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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的驱动肿瘤发生的遗传异常通常与表观遗传改变相结合，例如由于组蛋白甲基转移酶和组蛋白赖氨酸失调导致组蛋白赖氨酸甲基化异常我们的长期目标是研究去甲基酶（KDM）的致癌机制。转录因子在肿瘤发生和疾病进展中“劫持”KDMs，并开发新疗法通过靶向 KDM 来阻断这些癌蛋白的功能是一种方法。肺泡 RMS (aRMS) 是一种对儿童和青少年来说具有毁灭性的软组织癌。更具侵袭性的亚型，具有更高的转移率，主要是由特征驱动的。融合癌蛋白 PAX3-FOXO1 或其变体 PAX7-FOXO1 通过染色体易位 t(2;13)(q35;q14) 或 t(1;13)(p36;q14)。改善了低风险 RMS 患者的生存率，融合阳性 aRMS 患者的结果即使对于预后良好的患者，积极的化疗和转移仍然令人沮丧。放射治疗可能会导致长期不良影响，因为儿童可能特别容易受到长期不良影响这些临床挑战强调迫切需要确定新的治疗靶点和方法。然而，有一个障碍却鲜为人知。 PAX3-FOXO1 转化细胞中出现的漏洞可用于治疗。在本申请中，我们将研究 KDM4 在 PAX3-驱动的肿瘤发生中的功能影响 FOXO1（目标 1）；剖析 KDM4 抑制 PAX3-FOXO1 驱动的 aRMS 的分子机制（目标 2)，并将 KDM4 抑制剂转化为 PAX3-FOXO1 阳性 aRMS 的新型治疗方法（目的 3) 这项创新研究整合了多种方法来识别和验证新的治疗靶点。并探索小分子在由肿瘤驱动的疾病中双重抑制癌蛋白拟议的研究将因其转化相关性而产生影响。治疗患有高危 RMS 的儿童，并有可能为分子生物学研究提供新的线索 PAX3-FOXO1驱动的aRMS机制。