刊:
- 影响因子:66.800
- 作者:
Rand Arafeh;Tsukasa Shibue;Joshua M. Dempster;William C. Hahn;Francisca Vazquez - 通讯作者:
Francisca Vazquez
Developing a library of authenticated Traditional Chinese Medicinal (TCM) plants for systematic biol
开发经过认证的中药 (TCM) 植物库,用于系统生物分析
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
David Eisenberg;Eric S. J. Harris;Bruce A. Littlefield;Shugeng Cao;Jane A. Craycroft;Robert Scholten;Peter E. Bayliss;Yanling Fu;Wenquan Wang;Yan;Zhongzhen Zhao;Hubiao Chen;Yong Liu;Ted J. Kaptchuk;William C. Hahn;Xiaoxin Wang;Thomas M. Roberts;C. Shamu;Jon Clardy - 通讯作者:
Jon Clardy
CDK8 is a colorectal cancer oncogene that regulates β-catenin activity
CDK8 是一种调节β-连环蛋白活性的结直肠癌致癌基因
- DOI:
10.1038/nature07179 - 发表时间:
2008-09-14 - 期刊:
- 影响因子:48.500
- 作者:
Ron Firestein;Adam J. Bass;So Young Kim;Ian F. Dunn;Serena J. Silver;Isil Guney;Ellen Freed;Azra H. Ligon;Natalie Vena;Shuji Ogino;Milan G. Chheda;Pablo Tamayo;Stephen Finn;Yashaswi Shrestha;Jesse S. Boehm;Supriya Jain;Emeric Bojarski;Craig Mermel;Jordi Barretina;Jennifer A. Chan;Jose Baselga;Josep Tabernero;David E. Root;Charles S. Fuchs;Massimo Loda;Ramesh A. Shivdasani;Matthew Meyerson;William C. Hahn - 通讯作者:
William C. Hahn
William C. Hahn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('William C. Hahn', 18)}}的其他基金
Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers
开发用于癌基因驱动癌症的 p300/CBP 组蛋白乙酰转移酶抑制剂
- 批准号:
10627744 - 财政年份:2022
- 资助金额:
$ 80.78万 - 项目类别:
Novel genetic dependencies in VRK2 methylated glioblastoma multiforme
VRK2甲基化多形性胶质母细胞瘤的新遗传依赖性
- 批准号:
10046375 - 财政年份:2020
- 资助金额:
$ 80.78万 - 项目类别:
Development and implementation of multiplex methods to understand the biology and heterogeneity of patient-derived cancer models
开发和实施多重方法来了解源自患者的癌症模型的生物学和异质性
- 批准号:
10004385 - 财政年份:2020
- 资助金额:
$ 80.78万 - 项目类别:
Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimens
系统研究患者来源标本中的胰腺癌微环境
- 批准号:
10250566 - 财政年份:2017
- 资助金额:
$ 80.78万 - 项目类别:
PROJECT 4: Interrogating PP2A Signaling in Human Cancers
项目 4:探究人类癌症中的 PP2A 信号传导
- 批准号:
9981674 - 财政年份:2017
- 资助金额:
$ 80.78万 - 项目类别:
Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimens
系统研究患者来源标本中的胰腺癌微环境
- 批准号:
10242454 - 财政年份:2017
- 资助金额:
$ 80.78万 - 项目类别:
Systematic identification of oncogenic KRAS synthetic lethal interactions
系统鉴定致癌 KRAS 合成致死相互作用
- 批准号:
9150537 - 财政年份:2015
- 资助金额:
$ 80.78万 - 项目类别:
The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center
丹娜—法伯癌症研究所癌症靶标发现和开发中心
- 批准号:
9362809 - 财政年份:2013
- 资助金额:
$ 80.78万 - 项目类别:
The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center
丹娜—法伯癌症研究所癌症靶标发现和开发中心
- 批准号:
9979771 - 财政年份:2013
- 资助金额:
$ 80.78万 - 项目类别:
Identification of TBK1 inhibitors in KRAS-dependent lung cancer
KRAS 依赖性肺癌中 TBK1 抑制剂的鉴定
- 批准号:
8237125 - 财政年份:2012
- 资助金额:
$ 80.78万 - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 80.78万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 80.78万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 80.78万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 80.78万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 80.78万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 80.78万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 80.78万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 80.78万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 80.78万 - 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
- 批准号:
2706416 - 财政年份:2022
- 资助金额:
$ 80.78万 - 项目类别:
Studentship