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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

基本信息

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
项目类别：
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

项目摘要

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.