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

• 批准号: 10739630
• 负责人: David Benner Lombard
• 金额: $ 51.83万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739630
• 关键词: ATAC-seq; Acceleration; 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; 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; Microsomes; 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; Quality of life; 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; Western Blotting; Work; analog; 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

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.

摘要 尤文肉瘤是一种发生于儿童和青少年软组织和骨骼的侵袭性肿瘤 成年人了EWS用细胞毒性化疗、局部放射和/或手术的组合治疗。 局限性疾病患者的总体生存率较好。然而，仍然有一个紧迫的 EWS需要新的治疗方法。转移性或复发性EWS的患者 预后不良。此外，目前的EWS治疗与许多短期和长期的 后遗症，例如加速的心血管疾病和继发性癌症。EWS-FLI 1是融合 癌蛋白存在于大多数EWS病例中。它作为一个先锋转录因子影响 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， 目标在EWS。该提案的重点是sirtuin SIRT 5作为EWS的新治疗靶点。SIRT5 在整个细胞中发现，并通过去除负性蛋白质来调节不同途径中的蛋白质靶点。 赖氨酸残基上的带电修饰，包括琥珀酰化。虽然正常的细胞类型和整个 小鼠耐受SIRT 5的损失，具有最小的表型，我们发现特定的癌症，特别是 包括EWS在内的细胞都非常依赖SIRT 5，并在SIRT 5后迅速发生凋亡。 耗尽我们已经将这种效应与SIRT 5在去琥珀酰化核组蛋白中的作用联系起来， 调节EWS中的基因表达。我们和其他人已经表明，SIRT 5原则上是适合的， 用小分子选择性抑制或降解。我们的长期目标是评估SIRT 5作为一种 EWS的潜在治疗靶点。这项提案的目的是产生新的生物学见解 研究SIRT 5在EWS中的功能，并表征SIRT 5抑制剂和基于SIRT 5 PROTAC的降解剂。 本申请的中心假设是：1）SIRT 5是EWS细胞存活所需的，通过组蛋白 去琥珀酰化和基因表达的调节;和2）SIRT 5抑制剂和降解剂将代表 询问SIRT 5生物学的有用工具化合物，以及潜在未来EWS的起点 治疗学这种应用的基本原理是，EWS细胞对SIRT 5表现出极其脆弱的脆弱性。 功能丧失，而其他细胞类型和整个小鼠没有显示出重大的不良影响。因此，SIRT 5抑制 在临床上可能耐受良好。这项工作将在两个具体目标的背景下进行。第一、 我们将阐明SIRT 5和Ksucc对组蛋白和基因表达的影响， 光谱法沿着转录组学和表观基因组学方法。第二，我们将优化和 验证SIRT 5抑制剂和降解剂，使用药物化学方法，部分基于 SIRT 5-抑制剂共晶体结构。该应用程序是创新的，因为目前没有公布的数据 将SIRT 5与EWS联系起来，目前还没有有效的选择性SIRT 5抑制剂或PROTAC。 介绍了这项工作是重要的，因为有一个未满足的临床需要，改善治疗EWS。