Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.
尽管采用包括手术切除、放疗和化疗在内的标准治疗方案，胶质母细胞瘤（GBM）的预后仍然不佳。肿瘤内异质性导致治疗抵抗和不良预后，因此亟需新的治疗方法。抗逆转录病毒疗法（ART）的药物重定位研究已在多种癌症中显示出有前景的抗肿瘤效果，但其在GBM中的疗效尚不明确。为深入理解ART对GBM的多效性抗癌作用，我们开展了ART在GBM中的系统性药物重定位分析，以揭示其在转化神经肿瘤学中的应用潜力。为探究ART在GBM中的抗癌作用，我们通过生物信息学分析和体外实验对抗逆转录病毒药物进行了系统性筛选。利用DepMap数据库和基因表达逆转评分方法，我们在40个胶质瘤细胞系中对16种抗逆转录病毒药物进行了无偏倚筛选，以确定具有GBM药物重定位潜力的候选药物。采用患者来源的神经球和胶质瘤细胞系，我们评估了神经球活力、增殖能力和干细胞特性。计算筛选结果显示，包括逆转录酶抑制剂（RTIs）和蛋白酶抑制剂（PIs）在内的多种ART药物表现出显著的抗胶质瘤活性，并能够逆转GBM疾病特征。RTIs能有效降低细胞活力、减少GBM干细胞标志物表达并抑制细胞增殖。本研究从机制和功能层面揭示了ART重定位在恶性胶质瘤治疗中的应用价值，为现有文献提供了支持证据。鉴于其安全性、临床前疗效和神经组织渗透性，ART可能成为GBM一种有前景的辅助治疗手段。
肿瘤(癌症)患者之家