Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
Clin Cancer Res. 2022 May 13;28(10):2180-2195. doi: 10.1158/1078-0432.CCR-21-0833.
To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas.
A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib.
Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response.
These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.
研究一种定位于线粒体的 HSP90 抑制剂 Gamitrinib 在多种脑胶质瘤模型中的抗肿瘤活性，并阐明 Gamitrinib 对脑胶质瘤的抗肿瘤机制。
通过细胞活力测定、流式细胞术和结晶紫测定筛选了广泛的原发性和替莫唑胺（TMZ）耐药的人脑胶质瘤细胞系，以研究 Gamitrinib 的治疗效果。使用 Seahorse 测定法测量脑胶质瘤细胞的线粒体呼吸。进行 RNA 测序（RNAseq）和反相蛋白阵列（RPPA）数据的综合分析，以揭示 Gamitrinib 的潜在抗肿瘤机制。生成神经球、患者来源的类器官（PDO）、细胞系衍生的异种移植物（CDX）和患者来源的异种移植物（PDX）模型，以进一步评估 Gamitrinib 的治疗效果。
Gamitrinib 抑制了 17 种原发性脑胶质瘤细胞系、6 种 TMZ 耐药脑胶质瘤细胞系、4 个神经球和 3 个 PDO 的细胞增殖，并诱导细胞凋亡和死亡。重要的是，Gamitrinib 显著延迟了皮下或颅内植入肿瘤的 CDX 和 PDX 模型中小鼠的肿瘤生长并改善了其生存。RNAseq 和 RPPA 数据的综合计算分析表明，Gamitrinib 通过（i）抑制线粒体生物发生、OXPHOS 和细胞周期进程，以及（ii）激活能量感应 AMP 激活的蛋白激酶、DNA 损伤和应激反应，发挥其抗肿瘤活性。
这些临床前研究结果确立了 Gamitrinib 在脑胶质瘤中的治疗作用，并揭示了抑制线粒体生物发生和肿瘤生物能量学是脑胶质瘤的主要抗肿瘤机制。
