sirolimus and Carcinoma--Adenoid-Cystic

Autophagy is a catabolic process that has been shown to have a role in many cellular processes including the removal of excessive or damaged proteins and protein aggregates. The salivary glands play a critical role in oral health, and their secretory capacity may be critically intertwined with the autophagic process. This review describes the role of autophagy activation in normal salivary gland homeostasis and during the glandular stress responses of therapeutic radiation, ductal ligation, autoimmunity, and salivary gland adenoid cystic carcinoma.

Topics: Animals; Autoimmune Diseases; Autophagy; Carcinoma, Adenoid Cystic; Disease Models, Animal; Homeostasis; Humans; Ligation; Salivary Gland Neoplasms; Salivary Glands; Sirolimus; Stress, Physiological

The aim of this study was to examine the efficacy and safety of everolimus in patients with progressive unresectable adenoid cystic carcinoma (ACC).. Histologically confirmed ACC patients with documented disease progression within 12 months prior to the study entry were eligible. Everolimus was given at a dose of 10 mg daily until progression or occurrence of unacceptable toxicities. The primary endpoint was a 4-month progression-free survival (PFS).. A total of 34 patients were enrolled. The 4-month PFS probability was 65.5% (95% one-sided confidence interval [CI], 47.7 to infinity). Median PFS duration was 11.2 months (95% CI, 3.6 to 15.8). Complete or partial response was not achieved. Twenty-seven (79.4%, 95% CI, 63.2 to 89.6) patients showed stable disease (SD). Tumor shrinkage within SD criteria was observed in 15 patients (44.1%) and SD lasting 6 months was observed in 13 patients (38.2%). Four patients had disease progression. Among the 18 patients with both pre- and post-treatment (at 8 weeks) FDG-PET scans available, 8 patients (44.4%) showed a partial metabolic response, defined as a ≥25% reduction in maximum standardized uptake values (SUVmax). The most common adverse events were stomatitis, anemia, asthenia, and leukopenia. No unexpected everolimus related toxicities were reported.. Everolimus showed promising efficacy and good tolerability in progressive unresectable ACC.. ClinicalTrials.gov identifier, NCT01152840.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Adenoid Cystic; Everolimus; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Positron-Emission Tomography; Sirolimus; Treatment Outcome; Tumor Burden

Previous genomic studies revealed phosphotidylinositol-3-kinase (PI3K)/Akt pathway mutation in human salivary gland adenoid cystic carcinoma (ACC). No validation of its prognostic value has been reported.. P-Akt, pan-Akt, phosphorylated-mammalian target of rapamycin (p-mTOR), PI3K, and insulin-like growth factor-1 receptor beta (IGF-1Rβ) were detected on 120 salivary gland ACC/adjacent salivary gland pairs immunohistochemically and were correlated with clinicopathological data.. Expression of cytoplasmic and nuclear p-Akt, cytoplasmic p-mTOR, nuclear pan-Akt, and nuclear IGF-1Rβ were higher in ACC than in adjacent salivary glands. P-Akt, p-mTOR, PI3K, and IGF-1Rβ expression were correlated with one another in both cytoplasm and nucleus. Low p-mTOR expression in both subcellular compartments was associated with locoregional recurrence, poor disease-free survival (DFS), and overall survival (OS). Low nuclear p-Akt (Ser473) and p-mTOR expression were independent predictors for poor OS and DFS, respectively.. High level of Akt/mTOR activation in ACC is correlated with a significantly improved survival. P-mTOR and nuclear p-Akt are prognostic biomarkers of salivary gland ACC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1145-1154, 2017.

Topics: Adult; Aged; Biopsy, Needle; Carcinoma, Adenoid Cystic; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Male; Middle Aged; Phosphorylation; Predictive Value of Tests; Proportional Hazards Models; Proto-Oncogene Proteins c-akt; Retrospective Studies; Risk Assessment; Salivary Gland Neoplasms; Signal Transduction; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases

Temsirolimus acts as a mammalian target of rapamycin (mTOR)-dependent autophagic inhibitor. In order to clarify its effects and mechanisms on human salivary adenoid cystic carcinoma (ACC), we examined whether temsirolimus induced autophagy as the mTOR inhibitor in ACC, both in vitro and in vivo. In this study, MTT assay showed that the inhibition effect of temsirolimus assumed an obvious dose-response relationship on ACC-M cells, and the 50% inhibitory concentration (IC(50)) approached 20 μmol/l; numerous autophagosomes were observed by the transmission electron microscopy (TEM) in temsirolimus treatment groups; notably, expression of LC3 and Beclin1 was significantly up-regulated by temsirolimus. More importantly, the xenograft model provided further evidence of temsirolimus-induced autophagy in vivo by inhibiting mTOR activation as well as up-regulation the expression of Beclin1. These results suggest that temsirolimus could act as an mTOR inhibitor to induce autophagy in adenoid cystic carcinoma both in vitro and in vivo.

Topics: Animals; Autophagy; Carcinoma, Adenoid Cystic; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Salivary Gland Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation