Investigating a hierarchical model for PI3K activation and inhibition in breast cancer by double PIK3CA mutations in cis
研究顺式 PIK3CA 双突变对乳腺癌 PI3K 激活和抑制的分层模型
基本信息
- 批准号:10437283
- 负责人:
- 金额:$ 26.3万
- 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:2020-08-13 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Advisory CommitteesAllelesAmino AcidsBindingBiochemicalBiological ProcessBreastBreast Cancer CellBreast Cancer PatientBreast OncologyCell modelCell physiologyCellsClinicClinicalClinical TrialsComplexDouble EffectDrug TargetingEnvironmentEpigenetic ProcessEstrogen ReceptorsEstrogen receptor positiveFamilyGenerationsGenetic TranscriptionGlobal ChangeGoalsGrowthGuanosine TriphosphateHistone-Lysine N-MethyltransferaseHumanHyperactivityIn VitroInstitutionInternationalInvestigationKnock-inLipid BindingLipidsMLL geneMalignant NeoplasmsMammary NeoplasmsMeasuresMedicineMembraneMembrane LipidsMemorial Sloan-Kettering Cancer CenterMentorsMentorshipMetastatic breast cancerModelingMutateMutationOncogene ActivationOncogenesPI3K/AKTPIK3CA genePathway interactionsPatientsPhasePhosphorylationPhosphotransferasesPhysiologyPositioning AttributeProgression-Free SurvivalsProtein BiochemistryProtein KinaseProteomicsProto-Oncogene Proteins c-aktRandomized Clinical TrialsReceptor ActivationReceptor Protein-Tyrosine KinasesRecombinantsRecurrenceRegulationResearchSamplingScienceScientistSecureServicesSignal PathwaySignal TransductionTestingTrainingWorkalpelisibanticancer researchbasecancer cellcandidate markercareercareer developmentexperienceexperimental studygenomic biomarkerhistone methyltransferaseimprovedin vivoinhibitor/antagonistmalignant breast neoplasmmedical schoolsmouse modelmutantnoveloverexpressionphosphoproteomicspre-clinicalreconstitutionresponseresponse biomarkerstandard of carestructural biologytenure track
项目摘要
PROJECT SUMMARY/ABSTRACT
PIK3CA is the most frequently mutated oncogene in human cancer. PI3Kα inhibitors are a new standard of
care in PIK3CA mutant ER+ metastatic breast cancer (ER+ MBC) and some patients have durable responses.
In this proposal, I capitalize on our recent discovery of a novel mechanism of oncogene activation by double
PIK3CA mutations. We have demonstrated that double PIK3CA mutations are frequent across all PIK3CA
mutant cancers, occur at recurrent amino acid positions, and are in cis on the same allele. Double mutations
activate PI3K signaling and growth more than single hotspot mutations in vitro and in vivo, and biochemically
activate PI3K through disruption of p85 inhibition and increased membrane binding. Double mutations increase
sensitivity to PI3Kα inhibition in cells and in PIK3CA mutant ER+ MBC patients. Our work has uncovered a
hierarchical model for the activation and inhibition of PI3K based on mutation number (Vasan, et al. Science
2019). I will test the hypotheses that this hierarchical model extends to PI3K regulation, crosstalk with the
estrogen receptor, and activation of novel AKT substrates. I will use recombinant double mutant PI3K
complexes reconstituted with Ras and RTK to dissect the mechanisms of regulation (Aim 1.1) and the
mechanisms of cellular generation of PIP3 (Aim 1.2). I will leverage knockin and overexpression cellular
models to measure activation and inhibition of double mutant ER+ breast cancer (Aim 2.1) and modulation of
ER-dependent transcription (Aim 2.2). These experiments will be performed in vitro, in vivo, in patient
samples, and under PI3K inhibitor treatment. I will utilize unbiased phosphoproteomics on double mutant cells
to credential new AKT protein kinase substrates (Aim 3.1) including the KMT family of histone lysine
methyltransferases (Aim 3.2). Together these aims will validate our hierarchical model of oncogene activation
by double PIK3CA mutants across a wide variety of cellular and biological processes and will lead to new
strategies to inhibit PI3K including testing PI3Kα inhibitors in multiple PIK3CA mutant patients. I am an
Assistant Attending with the Breast Medicine Service at Memorial Sloan Kettering Cancer Center (MSKCC),
and I have outlined a 5-year career plan that builds upon my background studying structural biology and my
clinical training in breast oncology. I have assembled an outstanding mentoring team of Dr. Lewis Cantley
(primary mentor) and Dr. Maurizio Scaltriti (co-mentor). My advisory committee will include Dr. Neal Rosen, Dr.
