Development of Trabectedin Analogs that Target the EWS-FLI1 Transcription Factor

开发针对 EWS-FLI1 转录因子的曲贝替定类似物

• 批准号: 9763540
• 负责人: Patrick J Grohar
• 金额: $ 2.8万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763540
• 关键词: Antisense DNA; Apoptosis; Back; Bone neoplasms; Cell Line; Cell Nucleolus; Cell Nucleus; Cell Survival; Cells; Chromosomal translocation; Clinic; Clinical; Clinical Data; Combined Modality Therapy; Connective and Soft Tissue Neoplasm; DNA Damage; Development; Disease; Dominant-Negative Mutation; Down-Regulation; Drug resistance; EWS-FLI1 fusion protein; Equilibrium; Ewings sarcoma; FLI1 Transcription Factor; Failure; Gene Expression; Genes; Genetic Transcription; Goals; In complete remission; Investigation; Methods; Molecular; Neoplasm Metastasis; Normal Cell; Oncogenic; Operative Surgical Procedures; Parents; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Process; Proteins; Radiation; Regimen; Relapse; Series; Serum; Small Interfering RNA; Specificity; Therapeutic; Therapeutic Index; Toxic effect; Transcriptional Regulation; Translating; United States National Institutes of Health; Vertebral column; Work; analog; angiogenesis; base; bench to bedside; chemotherapeutic agent; chemotherapy; clinical translation; cytotoxic; follow-up; genetic signature; improved; inhibitor/antagonist; novel; novel therapeutics; outcome forecast; phase 1 study; phase 2 study; phase II trial; programs; public health relevance; senescence; small molecule; t(11; 22)(q24; q12); targeted treatment; transcription factor; tumor

 DESCRIPTION (provided by applicant): Ewing sarcoma is a bone and soft tissue tumor with a poor prognosis, particularly for patients with relapsed or metastatic disease, where overall survival is less than 30%. In the last 25 years since the establishment of the currently employed 5-drug chemotherapeutic regimen, there has been very little improvement in survival and no change in the therapy for patients with this disease. Therefore, there is a great need for new compounds and approaches that directly target the genes responsible for Ewing sarcoma cell survival. The goal of this proposal is to build a therapy centered on the suppression of the defining molecular feature of this tumor, the EWS-FLI1 transcription factor. Ewing sarcoma absolutely depends on continued expression of EWS-FLI1 for cell survival. This oncogenic transcription factor alters the expression of more than 500 genes to create the transcriptional program responsible for the continued proliferation of Ewing sarcoma cells, drug resistance and even metastasis. The challenge in targeting EWS-FLI1 is that the protein is a transcription factor and widely believed to be an "undruggable target". In this proposal, we employ a bedside-to-bench and back again approach to develop a therapy that targets EWS-FLI1 using a compound called trabectedin as the backbone. In an early phase I study, a patient with Ewing sarcoma treated with Trabectedin achieved a complete response to this drug. Consistent with this result, we have previously shown that trabectedin interferes with the activity of the EWS-FLI1 transcription factor. Unfortunately, a follow-up phase II trial did not confirm that activity of th drug in Ewing sarcoma. In this proposal, we hypothesize that the failure of Ewing sarcoma patients to respond to the trabectedin in the phase II study was due to a poor therapeutic index of the drug that limited the exposure of trabectedin to levels that were not high enough to block EWS-FLI1. We believe that the drug associated toxicity that limited these serum levels was the collateral DNA damage that caused toxicity in normal cells as well as Ewing sarcoma cells. Therefore, in keeping with the NIH initiative of understanding extreme clinical responders, in this proposal, we will evaluate 82 analogs of trabectedin to identify compound(s) with an improved therapeutic index that will allow the blockade of EWS-FLI1 in patients. In the process, we will establish exactly how the drug works to block EWS-FLI1 activity and what the relative contribution of the drug associated DNA damage is to this activity. Finally, we will propose a novel combination therapy with improved EWS-FLI1 suppression that focuses the drug associated DNA damage specifically on Ewing sarcoma cells. Together, these results will provide the basis for the clinical translation of a trabectedin- based therapy centered on EWS-FLI1 blockade to improve patient survival.

 描述（由适用提供）：尤因肉瘤是一种骨和软组织肿瘤，预后较差，尤其是对于中继或转移性疾病的患者，总生存率小于30％。自目前使用5毒物化学治疗方案建立以来的过去25年中，这种疾病患者的生存率几乎没有改善，治疗的变化没有变化。因此，需要直接瞄准负责ewing肉瘤细胞存活的基因的新化合物和方法。该提案的目的是建立一种以抑制该肿瘤（EWS-FLI1转录因子）定义分子特征的为中心的疗法。 Ewing肉瘤绝对取决于EWS-FLI1在细胞存活中的持续表达。这种致癌转录因子改变了500多个基因的表达，以创建负责ewing肉瘤细胞，耐药性甚至转移的持续增殖的转录程序。靶向EWS-FLI1的挑战在于，该蛋白质是转录因子，被广泛认为是“不良目标”。在此提案中，我们采用了床头到基础的方法，然后再次使用后卫方法来开发一种靶向EWS-FLI1的疗法，该疗法使用称为TraceDIN的化合物作为骨架。在第一阶段的研究中，用Trabectedin治疗的Ewing肉瘤患者对该药物做出了完全反应。与此结果一致，我们先前已经表明，径向素干扰了EWS-FLI1转录因子的活性。不幸的是，II阶段试验没有证实TH药物在Ewing肉瘤中的活性。在该提案中，我们假设ewing肉瘤患者在第二阶段研究中无法对育曲素做出反应，这是由于该药物的治疗指数较差，该指数限制了将踪毒素暴露于不足以阻止EWS-FLI1的水平上的暴露水平。我们认为，限制这些血清水平的与药物相关的药物是导致正常细胞和ewing肉瘤细胞毒性的附带DNA损伤。因此，为了符合了解极端临床响应者的NIH计划 提案，我们将评估82种捕捉蛋白的类似物，以鉴定具有改进的治疗指数的化合物，这将允许患者的EWS-FLI1封锁。在此过程中，我们将准确地确定该药物如何阻止EWS-FLI1活性，以及​​与药物相关的DNA损伤的相对贡献对此活性。最后，我们将提出一种新型的组合疗法，并改善了EWS-FLI1抑制作用，该疗法将相关的DNA损伤聚焦于Ewing肉瘤细胞上。总之，这些结果将为以EWS-FLI1封锁为中心的基于抓蛋白的治疗的临床翻译提供基础，以改善患者的生存率。