Reference Detail

Ref Type

Journal Article

PMID

(25673697)

Authors

Owonikoko TK, Ramalingam SS, Miller DL, Force SD, Sica GL, Mendel J, Chen Z, Rogatko A, Tighiouart M, Harvey RD, Kim S, Saba NF, Pickens A, Behera M, Fu RW, Rossi MR, Auffermann WF, Torres WE, Bechara R, Deng X, Sun SY, Fu H, Gal AA, Khuri FR

Title

A Translational, Pharmacodynamic, and Pharmacokinetic Phase IB Clinical Study of Everolimus in Resectable Non-Small Cell Lung Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	8	2015 Apr 15	1859-68	Clin Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References