EXPLORE AND TARGET THE EPIGENETIC VULNERABILITY OF PAX3-FOXO1-DRIVEN RHABDOMYOSARCOMA

探索并针对 PAX3-FOXO1 驱动的横纹肌肉瘤的表观遗传脆弱性

• 批准号: 10521711
• 负责人: Xiang Chen
• 金额: $ 69.14万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521711
• 关键词: ATAC-seq; Adolescent; Adverse effects; Alveolar; Alveolar Rhabdomyosarcoma; Biochemical; Biological Testing; Biology; Cell Proliferation; Cells; Child; Childhood Soft Tissue Sarcoma; Chromatin; Chromatin Structure; Chromosomal translocation; Clinical; Combined Modality Therapy; Complementary DNA; Coupled; Data; Dependence; Disease; Disease Progression; EWS-FLI1 fusion protein; Epigenetic Process; Ewings sarcoma; FOXO1A gene; Family; Fusion Oncogene Proteins; Genes; Genetic; Genetic Transcription; Genomic approach; Goals; Histones; Human; In Vitro; Knock-out; Lead; Light; Lysine; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Methylation; Modality; Modeling; Modification; Molecular; Molecular Abnormality; Molecular Conformation; Neoplasm Metastasis; Oncogenic; Oncoproteins; Outcome; Output; PAX3 gene; PAX7 gene; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmacology; Play; Radiation therapy; Research; Rhabdomyosarcoma; Risk; Role; Techniques; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; Translating; Treatment Efficacy; Tumorigenicity; Validation; Variant; Xenograft Model; Xenograft procedure; base; cancer cell; cell motility; cell transformation; chemotherapy; effective therapy; epigenomics; exhaustion; experimental study; functional genomics; high risk; histone demethylase; histone methyltransferase; improved; in vivo; inhibitor; innovation; knock-down; member; methyl group; migration; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pre-clinical; programs; protein expression; single-cell RNA sequencing; small molecule; soft tissue; t(2; 13)(q35; q14); transcription factor; transcriptome; transcriptome sequencing; translational potential; tumor; tumor growth; tumorigenesis; young adult

ABSTRACT The genetic abnormalities that drive tumorigenesis are usually coupled with epigenetic alterations such as aberrant histone lysine methylations due to deregulation of histone methyltransferases and histone lysine demethylases(KDMs). Our long-term goal is to investigate the mechanism by which oncogenic transcription factors “hijack” KDMs in tumorigenesis and disease progression, and develop new therapies to block the functions of these oncoproteins by targeting KDMs. Rhabdomyosarcoma (RMS) is a devastating soft tissue cancer in children and adolescent young adults. The alveolar RMS (aRMS) is a more aggressive subtype, with a higher rate of metastasis. aRMS is primarily driven by the pathognomonic fusion oncoprotein PAX3-FOXO1 or its variant PAX7-FOXO1 through chromosomal translocations of t(2;13)(q35;q14) or t(1;13)(p36;q14). Despite the fact that current treatment modalities have steadily improved survival of low-risk RMS patients, the outcome for the fusion positive aRMS patients with metastasis remains dismal. Even for patients with favorable outcomes, the aggressive chemotherapy and radiotherapy may lead to long-term adverse effects as children may be particularly vulnerable to long-term toxicity. These clinical challenges underscore a pressing need to identify new therapeutic targets and develop better therapies for these patients. However, one obstacle is much less is known about vulnerabilities that arise in transformed cells by PAX3-FOXO1 that could be exploited therapeutically. In this application, we will investigate the functional impact of KDM4 in tumorigenesis driven by PAX3- FOXO1 (Aim 1); dissect the molecular mechanism of KDM4 inhibition on PAX3-FOXO1-driven aRMS (Aim 2), and translate KDM4 inhibitors into novel therapeutic approaches for PAX3-FOXO1 positive aRMS (Aim 3). This innovative study integrates multiple approaches to identify and validate new therapeutic targets and explore small molecules to dually inhibit oncoproteins in the context of a disease that is driven by a undruggable fusion oncoprotein. The proposed research will be impactful for its translational relevance for the treatment of children with high-risk RMS and have the potential to shed new light on the molecular mechanism of PAX3-FOXO1-driven aRMS.

摘要 驱动肿瘤发生的遗传异常通常与表观遗传改变相结合， 由于组蛋白甲基转移酶和组蛋白赖氨酸的失调引起的异常组蛋白赖氨酸甲基化 脱甲基酶（KDM）。我们的长期目标是研究致癌的机制， 转录因子在肿瘤发生和疾病进展中“劫持”KDM，并开发新的治疗方法 通过靶向KDM来阻断这些癌蛋白的功能。横纹肌肉瘤（RMS）是一种 儿童和青少年的毁灭性软组织癌。牙槽骨RMS（aRMS）是一种 侵袭性更强，转移率更高。aRMS主要由特异性 融合癌蛋白PAX 3-FOXO 1或其变体PAX 7-FOXO 1通过染色体易位 t（2;13）（q35;q14）或t（1;13）（p36;q14）。尽管目前的治疗方式已经稳定地 改善低风险RMS患者的生存率，融合阳性aRMS患者的结局 转移仍然令人沮丧。即使对于预后良好的患者，积极的化疗和 放疗可能会导致长期的不良反应，因为儿童可能特别容易受到长期的放射性治疗。 毒性这些临床挑战强调了迫切需要确定新的治疗靶点， 为这些患者开发更好的治疗方法。然而，有一个障碍是鲜为人知的， PAX 3-FOXO 1转化细胞中出现的脆弱性，可以在治疗上加以利用。在 在本申请中，我们将研究KDM 4在PAX 3驱动的肿瘤发生中的功能影响。 F0 X 01（Aim 1）;剖析KDM 4抑制PAX 3-F0 X 01驱动的aRMS的分子机制（Aim 2），并将KDM 4抑制剂转化为PAX 3-FOXO 1阳性aRMS的新治疗方法（Aim 3）。这项创新的研究整合了多种方法来识别和验证新的治疗靶点 并探索小分子在疾病的背景下双重抑制癌蛋白， 非药物性融合癌蛋白。拟议的研究将因其翻译相关性而产生影响， 治疗儿童高危RMS，并有可能揭示新的分子 PAX 3-FOXO 1驱动的aRMS的机制。