Suv39H Targeted Therapy for Treatment of Childhood Rhabdomyosarcoma

Suv39H靶向治疗儿童横纹肌肉瘤

• 批准号: 8313203
• 负责人: ASOKE K MAL
• 金额: $ 10万
• 依托单位: BUFFALO BIOLABS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313203
• 关键词: Accounting; Alveolar; Alveolar Rhabdomyosarcoma; Antineoplastic Agents; Binding; Biological; Biological Assay; Buffaloes; Cell Differentiation process; Cell Line; Cells; Chemical Structure; Child; Childhood Rhabdomyosarcoma; Collection; Commit; Data; Development; Disease; Dose; Epigenetic Process; Evaluation; Future; Gene Expression; Gene Targeting; Genetic Transcription; Goals; Growth; Histone H3; Human; Investigation; Libraries; Luciferases; Lysine; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Methyltransferase; Muscle; Myoblasts; Nomenclature; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preclinical Drug Evaluation; Proteins; Publications; Reporter; Rhabdomyosarcoma; Roswell Park Cancer Institute; Screening procedure; Skeletal Muscle; Small Molecule Chemical Library; Solid; Solid Neoplasm; Specificity; Structure; System; Testing; Therapeutic; Transactivation; Treatment outcome; Water; Work; Xenograft procedure; base; clinical application; disorder subtype; drug development; drug discovery; improved; in vivo; inhibitor/antagonist; multimodality; myogenesis; neoplastic cell; novel; novel strategies; outcome forecast; overexpression; progenitor; programs; prospective; response; restoration; skeletal muscle differentiation; small hairpin RNA; small molecule libraries; treatment strategy; tumor

DESCRIPTION (provided by applicant): Rhabdomyosarcoma (RMS) is a childhood malignant tumor and is thought to arise due to the arrest of skeletal muscle differentiation (myogenesis) program. It accounts for 3.5% of all malignancies in children. Despite multimodality therapeutic treatment approaches, the outlook for patients with metastatic subtype, alveolar rhabdomyosarcoma (ARMS), remains unchanged. Moreover, conventional toxic chemotherapeutic strategies fail to succeed for the treatment of metastatic rhabdomyosarcoma; therefore, urgent need of novel approaches for the development of new pharmaceuticals to treat this dreadful disease. Because rhabdomyosarcoma cells are defective to complete myogenic terminal differentiation program, restoration of this abortive differentiation program in these cels would be a novel promising anti-RMS chemotherapeutic approach. The ultimate goal of this proposal is to develop novel approach-based new pharmaceuticals capable of restoring the differentiation block in rhabdomyosarcoma cells for the treatment of metastatic rhabdomyosarcoma. While studying the anti-muscle differentiation mechanisms in alveolar rhabdomyosarcoma (ARMS) cells, we found increased level of epigenetic modifier histone H3 lysine-9 methyltransferase Suv39H protein (referred herein KMT1A as per new nomenclature) when these cells were grown in differentiation conditions. Investigation into the mechanism of induced KMT1A expression in the arrest of ARMS cell differentiation led us a recent publication (Cancer Res. (2011) 71(11): p. 3921-31). In this study, we have demonstrated that KMT1A depletion by shRNA restores growth arrest and terminal myogenic gene expression mediated by MyoD, which acts as a key myogenic transcriptional regulator of myogenic program and universally expresses in RMS cells. Moreover, KMT1A depleted ARMS cells fail to develop tumor in vivo. Thus, we are considering KMT1A as a prospective target for developing pharmaceuticals for restoration of MyoD mediated terminal differentiation as an unconventional novel chemotherapeutic strategy for the treatment of metastatic rhabdomyosarcoma disease. The current proposal is focused on exploiting this opportunity as a first step towards developing anti- KMT1A pharmaceuticals for the treatment of ARMS. We will use functional screening of small molecule chemical libraries to identify KMT1A inhibitors capable of inducing MyoD-mediated terminal differentiation in ARMS cells. Specifically, we plan to: 1) Small molecule chemical library screening for inhibitors of KMT1A that re-activate MyoD mediated transcription. 2) Characterization of "hits" for their ability to suppress KMT1A mediated inhibition of MyoD-induced muscle differentiation in metastatic RMS (ARMS) cells. Completion of this proposal should identify KMT1A inhibitors capable of reprogramming MyoD mediated terminal differentiation in ARMS cells and provide a solid platform for subsequent development of KMT1A antagonist pharmaceuticals for clinical applications to treat metastatic rhabdomyosarcoma and other diseases associated with KMT1A deregulation PUBLIC HEALTH RELEVANCE: Metastatic rhabdomyosarcoma (alveolar subtype, ARMS) is incurable using current treatment strategies. Targeting the histone H3 lysine-9 methyltransferase Suv39H, which appears to block MyoD-mediated terminal myogenic program in ARMS cells, represents a novel treatment strategy for the reactivation of MyoD, a key myogenic differentiation factor, in ARMS. This approach should provide a more efficacious and less toxic alternative to current treatment strategies and, thus, has major implications for the therapeutic management of all children with this aggressive disease.

