title: A Translational, Pharmacodynamic, and Pharmacokinetic Phase IB Clinical Study of Everolimus in Resectable Non-Small Cell Lung Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  This "window-of-opportunity" study demonstrated measurable, dose-dependent, biologic, metabolic, and antitumor activity of everolimus in early-stage NSCLC.
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors: Taofeek K
authors: TK
authors: Owonikoko
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors: Suresh S
authors: SS
authors: Ramalingam
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Surgery, Emory University, Atlanta, Georgia.
authors: Daniel L
authors: DL
authors: Miller
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Surgery, Emory University, Atlanta, Georgia.
authors: Seth D
authors: SD
authors: Force
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Pathology, Emory University, Atlanta, Georgia.
authors: Gabriel L
authors: GL
authors: Sica
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors: Jennifer
authors: J
authors: Mendel
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Statistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia.
authors: Zhengjia
authors: Z
authors: Chen
authors: Cedars Sinai Medical Center, Los Angeles, California.
authors: Andre
authors: A
authors: Rogatko
authors: Cedars Sinai Medical Center, Los Angeles, California.
authors: Mourad
authors: M
authors: Tighiouart
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors: R Donald
authors: RD
authors: Harvey
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors: Sungjin
authors: S
authors: Kim
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors: Nabil F
authors: NF
authors: Saba
authors: Department of Surgery, Emory University, Atlanta, Georgia.
authors: Allan
authors: A
authors: Pickens
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.
authors: Madhusmita
authors: M
authors: Behera
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.
authors: Robert W
authors: RW
authors: Fu
authors: Department of Pathology, Emory University, Atlanta, Georgia. Department of Radiation Oncology, Emory University, Atlanta, Georgia.
authors: Michael R
authors: MR
authors: Rossi
authors: Department of Radiology, Emory University, Atlanta, Georgia.
authors: William F
authors: WF
authors: Auffermann
authors: Department of Radiology, Emory University, Atlanta, Georgia.
authors: William E
authors: WE
authors: Torres
authors: Division of Interventional Pulmonology, Emory University, Atlanta, Georgia.
authors: Rabih
authors: R
authors: Bechara
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Radiation Oncology, Emory University, Atlanta, Georgia.
authors: Xingming
authors: X
authors: Deng
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors: Shi-Yong
authors: SY
authors: Sun
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Pharmacology, Emory University, Atlanta, Georgia.
authors: Haian
authors: H
authors: Fu
authors: Winship Cancer Institute of Emory University, Atlanta, Georgia. Department of Pathology, Emory University, Atlanta, Georgia.
authors: Anthony A
authors: AA
authors: Gal
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute of Emory University, Atlanta, Georgia. fkhuri@emory.edu.
authors: Fadlo R
authors: FR
authors: Khuri
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D004252:DNA Mutational Analysis; D000068338:Everolimus / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D019788:Fluorodeoxyglucose F18; D000068338:Everolimus