Nanoscale analysis of proteomic response to novel targeted therapies for lymphoma

淋巴瘤新型靶向治疗的蛋白质组学反应的纳米级分析

基本信息

  • 批准号:
    8706072
  • 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

项目摘要

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.
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。我在使用转基因模型研究癌症方面建立了坚实的基础。我现在的目标是获得成为一名独立的翻译研究人员所需的技能,包括生物统计学和临床试验设计的严格知识以及在正在进行的研究中作为合作研究者的经验,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,以验证生物标志物用于临床决策。在工作台上,我开发了一种新的纳米流体蛋白质组学免疫测定(NIA),用于分析使用微创技术(如细针抽吸(FNA)或抽血)收集的患者标本中的细胞中的癌蛋白,在4纳升的裂解液中只有25个细胞。NIA可用于同时鉴定单个蛋白质的多种磷酸化和非磷酸化同种型。我已经开发了NIA的使用来测量总癌蛋白,包括淋巴瘤中的BCL 2、MYC、ERK和MEK,以测量MAP激酶(MAPK)通路中ERK和MEK蛋白的磷酸化百分比;并在CML治疗早期鉴定特定磷酸化ERK 2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性患者。最后,我使用NIA结合流式细胞术(FACS)来鉴定在接受阿托伐他汀单药临床试验治疗的低级别NHL患者细胞中RAS/MAPK/STAT信号转导的变化。我们发现,慢性淋巴细胞白血病(CLL)和边缘区淋巴瘤(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与细胞凋亡和信号抑制相关的可测量临床效应。在治疗前和治疗早期比较个体患者的蛋白质组特征可以提供无法从单个时间点收集的有价值的信息。我假设,血液和FNA中蛋白质组变化的纳米级分析可以揭示个体患者中新型疗法的分子活性。我还假设NIA可用于确定药物何时优先作用于特定的蛋白磷酸化亚型,并且FACS分析可分辨药物对肿瘤细胞与非肿瘤细胞的作用。我将开发互补的NIA和FACS技术,用于分析治疗前和治疗期间个体患者的微创血液或细针抽吸样本。我将确定BCL 2和RAS通路谱的变化是否可分别用于监测BCL 2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(包括用于执行NIA的CB 1000仪器)和技术支持的充分支持。斯坦福大学癌症中心和斯坦福大学临床试验办公室提供临床试验支持资源,包括对我们的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大楼的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,其中包括一个临床研究单位,以协助研究人员开发,实施和进行以患者为基础的研究,检查室和核心实验室,以执行专门的样本处理和存储,以支持研究方案。公共卫生研究所还设有定量科学股和生物信息学股,为研究设计和数据分析提供生物统计支持,并促进来自多个平台的数据整合。我将有权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,通过卫生研究和政策部的斯坦福大学临床和转化教育与研究中心完成31个单位的生物统计和临床设计课程。我将通过成为ABT-263正在进行的I期研究的共同研究者和我们的阿托伐他汀淋巴瘤研究的共同方案主任来获得临床经验。我的导师任命有100%的时间保护研究相关的活动,以实现这些目标,指导我的主要导师,博士院长费尔舍和共同导师,博士罗纳德利维。我很幸运能够组建这个致力于我职业发展的优秀团队。我们三个人每个月都会聚在一起。Felsher博士是斯坦福大学癌症中心分子治疗项目的主任,他建立了一个高超的、资金雄厚的研究项目,包括5个不同的联邦赠款,研究“癌基因成瘾”的机制。Felsher博士将确保我获得教育,评估和指导,财务支持和资源,用于我的学习,领导机会和受保护的时间,并为职业发展提供具体指导。Levy博士是淋巴瘤转化研究的世界领导者,将为进行转化临床试验和实现学术进步提供指导。我的职业生涯致力于转化研究,以实现个性化癌症治疗的目标。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cryptococcal osteomyelitis and meningitis in a patient with non-hodgkin's lymphoma treated with PEP-C.
使用 PEP-C 治疗的非霍奇金淋巴瘤患者的隐球菌骨髓炎和脑膜炎。
  • DOI:
    10.1136/bcr.08.2011.4578
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0.9
  • 作者:
    To,ChristinaA;Hsieh,RobertW;McClellan,JamesScott;Howard,Walter;Fischbein,NancyJ;Brown,JaniceMY;Felsher,DeanW;Fan,AliceC
  • 通讯作者:
    Fan,AliceC
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ALICE Chen FAN其他文献

ALICE Chen FAN的其他文献

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{{ truncateString('ALICE Chen FAN', 18)}}的其他基金

Analysis of CTCs for Early Prediction of Response to Treatment in RCC
分析 CTC 以早期预测 RCC 治疗反应
  • 批准号:
    8814773
  • 财政年份:
    2014
  • 资助金额:
    $ 17.34万
  • 项目类别:
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
  • 批准号:
    7989932
  • 财政年份:
    2010
  • 资助金额:
    $ 17.34万
  • 项目类别:
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
  • 批准号:
    8307524
  • 财政年份:
    2010
  • 资助金额:
    $ 17.34万
  • 项目类别:
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
  • 批准号:
    8131666
  • 财政年份:
    2010
  • 资助金额:
    $ 17.34万
  • 项目类别:
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
  • 批准号:
    8517030
  • 财政年份:
    2010
  • 资助金额:
    $ 17.34万
  • 项目类别:
Clinical Translational Core
临床转化核心
  • 批准号:
    9324947
  • 财政年份:
  • 资助金额:
    $ 17.34万
  • 项目类别:
Clinical Translational Core
临床转化核心
  • 批准号:
    9150889
  • 财政年份:
  • 资助金额:
    $ 17.34万
  • 项目类别:

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职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
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用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
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