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ZNF-Mediated Resistance to Imatinib Mesylate in Gastrointestinal Stromal Tumor

ZNF 介导的胃肠道间质瘤对甲磺酸伊马替尼的耐药性

基本信息

批准号：
9130763
负责人：
Lori Rink
金额：
$ 24.9万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130763
关键词：
70-kDa Ribosomal Protein S6 Kinases Address Adult Advisory Committees Affect American Association of Cancer Research American Society of Clinical Oncology Award Biological Assay Biopsy Specimen Cancer Burden Cell Line Cells Clinic Clinical Clinical Research Combined Modality Therapy Communities Comprehensive Cancer Center Dasatinib Data Developmental Therapeutics Program Drug resistance Exons Faculty Feedback Fellowship Fox Chase Cancer Center Funding Gastrointestinal Stromal Tumors Genes Goals Human Hypoxia Imatinib mesylate Immunoblotting In Vitro Kansas Leadership Light Malignant Neoplasms Measures Mediating Medical Oncology Mentors Modeling Molecular Profiling National Cancer Institute Neoadjuvant Therapy Oncogenic PDGFRA gene PI3 gene PI3K/AKT Pathway interactions Patients Pharmaceutical Preparations Phase II Clinical Trials Philadelphia Positioning Attribute Proto-Oncogene Proteins c-akt Public Health RNA Interference RNA Splicing Radiation Oncology Radiation Therapy Oncology Group Recurrence Refractory Reporting Research Research Infrastructure Resistance Role Route Sampling Scientific Advances and Accomplishments Serum Signal Pathway Signal Transduction Small Interfering RNA Statistical Data Interpretation Stream Surgical Oncology Testing Time Training Training Programs Transactivation Transforming Growth Factor beta Translating Translational Research Tumor Cell Line Universities Videoconferences Videoconferencing Work Xenograft Model anticancer research base career cytotoxicity experience genetic signature improved in vivo inhibitor/antagonist interest knock-down medical schools meetings member molecular oncology neoplastic cell novel novel strategies overexpression periostin phase II trial post-doctoral training pre-clinical predicting response predictive marker predictive signature prevent professor programs prospective research study resistance mechanism response sarcoma small molecule inhibitor sunitinib malate targeted agent tenure track tumor tumor growth tumor xenograft tumorigenesis working group

