Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death

鉴定可降解 Myc 并特异性诱导癌细胞死亡的靶向抗有丝分裂剂

• 批准号: 10534020
• 负责人: Jessica Teitel
• 金额: $ 3.91万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534020
• 关键词: Address; Affect; Amiodarone; Anaphase; Anti-Arrhythmia Agents; Antimitotic Agents; Apoptosis; Apoptotic; Award; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chemoresistance; Cisplatin; Core Facility; Data; Dependence; Development; Disease; Disease Resistance; Dose-Limiting; Drug Kinetics; Drug Stability; Environment; Flow Cytometry; Foundations; G2/M Arrest; Goals; Immunohistochemistry; Kinetics; Knowledge; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mentorship; Michigan; Mitotic; Molecular; Molecular Target; Mutate; Oncogenes; Outcome; Ovarian; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Platinum; Process; Proliferation Marker; Property; Protein Analysis; Proteomics; RNA analysis; Recurrence; Relapse; Research Personnel; Resistance; Serous; Structure-Activity Relationship; Sum; Survival Rate; Testing; Therapeutic; Threonine; Toxic effect; Training; Tubulin; Universities; Woman; anti-cancer; base; c-myc Genes; cancer cell; cancer therapy; cancer type; chemotherapy; cyclin B1; disease heterogeneity; experience; homologous recombination; improved; in vivo; inhibitor; insight; live cell imaging; multicatalytic endopeptidase complex; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; prevent; recombinational repair; restoration; secondary outcome; standard of care; therapy resistant; tumor; ubiquitin-protein ligase

PROJECT SUMMARY Ovarian cancer is the fifth leading cause of cancer death in women and chemotherapy has remained the standard of care for decades. Although 70% of high grade serous ovarian cancer (HGSOC) patients initially respond to platinum-based therapy, nearly all patients succumb due to lack of therapies to treat recurrent, chemotherapy-resistant disease. Therefore, there is an urgent need to identify targetable vulnerabilities of HGSOC and to develop new treatments to prolong survival of these patients. To address this problem, our lab used a computational drug repositioning platform, Drug Predict, to identify amiodarone, an antiarrhythmic agent, as a potential ovarian cancer treatment. Amiodarone potently decreased cell viability and triggered apoptosis in numerous patient-derived HGSOC cell lines, including those that were cisplatin-resistant. These effects were mediated through its ability to degrade c-Myc, which is overexpressed in >45% of HGSOC patients. However, given the dose-limiting toxicity of amiodarone, we applied structure-activity relationship analysis to identify DL78, which lacked hERG activity but retained the anti-cancer properties and ability to regulate Myc. DL78 was significantly more potent and tumor specific than amiodarone, and sensitized cells to platinum therapy. In addition, DL78 rapidly induced G2/M arrest and mitotic catastrophe, which ultimately led to apoptosis in several types of cancer cells. Furthermore, though both amiodarone and DL78 affected degradation of Myc, DL78 enhanced Myc phosphorylation on Threonine-58, consequently increasing proteasome-mediated Myc degradation. Thus, we hypothesize that DL78 induces mitotic catastrophe through Myc degradation and prolonged spindle assembly checkpoint (SAC) activation. We will test this hypothesis through two aims: 1) Examine DL78 effects on SAC activity and determine its dependency on Myc. 2) Investigate the compound’s in vivo efficacy in well-defined patient-derived xenografts. Successful completion of this proposal will improve our understanding of what molecular processes are vital to ovarian cancer cells’ survival. As a secondary outcome, it provides a compound that can be further developed into a preclinical candidate for ovarian & other Myc-driven cancers. The encouraging training environment, plentiful core facilities, and diverse mentorship presented to me at the University of Michigan will facilitate prosperous completion of these aims and bolster my professional development as a translational cancer researcher.

项目摘要 卵巢癌是妇女癌症死亡的第五个主要原因，化学疗法仍然是 尽管最初有70％的高级浆液卵巢癌（HGSOC）患者 对基于铂的治疗做出反应，几乎所有患者由于缺乏治疗复发性治疗的疗法而屈服 抗化疗的疾病。因此，迫切需要确定 HGSOC并开发新的治疗方法以延长这些患者的生存。为了解决这个问题，我们的实验室 药物预测，使用计算药物重新定位平台来识别抗心律失常剂Amidarone， 作为潜在的卵巢癌治疗。胺碘酮可能会降低细胞活力并触发凋亡 许多患者衍生的HGSOC细胞系，包括抗顺铂的细胞系。这些影响是 通过其降解C-MYC的能力进行介导，该C-MYC在> 45％的HGSOC患者中过表达。然而， 鉴于胺酮的剂量限制性毒性，我们应用结构活性分析以识别DL78， 缺少HERG活动，但保留了抗癌特性和调节MYC的能力。 DL78是 比amidarone明显更重要的和肿瘤的特异性，以及对铂疗法的敏感细胞。 此外，DL78迅速诱导G2/m停滞和有丝分裂灾难，最终导致了几种凋亡 癌细胞的类型。此外，尽管amidarone和DL78都影响了MYC的降解，但DL78 苏氨酸-58上增强了MYC磷酸化，因此增加了蛋白酶体介导的MYC 降解。那我们假设DL78通过MYC降解和 长时间的主轴组件检查点（SAC）激活。我们将通过两个目的检验这一假设：1） 检查DL78对SAC活动的影响并确定其对MYC的依赖性。 2）研究该化合物 定义明确的患者衍生Xenographtics的体内效率。成功完成此建议将改善我们的 了解哪些分子过程对卵巢癌细胞的生存至关重要。作为次要结果， 它提供了一种可以进一步发展为卵巢和其他MYC驱动的临床前候选的化合物 癌症。令人鼓舞的培训环境，丰富的核心设施和介绍给我的差异 密歇根大学将有助于完成这些目标，而我的专业人士 作为翻译的癌症研究员的发展。