SIRT5 inhibitors and degraders as novel treatments for Ewing sarcoma

SIRT5 抑制剂和降解剂作为尤文肉瘤的新型治疗方法

基本信息

批准号：
10385995
负责人：
David Benner Lombard
金额：
$ 52.89万
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：
2022
资助国家：
美国
起止时间：
2022-01-28 至 2022-01-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385995
关键词：
ATAC-seq Affect Apoptosis Apoptotic Biological Biology Bone Tissue Bone neoplasms Cardiovascular Diseases Cell Survival Cells Cessation of life Charge Child Chromatin Chromatin Structure Clinical Clinical Trials Crystallization Cytotoxic Chemotherapy Data Disease Drug Kinetics Drug Targeting EWSR1 gene Enhancers Ewings sarcoma FDA approved FLI1 gene Family Family member Fusion Oncogene Proteins Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Family Genes Genetic Transcription Goals Growth Health Histones Impairment In Vitro Knockout Mice Libraries Link Localized Disease Lysine Malignant Childhood Neoplasm Malignant Neoplasms Maps Mass Spectrum Analysis Maximum Tolerated Dose Mission Modality Modification Mus Normal Cell Nuclear Oncogenic Operative Surgical Procedures Pathway interactions Patients Pediatric Oncology Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Post-Translational Protein Processing Prognosis Property Proteins Proteomics Public Health Publishing Radiation Reader Recurrence Relapse Research Research Support Role Second Primary Cancers Sirtuins Site Specificity Structure Survival Rate Survivors Testing Therapeutic United States National Institutes of Health Work analog base bone cell type druggable target epigenomics experimental study fusion gene genome-wide histone modification human disease improved in vivo inhibitor innovation insight long-term sequelae loss of function new therapeutic target novel novel therapeutic intervention programs side effect small molecule soft tissue therapeutic target tool transcription factor transcriptome transcriptome sequencing transcriptomics tumor young adult

项目摘要

Abstract Ewing sarcoma (EWS) is an aggressive tumor arising in soft tissue and bone of children and young adults. EWS is treated with a combination of cytotoxic chemotherapy, local radiation, and/or surgery. Patients with localized disease show a favorable overall survival rate. However, there is still a pressing need for new therapeutic approaches for EWS. Patients with metastatic or recurrent EWS have a very poor prognosis. Moreover, current EWS treatments are associated with many short- and long-term sequelae, e.g. accelerated cardiovascular disease and secondary cancers. EWS-FLI1 is the fusion oncoprotein present in most cases of EWS. It functions as a pioneer transcription factor to affect expression of many target genes. The aberrant EWS transcriptome represents a potential therapeutic target in EWS. This proposal focuses on the sirtuin SIRT5 as a novel therapeutic target in EWS. SIRT5 is found throughout the cell, and regulates protein targets in diverse pathways by removing negatively charged modifications on lysine residues, including succinylation. Although normal cell types and whole mice tolerate loss of SIRT5 with minimal phenotypes, we have found that specific cancers, notably including EWS, are exquisitely dependent on SIRT5, and rapidly undergo apoptosis following SIRT5 depletion. We have linked this effect to a role for SIRT5 in desuccinylating nuclear histones, thereby modulating gene expression in EWS. We and others have shown that SIRT5 is in principle amenable to selective inhibition or degradation with small molecules. Our long-term goal is to evaluate SIRT5 as a potential therapeutic target for EWS. The objective of this proposal is to generate new biological insights into SIRT5 function in EWS, and characterize SIRT5 inhibitors and SIRT5 PROTAC-based degraders. The central hypotheses of this application are that: 1) SIRT5 is required for EWS cell survival via histone desuccinylation and regulation of gene expression; and 2) SIRT5 inhibitors and degraders will represent useful tool compounds to interrogate SIRT5 biology, and a starting point for potential future EWS therapeutics. The rationale for this application is that EWS cells show exquisite vulnerability to SIRT5 loss-of-function, while other cell types and whole mice show no major ill effects. Hence, SIRT5 inhibition would likely be well tolerated clinically. The work will take place in the context of two Specific Aims. First, we will elucidate the impact of SIRT5 and Ksucc on histones and gene expression, using mass spectrometry along with transcriptomic and epigenomic approaches. Second, we will optimize and validate SIRT5 inhibitors and degraders, using medicinal chemistry approaches and based in part on SIRT5-inhibitor co-crystal structures. The application is innovative, in that no published data currently link SIRT5 to EWS, and no potent and selective SIRT5 inhibitors or PROTACs have as yet been described. The work is significant, since there is an unmet clinical need for improved therapies for EWS.

抽象的尤文肉瘤 (EWS) 是一种发生在儿童和青少年软组织和骨骼中的侵袭性肿瘤成年人。 EWS 采用细胞毒性化疗、局部放疗和/或手术相结合的治疗方法。患有局部疾病的患者表现出良好的总体生存率。然而，仍然存在紧迫的问题 EWS 需要新的治疗方法。转移性或复发性 EWS 患者的病情非常严重预后不良。此外，当前的 EWS 治疗与许多短期和长期的症状相关。后遗症，例如加速心血管疾病和继发性癌症。 EWS-FLI1 是融合大多数 EWS 病例中都存在癌蛋白。它作为先锋转录因子发挥作用，影响许多靶基因的表达。异常的 EWS 转录组代表了一种潜在的治疗方法 EWS 中的目标。该提案重点关注 Sirtuin SIRT5 作为 EWS 的新型治疗靶点。 SIRT5 存在于整个细胞中，并通过负向去除来调节多种途径中的蛋白质靶标赖氨酸残基上的带电修饰，包括琥珀酰化。尽管正常细胞类型和整体小鼠能够以最小的表型耐受 SIRT5 的缺失，我们发现特定的癌症，特别是包括 EWS，都高度依赖 SIRT5，并在 SIRT5 后迅速发生细胞凋亡消耗。我们将这种效应与 SIRT5 在去琥珀酰化核组蛋白中的作用联系起来，从而调节 EWS 中的基因表达。我们和其他人已经证明 SIRT5 原则上适合用小分子选择性抑制或降解。我们的长期目标是将 SIRT5 评估为 EWS 的潜在治疗靶点。该提案的目的是产生新的生物学见解深入研究 EWS 中的 SIRT5 功能，并表征 SIRT5 抑制剂和基于 SIRT5 PROTAC 的降解剂。本申请的中心假设是：1) SIRT5 是 EWS 细胞通过组蛋白存活所必需的基因表达的脱琥珀酰化和调节； 2) SIRT5抑制剂和降解剂将代表探究 SIRT5 生物学的有用工具化合物，以及未来潜在 EWS 的起点疗法。该应用的基本原理是 EWS 细胞对 SIRT5 表现出极大的脆弱性功能丧失，而其他细胞类型和整个小鼠没有表现出重大不良影响。因此，SIRT5 抑制临床上可能具有良好的耐受性。这项工作将在两个具体目标的背景下进行。第一的，我们将使用质量阐明 SIRT5 和 Ksucc 对组蛋白和基因表达的影响光谱测定法以及转录组学和表观基因组学方法。其次，我们将优化和使用药物化学方法并部分基于 SIRT5 抑制剂共晶结构。该应用程序具有创新性，目前尚未发布数据将 SIRT5 与 EWS 连接起来，但尚未发现有效且选择性的 SIRT5 抑制剂或 PROTAC 描述的。这项工作意义重大，因为改进 EWS 疗法的临床需求尚未得到满足。