项目摘要

PROJECT SUMMARY/ABSTRACT Imatinib mesylate (IM) has revolutionized the treatment of patients with gastrointestinal stromal tumors (GISTs); however, clinical resistance to IM has become a reality, despite the initial efficacy observed. Furthermore, very limited options exist for patients (~20%) that are refractory at the start of treatment. Using clinical pre-treatment biopsy samples from a prospective neoadjuvant phase II trial (RTOG 0132), I identified a 32-gene signature that includes KRAB-ZNF 91 subfamily members that can predict response to IM. I subsequently demonstrated that many of these genes were not only predictive of IM response but mediated the drug's activity. In order to determine mechanistically how these ZNFs might be modulating response to IM, RNAi approaches were used to knockdown genes within the predictive signature (including 10 ZNFs) in GIST cells and expression profiling was performed using exon 1.0 ST arrays. This led to the finding that periostin, NEDD9 and TGFβ3, are universally downregulated following siRNA-mediated knockdown. This is intriguing because TGFβ3 is a known inducer of periostin and NEDD9, both of which have been reported as frequently overexpressed in a variety of human cancers and indicates that these ZNFs uncovered from these clinical studies may be a “master controller” over these pathways. Interestingly, hypoxia has been shown to upregulate expression of both NEDD9 and periostin (through the PI3K) leading to increased aggressiveness and enhanced survival of tumor cells. Therefore, it is possible that both periostin and NEDD9 are regulated in a similar mechanism by TGFβ and hypoxia, controlled by ZNFs, to modulate IM response in GIST cells. NEDD9 was also shown to be overexpressed and SRC hyper-activated in an IM-resistant GIST cell line, with knockdown of NEDD9 restoring IM sensitivity. I hypothesize that IM resistance in GISTs may be associated with hypoxia leading to the transactivation of TGFβ3 by ZNFs causing subsequent induction of periostin and/or NEDD9 and activation of the PI3-K or SRC pathways, respectively. The activation of these potential “rescue routes” occurs independent of KIT/PDGFRA signaling, thereby overcoming inhibiting activities of IM on pro- survival pathways. My preliminary data suggest that these ZNFs are responsible for regulating this pathway and overexpression of these genes is associated with clinical resistance of GIST patients to IM-based therapy. To test my hypothesis, I propose in Aim 1 to determine if expression of TGFβ3, NEDD9 and/or periostin in primary GIST samples correlate to IM response (both short and long-term) and ZNF expression. In Aim 2 I will investigate how these ZNFs affect TGFβ3, NEDD9 and periostin expression and ultimately response to IM. Aim 3 will establish whether targeting the hypoxia-induced TGFβ3→ periostin→ PI-3K/AKT and/or hypoxia- induced TGFβ3→ NEDD9→ SRC rescue pathway in vivo will abrogate resistance to IM. The central tenet of this proposal is that targeted agents will become potent when used in combinations that simultaneously block multiple oncogenic pathways, preventing the circumvention of parallel pathways that can act as “rescue routes” for these tumor cells. The proposed research will be accomplished at Fox Chase Cancer Center (FCCC) in Philadelphia, PA. FCCC is a comprehensive cancer center as designated by the National Cancer Institute, nationally recognized for its leadership in medical, radiation and surgical oncology. FCCC leadership is committed to providing the necessary infrastructure and support for me to successfully complete my proposed studies. I will be mentored by Drs. Margaret von Mehren (Professor & Director, Sarcoma Program), Andrew K. Godwin (Professor & Director of Molecular Oncology at the University of Kansas Medical School (KUMC), and Erica Golemis (Professor & Deputy Chief Scientific Officer at FCCC), esteemed faculty members at FCCC and KUMC and internationally recognized experts in the field of translational research and medical oncology. I will have the opportunity to interact and discuss my research in regular meetings of working groups including the Sarcoma Program, Translational Research Forum, Developmental Therapeutics and bi-monthly lab meetings attended by both Drs. von Mehren and Godwin (by videoconference). My primary goal is to obtain an independent academic career in cancer research. To help accomplish this goal, I have assembled an advisory committee consisting of my mentors and other FCCC faculty members (Drs. Maureen Murphy, Director of Postdoctoral Training Program and Edna Cukierman) in order to review my research progress and provide feedback. During the first two years of funding, I will continue to work closely with my mentors to address the research goals proposed in Aims 1 and 2. During this time I will transition into independence seeking out a tenure-track faculty position. In the last three years of funding, I will continue the studies proposed in Aims 2 and 3 while establishing my independent research program. As part of my future research objectives, I am interested not only in mechanisms of resistance to novel biologics, such as IM, but in establishing models and challenging existing paradigms to rationally develop combination therapies in order to reduce the burden of cancer. I have already made significant scientific accomplishments in my short career and have established myself to be an important member of the GIST research community. I have authored 10 research articles and scholarly reviews. I have received a number of awards and training fellowships and was selected to orally present my work, the basis of this proposal, at both the AACR and ASCO meetings in 2009.

