Mammalian Target of Rapamycin Inhibitors as Possible Adjuvant Therapy for Microscopic Residual Disease in Head and Neck Squamous Cell Cancer

Abstract

Molecular therapeutics identifies an aberration in tumors to select patients that benefit from molecular targeted therapy. Overexpression of eIF4E in histologically ''tumor-free'' surgical margins of head and neck squamous cell cancer (HNSCC) patients is an independent predictor of recurrence and is functionally activated through the Akt/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibitors are cytostatic agents, best used in combination therapy, we hypothesize that they can be used as long-term single agents in an HNSCC model of minimal residual disease (MRD). CCI-779, an mTOR inhibitor, arrested growth of a phosphatase and tensin homologue deleted on chromosome 10 (PTEN) abnormal HNSCC cell line FaDu, inhibiting phosphorylation of 4E-binding protein 1, resulting in increased association with eIF4E and inhibition of basic fibroblast growth factor and vascular endothelial growth factor. Fluorescence in situ hybridization detected PTEN abnormalities in 68% of patient tumors and 35% of tumor-free margins. CCI-779 inhibited growth of established tumors in nude mice. However, in the MRD model, there were significant differences in the tumorfree rate between the control (4%) and the treatment group (50%), and the median tumor-free time was 7 versus 18 days, respectively (P < 0.0001). In those animals that formed tumors, CCI-779 caused a significant decrease in the tumor volume. The Kaplan-Meier curve showed that CCI-779 significantly increased survival (P < 0.0001). The mTOR pathway was inhibited in peripheral blood mononuclear cells potential surrogate markers of response to therapy. Stable transfection of FaDu with luciferase allowed us to monitor the effects of CCI-779 with bioluminescence imaging in the MRD model. These results pave the way for a clinical trial using targeted molecular therapy with CCI-779 as a single agent for mTORactivated residual cells. [Cancer Res 2007;67(5):2160-8]

Novel Phosphoinositide 3-Kinase/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibitory Activity against Human Head and Neck Cancer Cells In Vitro and In Vivo

“…Recent studies have focused on the disorder of this pathway in HNSCC with one of its key proteins, AKT, actively expressed in clinical tumor samples (10,11). Moreover, aberration of the other cascade proteins was also emphasized in HNSCC, including PTEN and mTOR (12). These findings highlight the signals leading to tumorigenesis, and specific targeting agents are designed for the treatment of the disease.…”

Curcumin Inhibits Carcinogen and Nicotine-Induced Mammalian Target of Rapamycin Pathway Activation in Head and Neck Squamous Cell Carcinoma

“…SCC40, SCC066, SCC114, SCC116 were obtained from Susanne M. Gollin (University of Pittsburgh), and PCI13, PCI15a, and PCI30 were provided by Teresa Whiteside (University of Pittsburgh). SCC40, SCC066, SCC116, and FaDu are hyperdiploid for PTEN (23,24). Cancer cell lines were maintained as previously described (23).…”

“…SCC40, SCC066, SCC116, and FaDu are hyperdiploid for PTEN (23,24). Cancer cell lines were maintained as previously described (23). OKF6 cells were cultured in media containing human keratinocyte growth supplement (Invitrogen).…”

Antitumor Effect of Temsirolimus against Oral Squamous Cell Carcinoma Associated with Bone Destruction

“…injection of 200 μL solution containing temsirolimus (20 mg/kg; refs. 15,16) or vehicle only twice a week for 14 days. Body weights and the volume of tumors were measured from 14 days after tumor inoculation.…”