Nanoscale analysis of proteomic response to novel targeted therapies for lymphoma
淋巴瘤新型靶向疗法的蛋白质组反应的纳米级分析
基本信息
- 批准号:8131666
- 负责人:
- 金额:$ 17.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-19 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAntibodiesApoptosisAppointmentBCL-2 ProteinBCL2 geneBioinformaticsBiological AssayBiological MarkersBiometryBloodBurkitt LymphomaCancer CenterCell CountCellsChronic Lymphocytic LeukemiaChronic Myeloid LeukemiaClinicalClinical SciencesClinical TrialsClinical Trials DesignCommitData AnalysesData Base ManagementDevelopmentDiagnosticEducationEquipmentFamilyFinancial SupportFine needle aspiration biopsyFlow CytometryFollicular LymphomaFoundationsFundingGleanGoalsGrantHealthHealth SciencesImmuneImmunoassayIndividualInstitutesInvestigationIsoelectric FocusingIsomerismKnowledgeLaboratoriesLeadershipLymphomaMAPK1 geneMEKsMYC Family ProteinMalignant NeoplasmsMeasurableMeasurementMeasuresMentorsMethodsMitogen-Activated Protein KinasesMolecularMonitorNon-Hodgkin&aposs LymphomaOncogene ProteinsOncogenesOncogenicPathway interactionsPatientsPatternPharmaceutical PreparationsPhosphorylationPolicy ResearchProcessProtein IsoformsProteinsProteomicsProtocols documentationRefractoryResearchResearch DesignResearch PersonnelResearch SupportResourcesSTAT3 geneSTAT5A geneSamplingScienceSignal TransductionSpecimenTechniquesTechnologyTherapeuticTherapeutic AgentsTimeTransgenic ModelTranslational ResearchTyrosine Kinase InhibitorWorkaddictionatorvastatinbasecancer therapycareercareer developmentclinical decision-makingclinical effectdata integrationdesigneducation evaluationexperienceinhibitor/antagonistinnovative technologiesinstructorinstrumentmeetingsminimally invasivenanofluidicnanolitrenanoscaleneoplastic cellnew technologynovelnovel therapeuticspatient oriented researchphase 1 studyphase 2 studypopulation healthprogramsprotein activationprotein profilingresearch studyresponseskillssquare footstandard caretherapy designtranslational clinical trialtumor
项目摘要
DESCRIPTION (provided by applicant): The focus of my research is to develop novel technologies to measure the proteomic response of individual patients to targeted therapies for lymphoma. I have established a strong foundation in the use of transgenic models to study cancer. I now aim to gain the skills needed to become an independent translational researcher, including rigorous knowledge of biostatistics and clinical trial design and experience as a co- investigator in ongoing studies, with the goal to successfully incorporate potential new biomarkers into patient oriented research to validate biomarkers for clinical decision making. At the bench, I have developed a novel nanofluidic proteomic immunoassay (NIA) for the analysis of oncoproteins in cells from patient specimens collected using minimally invasive techniques such as fine needle aspirate (FNA) or blood draw, in as few as 25 cells in 4 nanoliters of lysate. NIA can be used to simultaneously identify multiple phosphorylated and non- phosphorylated isoforms of individual proteins. I have developed the use of NIA to measure total oncoproteins, including BCL2, MYC, ERK and MEK in lymphoma, to measure percent phosphorylation of ERK and MEK proteins in the MAP Kinase (MAPK) pathway; and identify decreases of a specific phosphorylated ERK2 isomer early during CML treatment that could distinguish patients who would respond to tyrosine kinase inhibitors from those that were treatment refractory. Finally, I have used NIA together with flow cytometry (FACS) to identify changes in RAS/MAPK/STAT signaling in cells from patients with low grade NHL treated on a clinical trial of single agent atorvastatin. We discovered that patients with Chronic Lymphocytic Leukemia (CLL) and Marginal Zone Lymphoma (MZL) showed an increase in tumor cell apoptosis and a decrease in circulating tumor cells upon treatment with atorvastatin, indicating that atorvastatin may have a measurable clinical effect associated with apoptosis and signaling inhibition. Comparison of proteomic signatures in individual patients before and early during treatment can provide valuable information that can not be gleaned from a single timepoint. I hypothesize that nanoscale analysis of proteomic changes in blood and FNA's can reveal the molecular activity of novel therapeutics in individual patients. I also hypothesize that NIA can be used to identify when a drug preferentially effects a specific protein phospho-isoform and FACS analysis can resolve drug effects on tumor cells versus non-tumor cells. I will develop complementary NIA and FACS technologies for analysis of minimally invasive blood or fine needle aspirate samples from individual patients before and during treatment. I will determine if changes in BCL2 and RAS pathway profiles can be used to monitor the molecular activity of a BCL2 family inhibitor (ABT-263) and atorvastatin, respectively. My proposal will be amply supported by state-of-the art facilities, equipment, including a CB1000 instrument to perform NIA, and technical support. The Stanford Cancer Center and Stanford Clinical Trials Office provide resources for clinical trial support, including support for Oncore, our online research management database. Biomarker studies will be performed in the laboratory of Dr. Felsher in the Center for Clinical Sciences Research building. Finally, our new Population Health Sciences Institute (PHSI) is a newly opened patient-based research center that occupies 40,000 square feet containing a Clinical Investigation Unit to assist investigators with the development, implementation, and conduct of patient-based research studies, examination rooms and a core laboratory to perform specialized sample processing and storage in support of research protocols. The PHSI also has a Quantitative Sciences Unit and a Bioinformatics Unit to provide biostatistical support in research design and data analysis and to facilitate integration of data from multiple platforms. I will have access to all these facilities, and equipment. A key component to my career development is an ambitious plan to complete 31 units of biostatistical and clinical design coursework through the Stanford Center for Clinical and Translational Education and Research, Department of Health Research and Policy. I will gain clinical experience by becoming a co-investigator on an ongoing Phase I study of ABT-263, and as co-protocol director for our investigator-initiated study of atorvastatin in lymphoma. My instructor appointment has 100% protected time for research-related activities in order to accomplish these goals, guided my Primary Mentor, Dr. Dean Felsher and Co-Mentor, Dr. Ronald Levy. I am fortunate to have assembled this well-matched team committed to my career development. The three of us will meet together monthly. Dr. Felsher, Director of the Stanford Cancer Center Molecular Therapeutics Program, has established a superb and highly funded research program, including 5 different federal grants, studying the mechanism of "oncogene addiction". Dr. Felsher will assure that I receive the education, evaluation and guidance, financial support and resources for my studies, leadership opportunities and protected time, and provide specific guidance for career development. Dr. Levy, a world leader in translational research for lymphoma, will provide guidance in performing translational clinical trials and in achieving academic advancement. My career is dedicated to translational investigation for realizing the goal of individualized cancer treatment.
