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Targeting the RNA Exosome for Cancer Therapeutics

靶向 RNA 外泌体用于癌症治疗

基本信息

批准号：
10208799
负责人：
MATS LJUNGMAN
金额：
$ 48.94万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208799
关键词：
Age Auxins BODIPY Biological Assay Biology Bioluminescence Biotin Cancer cell line Cell Death Cell Proliferation Cell Survival Cells Chemosensitization Chemotherapy and/or radiation Data Development Epithelial Cells Event Generations Genetic Transcription Grant Human In Vitro Ionizing radiation Lead Malignant Neoplasms Malignant neoplasm of pancreas Mediating Neoplasm Metastasis Paclitaxel Pancreas Pharmaceutical Preparations Play Process Quality Control RNA RNA Degradation RNA Splicing Radiation Reagent Regimen Role System Technology Testing Therapeutic Therapeutic Intervention Toxic effect Transcript Xenograft Model Xenograft procedure anti-cancer base cancer cell cellular targeting chemotherapeutic agent exosome gemcitabine in vivo in vivo evaluation inhibitor/antagonist innovation lead optimization neoplastic cell new therapeutic target novel pancreas xenograft pancreatic cancer cells pancreatic cancer model pharmacophore pre-clinical protein degradation small hairpin RNA small molecule small molecule inhibitor synergism therapeutic target tumor tumor growth

项目摘要

The RNA exosome is a RNA degradation machinery that plays a critical role in RNA quality control by degrading erroneous or incorrectly spliced RNAs. In many cancers, such as pancreatic cancer, the splicing process is compromised, resulting in the generation of large amounts of aberrant transcripts. We hypothesize that cancer cells are uniquely dependent on RNA exosome activity to remove excess amounts of aberrant transcripts and that the RNA exosome therefore may be an impactful new target for therapeutic intervention for pancreatic cancer. We have developed a set of first-in-class small molecule inhibitors of the RNA exosome and will in this proposal refine these compounds and assess their tumor- targeting efficacy for pancreatic cancer in three specific Aims. In Aim 1 a lead optimization campaign will be initiated of our first-in-class RNA exosome inhibitors. The refined compounds will be evaluated for their RNA exosome-targeting activities using both in vitro and cell-based RNA exosome activity assays and we will identify their cellular targets. In Aim 2, the potencies of the 10 top RNA exosome inhibitors will be assessed by MTT and clonogenic survival assays to select the top three compounds for in vivo studies. These top three compounds will then be used in combination with either ionizing radiation or gemcitabine to assess synergy. Inducible shRNA and auxin-inducible protein degradation technologies will be used to inactivate the RNA exosome and these systems will be compared with the top three inhibitors to explore fundamental mechanisms of action of the RNA exosome in transcriptional and post-transcriptional events. In Aim 3, we will test the 3 most promising compounds in a PDX orthotopic model for pancreatic cancer either alone or in combination regimens with gemcitabine and nab-paclitaxel. This is a very innovative proposal exploring a novel cancer therapeutic target and highly focused on the development of new impactful treatments for pancreatic cancer. Upon the successful completion of this grant period, we intend to perform IND-enabling studies of the best candidate compounds.

RNA外泌体是一种RNA降解机制，它在RNA质量控制中起着关键作用，降解错误或不正确剪接的RNA。在许多癌症中，如胰腺癌，这一过程受到损害，导致产生大量的异常转录本。我们假设癌细胞独特地依赖于RNA外泌体活性来去除过量的因此，RNA外泌体可能是一个有影响力的新靶点，胰腺癌的治疗干预。我们开发了一套一流的小分子 RNA外泌体的抑制剂，并将在本提案中完善这些化合物，并评估它们的肿瘤- 在三个特定目的中对胰腺癌的靶向功效。在目标1铅优化活动将我们的第一个RNA外泌体抑制剂。将对精制化合物的RNA进行评价外泌体靶向活性使用体外和基于细胞的RNA外泌体活性测定，我们将识别它们的细胞目标在目标2中，10种顶级RNA外泌体抑制剂的效力将通过以下评估： MTT和克隆形成存活测定以选择用于体内研究的前三种化合物。这三大然后将化合物与电离辐射或吉西他滨组合使用以评估协同作用。可诱导的shRNA和生长素诱导的蛋白质降解技术将被用于对RNA进行重定向外泌体和这些系统将与前三名抑制剂进行比较，以探索基本机制 RNA外泌体在转录和转录后事件中的作用。在目标3中，我们将测试3 在胰腺癌的PDX原位模型中单独或组合的最有前途的化合物使用吉西他滨和白蛋白结合型紫杉醇的方案。这是一个非常创新的提议，治疗目标，并高度关注胰腺癌新的有效治疗方法的开发。在成功完成该资助期后，我们打算对最好的项目进行IND支持研究候选化合物。