Ross Levine, and Dr. Komal Jhaveri. They are internationally renowned scientists in their respective fields who
will provide me the mentorship and support to attain scientific independence. I will have access to unparalleled
institutional support at MSKCC and Weill Cornell Medical College. Both institutions are at the leading edge of
cancer research and are heavily invested in career development. Collectively, this training environment will
enable me to achieve my goals of ultimately securing a tenure-track independent position.
项目摘要/摘要
PIK3CA是人类癌症中最常见的癌基因。 PI3Kα抑制剂是一个新标准
PIK3CA突变ER+转移性乳腺癌(ER+ MBC)和一些患者的护理有持久的反应。
在此提案中,我利用了我们最近发现的一种新颖的致癌基因激活机制
PIK3CA突变。我们已经证明了双PIK3CA突变经常在所有PIK3CA中
突变癌发生,发生在复发氨基酸位置,并在同一等位基因的顺式中。双重突变
在体外和体内激活PI3K信号传导和增长超过单个热点突变,并在生化上
通过破坏p85抑制和增加膜结合来激活PI3K。双重突变增加
细胞和PIK3CA突变ER+ MBC患者中PI3Kα抑制的敏感性。我们的工作发现了
基于突变数的激活和抑制PI3K的分层模型(Vasan等。
2019)。我将测试该层次模型扩展到PI3K调节的假设,与
雌激素受体和新型Akt底物的激活。我将使用重组双突变体PI3K
复合物与RAS和RTK重构以剖析调节机制(AIM 1.1)和
细胞生成PIP3的机制(AIM 1.2)。我将利用敲除和过表达的蜂窝
测量双突变ER+乳腺癌激活和抑制的模型(AIM 2.1)
ER依赖性转录(AIM 2.2)。这些实验将在体内进行体外,患者进行
样品,以及在PI3K抑制剂治疗下。我将在双突变细胞上利用无偏的磷蛋白质组学
到凭证新的Akt蛋白激酶底物(AIM 3.1),包括KMT组蛋白歌词
甲基转移酶(AIM 3.2)。这些目标共同验证我们的癌基因激活的分层模型
通过在各种细胞和生物过程中的双Pik3ca突变体中,将导致新的
抑制PI3K的策略,包括在多个PIK3CA突变患者中测试PI3Kα抑制剂。我是一个
助理在纪念斯隆·克特林癌症中心(MSKCC)参加乳房医学服务
我概述了一个为期5年的职业计划,该计划是基于我的背景研究结构生物学和我的
乳房肿瘤学的临床训练。我已经组建了一个杰出的刘易斯·坎特利博士的心理团队
(主要导师)和Maurizio Scaltriti博士(Co-Incertor)。我的咨询委员会将包括尼尔·罗森博士,博士。
罗斯·莱文(Ross Levine)和科马尔·贾维里(Komal Jhaveri)博士。他们是各自领域的国际知名科学家
将为我提供指导和支持以获得科学独立性。我将可以访问无与伦比的
MSKCC和Weill Cornell医学院的机构支持。这两个机构都处于领先地位
癌症研究,大量投资于职业发展。总体而言,这种培训环境将
使我能够实现最终确保任期独立职位的目标。
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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Neil Vasan其他文献
Neil Vasan的其他文献
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{{ truncateString('Neil Vasan', 18)}}的其他基金
Base-Editing the Cancer Kinome to Enable Drug Discovery
对癌症激酶组进行碱基编辑以实现药物发现
- 批准号:
10687392 - 财政年份:2023
- 资助金额:
$ 26.3万 - 项目类别:
Investigating a hierarchical model for PI3K activation and inhibition in breast cancer by double PIK3CA mutations in cis
研究顺式 PIK3CA 双突变对乳腺癌 PI3K 激活和抑制的分层模型
- 批准号:
10055519 - 财政年份:2020
- 资助金额:
$ 26.3万 - 项目类别:
Investigating a hierarchical model for PI3K activation and inhibition in breast cancer by double PIK3CA mutations in cis
研究顺式 PIK3CA 双突变对乳腺癌 PI3K 激活和抑制的分层模型
- 批准号:
10659151 - 财政年份:2020
- 资助金额:
$ 26.3万 - 项目类别:
Investigating a hierarchical model for PI3K activation and inhibition in breast cancer by double PIK3CA mutations in cis
研究顺式 PIK3CA 双突变对乳腺癌 PI3K 激活和抑制的分层模型
- 批准号:
10469648 - 财政年份:2020
- 资助金额:
$ 26.3万 - 项目类别:
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