Govindarajan Baskaran, Willoughby Laura, Band Hamid, Curatolo Adam S, Veledar Emir, Chen Suephy, Bonner Michael Y, Abel Martin-Garrido, Moses Marsha A, Arbiser Jack L
Department of Dermatology, Emory University School of Medicine; Winship Cancer Institute and Atlanta Veterans Administration Hospital, WMB 5309, 1639 Pierce Drive, Atlanta, GA, 30322, USA.
Vasc Cell. 2012 Jul 5;4(1):11. doi: 10.1186/2045-824X-4-11.
Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.
结节性硬化症（TS）是一种常见的常染色体显性疾病，其特征为皮肤、肺、脑和肾脏出现肿瘤。然而，雷帕霉素单药治疗仅使肿瘤部分消退，这表明还涉及其他信号通路。我们之前已证实血小板衍生生长因子 - BB与TS相关的肿瘤发生有关，这为联合使用雷帕霉素和伊马替尼阻断mTOR/PDGF信号通路提供了理论依据。在此，我们使用一种成熟的TS皮肤肿瘤发生临床前模型——源自一只tsc2杂合小鼠皮肤肿瘤的tsc2ang1细胞，来测试这种联合治疗方案。与溶剂处理、雷帕霉素单药治疗或伊马替尼单药治疗相比，雷帕霉素和伊马替尼联合处理tsc2ang1细胞可抑制细胞增殖。联合治疗还导致Akt激活减少。在动物实验中，联合治疗显示出强大的体内活性，且对动物无毒性。我们的研究结果为联合使用雷帕霉素和伊马替尼（两种均已获美国食品药品监督管理局批准的药物）治疗TS提供了理论依据。
