Identification and Targeting Therapy Resistant Osteosarcoma

骨肉瘤耐药性的识别和靶向治疗

• 批准号: 8814732
• 负责人: Carl G Maki
• 金额: $ 21.52万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814732
• 关键词: ATM activation; Adolescent; Affect; Animal Model; Apoptosis; Bone neoplasms; CHES1 gene; Cell Line; Cells; Child; Cisplatin; Clinical; Cultured Tumor Cells; DNA Damage; DNA Repair; Development; Diagnosis; Disease; Excision; Goals; Grant; Human; Label; Life; Localized Disease; MDM2 gene; Malignant Bone Neoplasm; Malignant Neoplasms; Mixed Neoplasm; Modeling; Molecular; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Postoperative Period; Recurrence; Relapse; Resistance; Risk; Survival Rate; TP53 gene; Treatment Failure; base; cellular imaging; chemotherapy; in vivo; inhibitor/antagonist; killings; novel; nutlin 3; osteosarcoma; public health relevance; resistance mechanism; response; small molecule; standard care; targeted treatment; therapy resistant; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Osteosarcoma (OS) is an aggressive bone cancer that primarily affects children and adolescents. Standard OS treatment includes pre- and post-operative chemotherapy and aggressive surgical resection. Nonetheless, approximately 30% of patients with localized disease and 80% of patients with metastatic disease at diagnosis will fail therapy and die due to tumor progression or relapse. The main reason for treatment failure is the development of tumor therapy resistance. Clearly, it is important to identify the molecular basis for therapy resistance in OS, and ways to target therapy resistant cells. Cisplatin (CP) has been a mainstay OS therapy agent for over 30 yrs, though mechanisms for resistance to CP remain ill-defined. We established Cisplatin (CP) resistant clones from OS cells and compared them with sensitive counterparts. P53 was induced to a lower level and less active after CP in resistant clones. Resistant clones also displayed a heightened DNA damage response after CP treatment that included DNA repair and heightened/prolonged activation of the ATM-ATR-CHK1/2 damage response pathways. Importantly, we determined that small molecule MDM2 antagonists that activate p53 and p73 and which are currently in clinical development (Nutlin-3, MI-319) could effectively kill the CP resistant OS clones. Moreover, we observed that a small molecule Chk1 inhibitor (UCN01) could sensitize multiple resistant OS cell lines and selected clones to CP. Based on these findings, we hypothesize 1) that CP resistance in OS will associate with lower levels/activation of p53 or p73, a heightened DNA damage response, and DNA repair, and 2) that MDM2 antagonists and/or Chk1 inhibitors will effectively target CP resistant OS, and will block tumor regrowth in a novel animal model of human OS tumor recurrence.

描述（由申请人提供）：骨肉瘤（OS）是一种侵袭性骨癌，主要影响儿童和青少年。标准 OS 治疗包括术前和术后化疗以及积极的手术切除。尽管如此，大约 30% 的局部疾病患者和 80% 的诊断时患有转移性疾病的患者将因肿瘤进展或复发而治疗失败并死亡。治疗失败的主要原因是肿瘤治疗耐药性的产生。显然，确定 OS 中治疗抵抗的分子基础以及针对治疗抵抗细胞的方法非常重要。 30 多年来，顺铂 (CP) 一直是 OS 治疗的主要药物，但对 CP 的耐药机制仍不明确。我们从 OS 细胞中建立了顺铂 (CP) 抗性克隆，并将其与敏感的对应克隆进行比较。在抗性克隆中进行 CP 后，P53 被诱导至较低水平且活性较低。抗性克隆在 CP 处理后还表现出增强的 DNA 损伤反应，包括 DNA 修复和 ATM-ATR-CHK1/2 损伤反应途径的增强/延长激活。重要的是，我们确定激活 p53 和 p73 且目前处于临床开发阶段的小分子 MDM2 拮抗剂（Nutlin-3、MI-319）可以有效杀死 CP 耐药 OS 克隆。此外，我们观察到小分子 Chk1 抑制剂 (UCN01) 可以使多种耐药 OS 细胞系和选定的克隆对 CP 敏感。基于这些发现，我们假设 1) OS 中的 CP 耐药性与 p53 或 p73 的较低水平/激活、增强的 DNA 损伤反应和 DNA 修复有关，2) MDM2 拮抗剂和/或 Chk1 抑制剂将有效地靶向 CP 耐药性 OS，并在人类 OS 肿瘤复发的新型动物模型中阻止肿瘤再生。