Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
基本信息
- 批准号:10209682
- 负责人:
- 金额:$ 53.18万
- 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:2015-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressAdultAllelesAntineoplastic AgentsBioavailableBiochemicalBiochemistryBiological ModelsBiologyCRISPR interferenceCancer Cell GrowthCell LineCell membraneCellsChemical ActionsChemicalsCo-ImmunoprecipitationsCollaborationsComplexCysteineDataDevelopmentDrug TargetingEnzymesExhibitsFamilyFoundationsFundingGOLGA7 geneGenotypeGoalsGrowthHematologic NeoplasmsHumanIndividualKnock-in MouseKnowledgeLeadMalignant Childhood NeoplasmMalignant NeoplasmsMeasuresModelingMolecularMusMutant Strains MiceMutateMutationMyelogenousNRAS geneNormal tissue morphologyOncogenicOutputPathway interactionsPre-Clinical ModelProductionPropertyProtein IsoformsProteinsRAS genesRAS inhibitionRas InhibitorReactionResearch PersonnelRoleSerine HydrolaseSignal TransductionStructureTestingTherapeuticTransferaseXenograft procedureacute myeloid leukemia cellbasecancer cellconditional mutantdrug developmentdrug discoveryexperimental studyin vivoinhibitor/antagonistinnovationleukemiamutantnovelnovel strategiesnovel therapeutic interventionpalmitoylationpre-clinicalras GTPase-Activating Proteinsras Proteinstargeted agenttargeted treatmenttherapeutic targettraffickingtranscriptome
项目摘要
SPECIFIC AIMS
Oncogenic RAS mutations, which are among the most common molecular alterations in cancer, encode
mutant proteins that dominantly drive aberrant growth. Unfortunately, structural and biochemical properties of
the mutant Ras/GTPase activating protein (Ras/GAP) molecular switch pose formidable barriers to
mechanism-based drug discovery and no targeted therapies have been approved for Ras-driven cancers to
date. The Ras palmitoylation/depalmitoylation cycle regulates the subcellular trafficking of the N-Ras, H-Ras,
and K-Ras4a isoforms, but not of K-Ras4b. Thus, developing potent and selective inhibitors of the Ras
palmitoylation/depalmitoylation cycle has the potential to treat malignancies dependent on oncogenic N-Ras
without interfering with K-Ras4b signaling in normal tissues. This ongoing project involves a cross-disciplinary
collaboration between investigators with complementery expertise in biochemistry, chemical biology,
hematologic cancer, Ras signaling, and preclinical therapeutics. During the current funding period we: (1)
validated N-Ras palmitoylation as a promising therapeutic target for NRAS mutant cancers in a novel strain of
NrasG12D,C181S “knock in” mice; (2) identified the ABHD17 family of serine hydrolase (SH) enzymes as N-Ras
depalmitoylases; (3) showed that the Palmostatin class of SH inhibitors are too promiscuous for use as
selective probes of ABHD17 function; (4) identified, in collaboration with Lundbeck, a structurally distinct class
of selective ABHD17 inhibitors that reduce the growth of NRAS mutant acute myeloid leukemia (AML) cells
and exhibit genotype-specific activity in isogenic models; and, (5) demonstrated that reduced growth of NRAS
mutant AML cells treated with ABHD17 inhibigtors correlates with biochemical inhibition of Ras effector
pathways. The experiments proposed in this renewal application will extend these exciting studies through the
following specific aims: Aim 1. To investigate the roles of ABHD17s and additional SH enzymes in N-Ras
depalmitoylation and to test the potent and bioavailable ABHD17 inhibitor ABD778 in preclinical models of
AML; and, Aim 2. To identify palmitoyl acyl transferase (PAT) proteins that modify N-Ras and to validate them
as targets for N-Ras mutant cancers. We anticipate that the studies described in this interdisciplinary project
will determine fundamental mechanisms of N-Ras palmitoylation, ascertain the efficacy and mechanism of
action of chemical inhibitors of ABHD17s alone and in combination with other targeted agents, and generate
essential foundational knowledge for developing PAT inhibitors as anti-cancer drugs. The development of
selective inhibitors of oncogenic N-Ras signaling would have significant therapeutic impact for a number of
different aggressive adult and pediatric cancers.
