Targeting the Tumor Microenvironment through mTOR Inhibition and Chemotherapy as Induction Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: The CAPRA Study.

Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-ß) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents.

Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines.

PURPOSE: Recent data suggested that combining targeted therapies with chemotherapy may counteract drug resistance. Activation of the PI3K/AKT/mTOR pathway downstream to kinase receptors, such as EGFR, was found in 57-81% of head and neck squamous cell carcinoma (HNSCC), and was eventually associated with a loss of PTEN function. mTOR was shown to modulate cell proliferation, apoptosis, invasion, and angiogenesis. This study aimed to evaluate molecular and cellular effects of rapamycin in a panel of cell lines either as single agent or in combination with cytotoxics commonly used in HNSCC. METHODS: Antiproliferative effects of rapamycin, carboplatin, and paclitaxel were evaluated in a panel of three HNSCC cell lines (SCC61, SQ20B and HEP2). Cells were exposed to rapamycin for 48 h, to carboplatin for 48 h, or to paclitaxel for 24 h. Antiproliferative effects of simultaneous and sequential rapamycin-based combinations were studied using MTT assay and median effect plot analysis. Cell cycle effects were analysed using flow cytometry. RESULTS: Rapamycin induced concentration dependent antiproliferative effects in HNSCC cell lines with IC(50) of 5 +/- 1, 12 +/- 2 and 20 +/- 2 microM in SCC61, SQ20B, and HEP2 cells, respectively. Higher antiproliferative effects were observed in SCC61 cells overexpressing NOXA and cyclin D1 than in HEP2 that overexpressed MDR1 and BCL2. In our panel, antiproliferative effects of rapamycin were associated with G0/G1 cell cycle accumulation and apoptosis induction, at concentrations ranging 3-30 microM. Combinations of rapamycin with paclitaxel and carboplatin displayed synergistic and additive effects. Synergistic effects were observed with paclitaxel in SQ20B and HEP2 cells and with carboplatin in SQ20B cells, when cells were exposed to cytotoxics prior to rapamycin. CONCLUSION: Our results show that rapamycin displays antiproliferative effects and induces apoptosis in HNSCC cell lines, cellular effects being more potent in cells that do not express BCL2 and MDR1. Additive and synergistic effects were observed when rapamycin was combined with carboplatin and paclitaxel.