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: 8887853
• 负责人: Patrick J Grohar
• 金额: $ 43.46万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887853
• 关键词: Antisense DNA; Apoptosis; Back; Bone Tissue; Bone neoplasms; Cell Line; Cell Nucleolus; Cell Nucleus; Cell Survival; Cells; Childhood; Chromosomal translocation; Clinic; Clinical; Clinical Data; Combined Modality Therapy; DNA Damage; Development; Disease; Dominant-Negative Mutation; Down-Regulation; Drug resistance; EWS-FLI1 fusion protein; Equilibrium; Ewings sarcoma; Failure; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; In complete remission; Investigation; Methods; Molecular; Neoplasm Metastasis; Normal Cell; Oncogenic; Operative Surgical Procedures; Parents; Patients; Pharmaceutical Preparations; Process; Proteins; Radiation; Regimen; Relapse; Relative (related person); Series; Serum; Small Interfering RNA; Soft Tissue Neoplasms; Specificity; Therapeutic; Therapeutic Index; Toxic effect; Translating; Translations; United States National Institutes of Health; Vertebral column; Work; analog; angiogenesis; base; bench to bedside; chemotherapeutic agent; chemotherapy; cytotoxic; follow-up; improved; inhibitor/antagonist; novel; 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（申请人提供）：尤文肉瘤是一种预后不良的骨和软组织肿瘤，特别是对于复发或转移性疾病的患者，自目前建立以来的过去25年中，其总生存率低于30%。采用 5 种药物的化疗方案，对这种疾病患者的生存率几乎没有改善，治疗方法也没有改变，因此，非常需要直接靶向该疾病的新化合物和方法。该提案的目标是建立一种以抑制该肿瘤的定义分子特征（EWS-FLI1 转录因子）为中心的疗法，该疗法绝对依赖于 EWS-FLI1 的持续表达。这种致癌转录因子会改变 500 多个基因的表达，从而产生导致尤文肉瘤细胞持续增殖、耐药性甚至转移的转录程序。 EWS-FLI1 是一种转录因子，被广泛认为是“不可成药的靶标”。在本提案中，我们采用从床边到工作台再返回的方法来开发一种使用化合物靶向 EWS-FLI1 的疗法。在一项早期的 I 期研究中，接受曲贝替定治疗的尤文肉瘤患者获得了对该药物的完全缓解，与此结果一致，我们之前已经证明了这一点。不幸的是，曲贝替定干扰 EWS-FLI1 转录因子的活性，后续 II 期试验并未证实该药物在尤文肉瘤中的活性。 II期研究中的曲贝替定是由于该药物的治疗指数较差，限制了曲贝替定的暴露水平，不足以阻断EWS-FLI1。相信限制这些血清水平的药物相关毒性是导致正常细胞和尤文肉瘤细胞毒性的附带 DNA 损伤，因此，为了与 NIH 了解极端临床反应者的倡议保持一致，在此。 根据该提案，我们将评估 82 种曲贝替定类似物，以确定具有改善治疗指数的化合物，从而能够阻断患者的 EWS-FLI1 在此过程中，我们将准确确定该药物如何阻断 EWS-FLI1 活性。最后，我们将提出一种改进 EWS-FLI1 抑制的新型联合疗法，将药物相关的 DNA 损伤专门针对尤文肉瘤细胞。总之，这些结果将为基于曲贝替定的疗法的临床转化提供基础，该疗法以 EWS-FLI1 阻断为中心，以提高患者的生存率。