描述(由申请人提供):我的研究重点是开发新技术来测量个体患者对淋巴瘤靶向治疗的蛋白质组学反应。我已经在利用转基因模型研究癌症方面打下了坚实的基础。我现在的目标是获得成为一名独立的转化研究人员所需的技能,包括严格的生物统计学知识和临床试验设计,以及作为正在进行的研究的共同研究者的经验,目标是成功地将潜在的新生物标志物纳入面向患者的研究中,以验证临床决策的生物标志物。在实验台上,我开发了一种新型的纳米流体蛋白质组免疫分析法(NIA),用于分析患者标本中细胞中的癌蛋白,这些标本采用微创技术收集,如细针抽吸(FNA)或抽血,在4纳米升的裂解液中只有25个细胞。NIA可用于同时鉴定单个蛋白的多种磷酸化和非磷酸化亚型。我已经开发了使用NIA来测量总癌蛋白,包括淋巴瘤中的BCL2, MYC, ERK和MEK,以测量MAP激酶(MAPK)途径中ERK和MEK蛋白的磷酸化百分比;并在CML治疗早期识别特异性磷酸化ERK2异构体的减少,这可以区分对酪氨酸激酶抑制剂有反应的患者和治疗难治的患者。最后,我使用NIA和流式细胞术(FACS)来鉴定接受单药阿托伐他汀临床试验治疗的低级别NHL患者细胞中RAS/MAPK/STAT信号的变化。我们发现慢性淋巴细胞白血病(CLL)和边缘带淋巴瘤(MZL)患者在接受阿托伐他汀治疗后,肿瘤细胞凋亡增加,循环肿瘤细胞减少,表明阿托伐他汀可能具有可测量的与细胞凋亡和信号抑制相关的临床效果。比较个体患者在治疗前和治疗早期的蛋白质组特征可以提供无法从单一时间点收集到的有价值的信息。我假设对血液和FNA中蛋白质组学变化的纳米级分析可以揭示新疗法在个体患者中的分子活性。我还假设NIA可以用来确定药物何时优先作用于特定的蛋白磷酸化异构体,而FACS分析可以解决药物对肿瘤细胞和非肿瘤细胞的作用。我将开发互补的NIA和FACS技术,用于分析个体患者在治疗前和治疗期间的微创血液或细针抽吸样本。我将确定BCL2和RAS途径谱的变化是否可以分别用于监测BCL2家族抑制剂(ABT-263)和阿托伐他汀的分子活性。我的提议将得到最先进的设施、设备(包括一台CB1000仪器)和技术支持的充分支持。斯坦福癌症中心和斯坦福临床试验办公室为临床试验提供资源支持,包括对在线研究管理数据库Oncore的支持。生物标志物研究将在临床科学研究中心的Felsher博士实验室进行。最后,我们新的人口健康科学研究所(PHSI)是一个新开设的以患者为基础的研究中心,占地40,000平方英尺,包含一个临床调查单位,以协助研究人员开发,实施和开展以患者为基础的研究,检查室和一个核心实验室,以执行专门的样品处理和存储,以支持研究方案。物理科学研究所设有定量科学组和生物信息学组,为研究设计和数据分析提供生物统计学支持,并促进多个平台数据的整合。我可以使用所有这些设施和设备。我职业发展的一个关键组成部分是一个雄心勃勃的计划,即通过斯坦福大学卫生研究与政策系临床与转化教育与研究中心完成31个单元的生物统计学和临床设计课程。我将成为正在进行的ABT-263 I期研究的共同研究者,并作为研究者发起的阿托伐他汀治疗淋巴瘤研究的共同方案主任,从而获得临床经验。我的主要导师Dean Felsher博士和共同导师Ronald Levy博士指导我说,我的导师预约为研究相关活动提供了100%的时间,以实现这些目标。我很幸运地组建了这个团队,致力于我的职业发展。我们三个每月聚一次。Felsher博士是斯坦福癌症中心分子治疗项目的主任,他建立了一个极好的、资金雄厚的研究项目,包括5项不同的联邦拨款,研究“癌基因成瘾”的机制。Dr. Felsher将确保我得到教育、评估和指导、学业上的资金支持和资源、领导机会和保护时间,并为我的职业发展提供具体的指导。Levy博士是淋巴瘤转化研究领域的世界领导者,他将在进行转化临床试验和实现学术进步方面提供指导。我的职业是致力于实现个体化癌症治疗目标的转化研究。
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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ALICE Chen FAN其他文献
ALICE Chen FAN的其他文献
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Nanoscale analysis of proteomic response to novel targeted therapies for lymphoma
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7989932 - 财政年份:2010
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$ 17.34万 - 项目类别:
Nanoscale analysis of proteomic response to novel targeted therapies for lymphoma
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8706072 - 财政年份:2010
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Nanoscale analysis of proteomic response to novel targeted therapies for lymphoma
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8517030 - 财政年份:2010
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