PO.MCB04.01 · 分子与细胞生物学
较老的他汀类药物降低ccRCC的转移潜能：SIM（选择性转移抑制剂）开发的机制验证
Older statins reduce metastatic potential in ccRCC: Mechanistic validation of SIM (selective inhibitor of metastasis) development
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摘要 Abstract
中文摘要
目的：转移是透明细胞肾细胞癌（ccRCC）死亡的主要原因，目前尚无治疗能够预防转移进展。我们旨在明确驱动转移的机制，并开发能够阻断播散的小分子。
方法：共培养实验和异种移植模型表明，转移是由VHL缺陷型HIF1alpha高表达（VHL - HIF1alpha+）细胞与VHL正常（VHL+）ccRCC细胞之间的相互作用所促进的，其中VHL - HIF1alpha+细胞通过在邻近的VHL+细胞中诱导增殖和迁移程序来驱动转移。我们对超过18,000个小分子化合物进行了高通量筛选，以鉴定对VHL - HIF1alpha+细胞具有选择性毒性的药物。在2500个FDA批准的药物中，鉴定出7个命中化合物，其中4个是较老的他汀类药物。氟伐他汀（fluvastatin）效力最强，进一步在体内测试其预防转移的作用。转录组学和蛋白质组学分析比较了较老与较新的他汀类药物，以评估HIF1alpha依赖性机制。一项基于人群的研究纳入了来自芬兰癌症登记处的17,792名RCC患者，将癌症记录与处方数据（1998-2018年）关联。他汀类药物被分为较老的（氟伐他汀、辛伐他汀、洛伐他汀）或较新的（阿托伐他汀、普伐他汀、瑞舒伐他汀）。逻辑回归评估了出现转移的比值，时间依赖性Cox模型评估了RCC特异性死亡率，并对人口统计学、合并症、肿瘤范围和治疗进行了校正。
结果：筛选鉴定出氟伐他汀（SIM-1）作为选择性抑制剂，药物化学产生了效力提高>4倍的SIM-2。氟伐他汀预处理降低了体内转移负荷。尽管对HMGCR的亲和力较低，较老的他汀类药物对VHL - HIF1alpha+ ccRCC细胞表现出比较新的他汀类药物更强的选择性细胞毒性。HIF1alpha敲除消除了氟伐他汀敏感性，提示其HIF1alpha依赖性。人群分析显示，诊断前使用较老的他汀类药物与诊断时转移性RCC的比值降低相关，而较新的他汀类药物并未降低转移风险。
结论：机制、药理学和流行病学数据共同证实较老的他汀类药物是通过HIF1alpha通路发挥作用的转移抑制剂。这些发现支持进一步开发SIM，以实现针对ccRCC的转移预防治疗。
查看英文原文 English abstract
Purpose: Metastasis is the primary cause of mortality in clear cell renal cell carcinoma (ccRCC), and no current therapy prevents metastatic progression. We sought to define mechanism driving metastasis and develop small molecules capable of blocking dissemination.
Methods: Co-culture assays and xenograft models demonstrated that metastasis are promoted by interactions between VHL-deficient HIF1alpha-high (VHL - HIF1alpha+) and VHL-proficient (VHL+) ccRCC cells, with the VHL - HIF1alpha+ cells driving the metastasis by inducing proliferative and migratory programs in neighboring VHL+ cells. A high-throughput screen of over 18,000 small molecule compounds was undertaken to identify drugs selectively toxic to VHL - HIF1alpha+ cells. Amongst the 2500 FDA approved drugs, 7 hits were identified, with 4 of them being older statins. Fluvastatin, being the most potent, was further tested for metastasis prevention in vivo. Transcriptomic and proteomic analyses compared older versus newer statins to assess HIF1alpha-dependent mechanisms. A population-based study of 17,792 RCC patients from the Finnish Cancer Registry linked cancer records with prescription data (1998-2018). Statins were classified as older (fluvastatin, simvastatin, lovastatin) or newer (atorvastatin, pravastatin, rosuvastatin). Logistic regression evaluated odds of metastatic presentation, and time-dependent Cox models assessed RCC-specific mortality, adjusting for demographics, comorbidities, tumor extent, and treatments.
Results: Screening identified fluvastatin (SIM-1) as a selective inhibitor, and medicinal chemistry yielded SIM-2 with >4-fold higher potency. Pre-treatment with fluvastatin reduced metastatic burden in vivo. Older statins showed more potent selective cytotoxicity against VHL - HIF1alpha+ ccRCC cells than newer statins despite lower HMGCR affinity. HIF1alpha knockout abrogated fluvastatin sensitivity, suggesting its HIF1alpha dependence. Population analysis showed that pre-diagnostic use of older statins was associated with reduced odds of metastatic RCC at diagnosis, while newer statins did not reduce the risk of metastasis.
Conclusions : Mechanistic, pharmacologic, and epidemiologic data converge to identify older statins as inhibitors of metastasis acting through the HIF1alpha pathway. These findings support further development of SIMs towards achieving metastasis-preventive therapy for ccRCC.
利益披露 Disclosure
L. Wu, None..
J. Hu, None..
M. Ishihara, None..
G. Brodie, None..
J. Kim, None..
S. Conway, None..
R. Damoiseaux, None..
M. E. Jung, None.