具体目标
致癌性RAS突变是癌症中最常见的分子改变之一,
主要驱动异常生长的突变蛋白质。不幸的是,
突变型Ras/GTP酶激活蛋白(Ras/GAP)分子开关对
基于机制的药物发现和没有靶向治疗已被批准用于Ras驱动的癌症,
约会Ras棕榈酰化/脱棕榈酰化循环调节N-Ras、H-Ras、
和K-Ras 4a同种型,但不是K-Ras 4 b。因此,开发有效的和选择性的Ras抑制剂,
棕榈酰化/脱棕榈酰化循环有可能治疗依赖致癌N-Ras的恶性肿瘤
而不干扰正常组织中的K-Ras 4 b信号传导。这个正在进行的项目涉及跨学科
具有生物化学,化学生物学,
血液癌症、Ras信号传导和临床前治疗。在本财政年度,我们:(1)
验证了N-Ras棕榈酰化作为NRAS突变型癌症的有希望的治疗靶点,
NrasG 12 D、C181 S“敲入”小鼠;(2)将丝氨酸水解酶(SH)的ABHD 17家族鉴定为N-Ras
(3)表明帕莫司他丁类SH抑制剂过于混杂,不能用作
ABHD 17功能的选择性探针;(4)与Lundbeck合作,确定了一个结构独特的类别
选择性ABHD 17抑制剂,减少NRAS突变型急性髓性白血病(AML)细胞的生长
并在等基因模型中表现出基因型特异性活性;(5)证明NRAS的生长减少
ABHD 17受体处理的突变AML细胞与Ras效应子的生化抑制相关
途径。这项更新申请中提出的实验将通过以下方式扩展这些令人兴奋的研究:
具体目标:目标1。研究ABHD 17 s和其他SH酶在N-Ras中的作用
并在临床前模型中测试有效的和生物可利用的ABHD 17抑制剂ABD 778。
AML;以及,目标2。鉴定修饰N-Ras的棕榈酰酰基转移酶(PAT)蛋白并验证它们
作为N-Ras突变型癌症的靶点。我们预计,在这个跨学科项目中描述的研究
将确定N-Ras棕榈酰化的基本机制,确定
ABHD 17的化学抑制剂单独和与其他靶向药物组合的作用,并产生
开发PAT抑制剂作为抗癌药物的必要基础知识。的发展
致癌N-Ras信号传导的选择性抑制剂将对许多肿瘤具有显著的治疗作用。
不同的侵袭性成人和儿童癌症。
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)
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 }}
KEVIN M. SHANNON其他文献
KEVIN M. SHANNON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('KEVIN M. SHANNON', 18)}}的其他基金
In Vivo Functional Analysis of Chromosome 7q22 Deletions in Myeloid Malignancies
骨髓恶性肿瘤中染色体 7q22 缺失的体内功能分析
- 批准号:
9924474 - 财政年份:2017
- 资助金额:
$ 53.18万 - 项目类别:
Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
- 批准号:
10372214 - 财政年份:2015
- 资助金额:
$ 53.18万 - 项目类别:
Project 3: Efficacy of MEK Inhibition in Juvenile Myelomonocytic Leukemia
项目3:MEK抑制对幼年粒单核细胞白血病的疗效
- 批准号:
8932164 - 财政年份:2015
- 资助金额:
$ 53.18万 - 项目类别:
Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
- 批准号:
9040123 - 财政年份:2015
- 资助金额:
$ 53.18万 - 项目类别:
Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
- 批准号:
10610346 - 财政年份:2015
- 资助金额:
$ 53.18万 - 项目类别:
PROJECT 3: A High Content Clinical Trial of the MEK inhibitor Trametinib in JMML
项目 3:MEK 抑制剂 Trametinib 在 JMML 中的高内涵临床试验
- 批准号:
10270583 - 财政年份:2015
- 资助金额:
$ 53.18万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 53.18万 - 项目类别:
Research Grant