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

基本信息

批准号：
10652394
负责人：
Jessica Teitel
金额：
$ 4.01万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652394
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 Induction of Apoptosis 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 Poly(ADP-ribose) Polymerase Inhibitor Positioning Attribute Process Property Protein Analysis Proteomics RNA analysis Recurrence Relapse Research Personnel Resistance Serous Structure-Activity Relationship Survival Rate Testing Therapeutic Threonine Toxic effect Training Tubulin Universities Visualization Woman anti-cancer c-myc Genes cancer cell cancer therapy cancer type carcinogenesis chemotherapy cyclin B1 disease heterogeneity experience homologous recombination improved in vivo 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

项目摘要

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.

项目概要卵巢癌是女性癌症死亡的第五大原因，化疗仍然是导致女性死亡的第五大原因尽管 70% 的高级别浆液性卵巢癌 (HGSOC) 患者最初接受了标准护理。对铂类治疗有反应，几乎所有患者都因缺乏治疗复发的疗法而死亡，因此，迫切需要确定化疗耐药性疾病的可针对性的脆弱性。 HGSOC 并开发新的治疗方法来延长这些患者的生存期，我们的实验室。使用计算药物重新定位平台 Drug Predict 来识别胺碘酮（一种抗心律失常药物），作为一种潜在的卵巢癌治疗方法，胺碘酮可有效降低细胞活力并引发细胞凋亡。许多患者来源的 HGSOC 细胞系，包括那些对顺铂具有耐药性的细胞系，均存在这些效应。通过其降解 c-Myc 的能力介导，c-Myc 在 45% 以上的 HGSOC 患者中过度表达。考虑到胺碘酮的剂量限制性毒性，我们应用构效关系分析来鉴定 DL78，缺乏 hERG 活性，但保留了抗癌特性和调节 Myc 的能力。比胺碘酮更有效且具有肿瘤特异性，并且使细胞对铂类疗法敏感。此外，DL78 迅速诱导 G2/M 期停滞和有丝分裂灾难，最终导致多种细胞凋亡此外，虽然胺碘酮和 DL78 都会影响 Myc 的降解，但 DL78 会影响 Myc 的降解。苏氨酸 58 上的 Myc 磷酸化增强，导致蛋白酶体介导的 Myc 增加因此，我们发现 DL78 通过 Myc 降解诱导有丝分裂灾难。延长纺锤体装配检查点（SAC）激活我们将通过两个目标来检验这一假设：1）检查 DL78 对 SAC 活性的影响并确定其对 Myc 的依赖性 2) 研究该化合物的作用。该提案的成功完成将改善我们在明确的患者来源异种移植物中的体内疗效。了解哪些分子过程对卵巢癌细胞的生存至关重要。它提供了一种可以进一步开发为卵巢和其他 Myc 驱动的临床前候选药物的化合物令人鼓舞的培训环境、丰富的核心设施和多样化的指导给了我。在密歇根大学的学习将有助于顺利完成这些目标并增强我的专业水平发展为转化癌症研究员。