RG3039 对胶质母细胞瘤的影响。
Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma.
机构信息
Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
出版信息
J Transl Med. 2024 Sep 30;22(1):880. doi: 10.1186/s12967-024-05658-x.
BACKGROUND
Patients with glioblastoma (GBM) have a poor prognosis and limited treatment options. The mRNA decapping enzyme scavenger (DCPS) is a cap-hydrolyzing enzyme. The DCPS inhibitor RG3039 exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of RG3039 in various preclinical models of GBM.
METHODS
DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of RG3039 was determined using GBM cell lines, patient-derived organoids, and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored.
RESULTS
DCPS is overexpressed in GBM and is associated with poor survival of patients with GBM. The DCPS inhibitor RG3039 exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, RG3039 downregulated STAT5B expression, thereby suppressing proliferation, survival and colony formation of GBM cells.
CONCLUSIONS
DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy.
背景
胶质母细胞瘤（GBM）患者预后不良，治疗选择有限。mRNA 去帽酶清除剂（DCPS）是一种帽水解酶。DCPS 抑制剂 RG3039 在体内具有优异的中枢神经系统生物利用度，在健康志愿者的 I 期临床试验中安全且耐受良好。在这项研究中，我们研究了 DCPS 在 GBM 中的表达以及 RG3039 在各种 GBM 临床前模型中的抗肿瘤活性。
方法
检查了人 GBM 组织和配对的瘤周组织中的 DCPS 表达。评估了其与 GBM 患者的临床病理特征的相关性。使用 GBM 细胞系、患者来源的类器官和原位小鼠模型确定了 RG3039 的抗 GBM 作用。探讨了 DCPS 抑制的治疗机制。
结果
DCPS 在 GBM 中过度表达，与 GBM 患者的生存不良相关。DCPS 抑制剂 RG3039 在 GBM 细胞系、患者来源的类器官和原位小鼠模型中表现出强大的抗 GBM 活性，在人体中可达到药物暴露水平。在机制上，RG3039 下调 STAT5B 表达，从而抑制 GBM 细胞的增殖、存活和集落形成。
结论
DCPS 是 GBM 的一个有前途的靶点。用 RG3039 抑制 DCPS（在人体中可达到的剂量）可下调 STAT5B 表达，并减少 GBM 细胞的增殖、存活和集落形成。鉴于其在体内优异的抗癌活性和中枢神经系统生物利用度以及在人体中的良好耐受性，RG3039 值得进一步研究，作为一种潜在的 GBM 治疗方法。
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