描述（由申请人提供）：横纹肌肉瘤（RMS）是一种儿童恶性肿瘤，被认为是由于骨骼肌分化（肌生成）程序停滞而产生的。它占儿童所有恶性肿瘤的3.5%。尽管采取了多种治疗方法，但转移性亚型肺泡横纹肌肉瘤（ARMS）患者的前景仍然没有改变。此外，传统的毒性化疗策略未能成功治疗转移性横纹肌肉瘤。因此，迫切需要新方法来开发新药物来治疗这种可怕的疾病。由于横纹肌肉瘤细胞无法完成肌原性终末分化程序，因此恢复这些细胞中这种失败的分化程序将是一种新的有前途的抗 RMS 化疗方法。该提案的最终目标是开发基于新方法的新药物，能够恢复横纹肌肉瘤细胞的分化阻断，用于治疗转移性横纹肌肉瘤。在研究腺泡横纹肌肉瘤 (ARMS) 细胞的抗肌肉分化机制时，我们发现当这些细胞在分化条件下生长时，表观遗传修饰剂组蛋白 H3 赖氨酸-9 甲基转移酶 Suv39H 蛋白（根据新命名法在本文中称为 KMT1A）水平增加。对诱导 KMT1A 表达在 ARMS 细胞分化停滞中的机制的研究导致我们最近发表了一篇论文（Cancer Res. (2011) 71(11): p. 3921-31）。在这项研究中，我们证明 shRNA 消除 KMT1A 可恢复由 MyoD 介导的生长停滞和终末生肌基因表达，MyoD 是生肌程序的关键生肌转录调节因子，在 RMS 细胞中普遍表达。此外，KMT1A耗尽的ARMS细胞无法在体内形成肿瘤。因此，我们正在考虑将 KMT1A 作为开发用于恢复 MyoD 介导的终末分化的药物的前瞻性靶标，作为治疗转移性横纹肌肉瘤疾病的非常规新型化疗策略。当前提案的重点是利用这一机会作为开发用于治疗 ARMS 的抗 KMT1A 药物的第一步。我们将利用小分子化学文库的功能筛选来鉴定能够在 ARMS 细胞中诱导 MyoD 介导的终末分化的 KMT1A 抑制剂。具体来说，我们计划：1）小分子化学库筛选可重新激活 MyoD 介导的转录的 KMT1A 抑制剂。 2)“命中”的特征在于其抑制 KMT1A 介导的转移性 RMS (ARMS) 细胞中 MyoD 诱导的肌肉分化抑制的能力。该提案的完成应确定能够重编程 ARMS 细胞中 MyoD 介导的终末分化的 KMT1A 抑制剂，并为后续开发 KMT1A 拮抗剂药物用于临床应用治疗转移性横纹肌肉瘤和与 KMT1A 失调相关的其他疾病提供坚实的平台 公共卫生相关性：使用当前的治疗策略无法治愈转移性横纹肌肉瘤（肺泡亚型，ARMS）。靶向组蛋白 H3 赖氨酸 9 甲基转移酶 Suv39H 似乎可以阻断 ARMS 细胞中 MyoD 介导的终末生肌程序，代表了一种重新激活 ARMS 中关键的生肌分化因子 MyoD 的新治疗策略。这种方法应该为当前的治疗策略提供更有效、毒性更小的替代方案，因此对所有患有这种侵袭性疾病的儿童的治疗管理具有重大意义。