项目总结/摘要甲磺酸伊马替尼（IM）彻底改变了胃肠道间质瘤患者的治疗（GIST）;然而，尽管观察到初始疗效，但对IM的临床耐药性已成为现实。此外，治疗开始时难治性患者的选择非常有限（约20%）。使用从一项前瞻性新辅助治疗II期试验（RTOG 0132）的临床治疗前活检样本中，我发现了一种 32-基因签名，包括KRAB-ZNF 91亚家族成员，可以预测对IM的反应。我随后证实，这些基因中的许多不仅预测IM应答，而且介导药物的活性。为了从机制上确定这些ZNF如何调节对IM的反应， RNAi方法用于敲除GIST中预测标签（包括10个ZNF）内的基因使用外显子1.0 ST阵列进行表达谱分析。这导致了骨膜蛋白， NEDD 9和TGFβ3在siRNA介导的敲低后普遍下调。这是耐人寻味的因为TGFβ3是骨膜蛋白和NEDD 9的已知诱导剂，这两种蛋白经常被报道为在多种人类癌症中过表达，并表明这些ZNF从这些临床研究可能是这些途径的“主控制器”。有趣的是，缺氧已经被证明上调NEDD 9和骨膜蛋白的表达（通过PI 3 K），导致攻击性增加并提高肿瘤细胞的存活率。因此，有可能骨膜蛋白和NEDD 9都在骨形成过程中受到调节。 TGFβ和缺氧的类似机制，由ZNF控制，以调节GIST细胞中的IM反应。 NEDD 9也显示在IM抗性GIST细胞系中过表达和SRC超活化，敲低NEDD 9恢复IM敏感性。我假设GIST中的IM耐药性可能与缺氧导致ZNF反式激活TGFβ3，导致随后诱导骨膜蛋白和/或 NEDD 9和PI 3-K或SRC通路的激活。激活这些潜在的“拯救途径”的发生不依赖于KIT/PDGFRA信号传导，从而克服了IM对pro-PDGFRA的抑制活性。生存之路。我的初步数据表明，这些ZNF负责调节这一途径，并且这些基因的过表达与GIST患者对基于IM的治疗的临床抗性相关。为了验证我的假设，我在目的1中提出，确定TGFβ3、NEDD 9和/或骨膜蛋白的表达是否与骨形成有关。在原发性GIST样品中，与IM应答（短期和长期）和ZNF表达相关。In Aim 2 I 将研究这些ZNF如何影响TGFβ3、NEDD 9和骨膜蛋白表达以及最终对IM的反应。目的3将确定是否靶向低氧诱导的TGFβ3→ periostin→ PI-3 K/AKT和/或低氧诱导的TGFβ3 → periostin → PI-3 K/AKT。诱导的TGFβ3→ NEDD 9 → SRC拯救通路可消除IM的耐药性。的中心原则这一建议是，当靶向剂与同时阻断多个致癌途径，防止绕过平行途径，可以作为“救援路线” for these tumor肿瘤cells细胞. 这项研究将在宾夕法尼亚州费城的Fox Chase癌症中心（FCCC）完成。 FCCC是一个综合性的癌症中心，由国家癌症研究所指定，国家承认因其在医疗、放射和肿瘤外科领域的领导地位。气候变化框架公约领导层致力于提供必要的基础设施和支持，使我能够顺利完成我的研究建议。我会得到指导 Margaret von Mehren博士（教授兼主任，肉瘤项目），Andrew K.戈德温（教授& 堪萨斯大学医学院（KUMC）分子肿瘤学主任和埃里卡戈莱米斯（Golemis）（教授和副首席科学官在FCCC），尊敬的教员在FCCC和KUMC和国际公认的转化研究和医学肿瘤学领域的专家。我将有有机会在工作组的定期会议上互动和讨论我的研究，包括肉瘤计划，转化研究论坛，发展治疗学和双月实验室会议出席冯·梅伦博士和戈德温博士（通过视频会议）。我的主要目标是获得一个独立的癌症研究的学术生涯。为了帮助实现这一目标，我组建了一个咨询委员会，包括我的导师和其他FCCC教职员工（莫琳墨菲博士，博士后主任培训计划和埃德娜Cukierman），以审查我的研究进展，并提供反馈。在获得资助的头两年里，我将继续与我的导师密切合作，目标1和2中提出的目标。在此期间，我将过渡到独立寻求终身教职的轨道教师职位。在过去三年的拨款中，我将继续进行目标2和3中建议的研究，建立我的独立研究项目作为我未来研究目标的一部分，仅在对新生物制剂（如IM）的耐药机制方面，但在建立模型和挑战因此，我们必须利用现有的范例，合理开发联合疗法，以减轻癌症的负担。在我短暂的职业生涯中，我已经取得了重大的科学成就，我希望自己成为GIST研究社区的重要成员。我写了10篇研究文章，学术评论。我获得了许多奖项和培训奖学金，并被选为口头在2009年的AACR和ASCO会议上介绍我的工作，这一建议的基础。