Li Luyuan, Hashemi Lily, Eid Josiane, Tao Wensi, Campoverde Leticia, Yu Amy, Farooqi Ammad Ahmad, Al-Ali Hassan, D'Amato Gina, Hornicek Francis, Duan Zhenfeng, Lohse Ines, Trent Jonathan
Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL 33136, USA.
Int J Mol Sci. 2024 Dec 3;25(23):13003. doi: 10.3390/ijms252313003.
The term chondrosarcoma refers to a rare and heterogeneous group of malignant cartilaginous tumors that are typically resistant to chemotherapy and radiotherapy. Metastatic chondrosarcoma has a poor prognosis, and effective systemic therapies are lacking. Isocitrate dehydrogenase (IDH) mutations represent a potential therapeutic target, but IDH inhibitors alone have shown limited clinical efficacy to date. Although the role of conventional chemotherapy is still subject to debate, some evidence suggests it may provide therapeutic benefits in advanced cases. In this study, we aimed to identify effective compounds for combination therapy in chondrosarcoma. Using high-throughput screening, we evaluated a panel of anticancer agents in IDH1-mutant chondrosarcoma cell lines and their mutant IDH1 knockout derivatives. The top 20 most potent compounds were identified across all cell lines, irrespective of IDH mutation status. Representative drugs selected for further investigation included docetaxel, methotrexate, panobinostat, idarubicin, camptothecin, and pevonedistat. These drugs inhibited colony formation, induced apoptosis and cell cycle arrest, and exhibited synergistic antitumor activity in two-drug combinations. In conclusion, we identified several highly effective agents with potent anti-tumor activity in chondrosarcoma cells, independent of IDH mutation status. These agents represent promising candidates for chondrosarcoma therapy and warrant further preclinical investigation and potential inclusion in clinical trials.
软骨肉瘤是指一类罕见且异质性的恶性软骨肿瘤，通常对化疗和放疗具有抗性。转移性软骨肉瘤预后较差，且缺乏有效的全身治疗方法。异柠檬酸脱氢酶（IDH）突变是一个潜在的治疗靶点，但迄今为止，单独使用IDH抑制剂的临床疗效有限。尽管传统化疗的作用仍存在争议，但一些证据表明它可能对晚期病例有治疗益处。在本研究中，我们旨在确定用于软骨肉瘤联合治疗的有效化合物。通过高通量筛选，我们在IDH1突变的软骨肉瘤细胞系及其突变IDH1基因敲除衍生物中评估了一组抗癌药物。在所有细胞系中确定了最有效的20种化合物，而不考虑IDH突变状态。选择用于进一步研究的代表性药物包括多西他赛、甲氨蝶呤、帕比司他、伊达比星、喜树碱和pevonedistat。这些药物抑制集落形成，诱导细胞凋亡和细胞周期停滞，并在两药联合中表现出协同抗肿瘤活性。总之，我们确定了几种在软骨肉瘤细胞中具有高效抗肿瘤活性的药物，与IDH突变状态无关。这些药物是软骨肉瘤治疗的有希望的候选药物，值得进一步进行临床前研究并可能纳入临床试验。
