Owonikoko Taofeek K, Ramalingam Suresh S, Miller Daniel L, Force Seth D, Sica Gabriel L, Mendel Jennifer, Chen Zhengjia, Rogatko Andre, Tighiouart Mourad, Harvey R Donald, Kim Sungjin, Saba Nabil F, Pickens Allan, Behera Madhusmita, Fu Robert W, Rossi Michael R, Auffermann William F, Torres William E, Bechara Rabih, Deng Xingming, Sun Shi-Yong, Fu Haian, Gal Anthony A, Khuri Fadlo R
Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute of Emory University, Atlanta, Georgia.
Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Surgery, Emory University, Atlanta, Georgia.
Clin Cancer Res. 2015 Apr 15;21(8):1859-68. doi: 10.1158/1078-0432.CCR-14-1998. Epub 2015 Feb 11.
The altered PI3K/mTOR pathway is implicated in lung cancer, but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non-small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer.
We enrolled 33 patients and obtained baseline tumor biopsy and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1, and total Bim protein between pretreatment and posttreatment tissue samples.
There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 tumors (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, -21%, -24%; P = 0.014), tumor size (10.1%, 5.8%, -11.6%; P = 0.047), and modulation of S6 (-36.1, -13.7, -77.0; P = 0.071) and pS6 (-41.25, -61.57, -47.21; P = 0.063) in patients treated in the control, 5-mg, and 10-mg cohorts, respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity.
This "window-of-opportunity" study demonstrated measurable, dose-dependent, biologic, metabolic, and antitumor activity of everolimus in early-stage NSCLC.
PI3K/mTOR通路改变与肺癌相关，但mTOR抑制剂在晚期肺癌中未能显示出疗效。我们研究了依维莫司在可切除非小细胞肺癌（NSCLC）中的药效学作用，以为这些药物在肺癌中的进一步开发提供依据。
我们招募了33名患者，获取基线肿瘤活检和2-[18F]氟-2-脱氧-D-葡萄糖-正电子发射断层扫描/计算机断层扫描（FDG-PET/CT）影像，随后给予依维莫司治疗（每日5或至10毫克, 最长28天），或对照组不进行干预治疗。通过比较配对PET扫描的代谢活性以及治疗前和治疗后组织样本中mTOR、Akt、S6、eIF4e、p70S6K、4EBP1的活性磷酸化形式的表达和总Bim蛋白，在体内和体外对依维莫司的靶点调节进行定量。
治疗组有23名患者，对照组有10名；中位年龄64岁；22个肿瘤（67%）为腺癌。对照组、5毫克组和10毫克组患者的代谢活性（SUVmax：29.0%、-21%、-24%；P = 0.014）、肿瘤大小（10.1%、5.8%、-11.6%；P = = 0.047）以及S6（-36.1、-13.7、-77.0；P = 0.071）和pS6（-41.25、-61.57、-47.21；P = 0.063）的调节呈剂量依赖性降低。对所有患者进行靶向DNA测序，并对一名肿瘤高度敏感的索引患者进行外显子组和全转录组RNA测序，以进一步阐明依维莫司活性的机制。
这项“机会窗”研究证明了依维莫司在早期NSCLC中具有可测量的、剂量依赖性的生物学、代谢和抗肿瘤活性。
