sirolimus and Adenocarcinoma--Bronchiolo-Alveolar

The epidermal growth factor receptor inhibitor erlotinib is an approved treatment for chemotherapy-refractory advanced non-small-cell lung cancer (NSCLC). Because activated epidermal growth factor receptor signals through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, adding the oral mTOR inhibitor everolimus to erlotinib may improve efficacy by blocking multiple components of the same pathway. We conducted a phase I study to determine feasible dosages of combination therapy with erlotinib and everolimus for previously treated metastatic or unresectable NSCLC.. Participants had advanced NSCLC progressing after two or less previous chemotherapy regimens. Feasibility of daily/weekly everolimus plus daily erlotinib was determined using a 6 + 6 dose-escalation design based on the rate of dose-limiting toxicities. Antitumor activity was assessed by the Response Evaluation Criteria In Solid Tumors study.. Of the 94 patients enrolled, 90% had stage IV NSCLC, 19% never smoked, and 15% were current smokers. Eighty-nine patients experienced one or more adverse events possibly related to any study medication. The most common dose-limiting toxicities were stomatitis (n = 5), rash (n = 4), and diarrhea (n = 3). Maximum tolerated doses were everolimus 5 mg per day or 50 mg per week plus erlotinib 150 mg per day. In daily everolimus cohorts (n = 74), nine patients achieved a complete/partial response and 28 had stable disease (median duration disease control, 9.3 months). In weekly everolimus cohorts (n = 20), no tumor response was observed; seven patients had stable disease (median duration, 9.6 months).. Combination therapy with everolimus 5 mg per day or 50 mg per week and erlotinib 150 mg per day provided acceptable tolerability and disease control. A randomized phase II study evaluating this combination in comparison with erlotinib alone is complete and is being analyzed.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cohort Studies; Erlotinib Hydrochloride; Everolimus; Feasibility Studies; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Quinazolines; Sirolimus; Tissue Distribution

Acquisition of mesenchymal phenotype by epithelial cells by means of epithelial-mesenchymal transition (EMT) is considered as an early event in the multistep process of tumor metastasis. Therefore, inhibition of EMT might be a rational strategy to prevent metastasis.. Using the global gene expression profile from a cell culture model of transforming growth factor-β (TGF-β)-induced EMT, we identified potential EMT inhibitors. We used a publicly available database (www.broad.mit.edu/cmap) comprising gene expression profiles obtained from multiple different cell lines in response to various drugs to derive negative correlations to EMT gene expression profile using Connectivity Map, a pattern matching tool.. Experimental validation of the identified compounds showed rapamycin as a novel inhibitor of TGF-β signaling along with 17-AAG, a known modulator of TGF-β pathway. Both of these compounds completely blocked EMT and the associated migratory and invasive phenotype. The other identified compound, LY294002, demonstrated a selective inhibition of mesenchymal markers, cell migration and invasion, without affecting the loss of E-cadherin expression or Smad phosphorylation.. Our data reveal that rapamycin is a novel modulator of TGF-β signaling, and along with 17-AAG and LY294002, could be used as therapeutic agent for inhibiting EMT. This study demonstrates the potential of a systems approach in identifying novel modulators of a complex biological process.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Benzoquinones; Biomarkers, Tumor; Blotting, Western; Cadherins; Cell Movement; Chromones; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Gene Expression Profiling; HSP90 Heat-Shock Proteins; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Lung Neoplasms; Morpholines; Oligonucleotide Array Sequence Analysis; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Sirolimus; Smad Proteins; Transcription, Genetic; Transforming Growth Factor beta; Tumor Cells, Cultured