Improved Clearance during Treatment of HPV-Positive Head and Neck Cancer through mTOR Inhibition

Abstract

Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) incidence is increasing at a near epidemic rate. We investigated whether the mammalian (or mechanistic) target of rapamycin (mTOR) inhibitor, rapamycin, can be used as a concurrent agent to standard-of-care cisplatin/radiation therapy (CRT) to attenuate tumor lactate production, thus enhancing CRT-induced immune-mediated clearance of this antigenic tumor type. A C57Bl/6-derived mouse oropharyngeal epithelial cell line retrovirally transduced with HPV type 16 E6/E7 and human squamous cell carcinoma cell lines were evaluated for their response to rapamycin in vitro with proliferation assays, Western blots, and lactate assays. Clonogenic assays and a preclinical mouse model were used to assess rapamycin as a concurrent agent to CRT. The potential of rapamycin to enhance immune response through lactate attenuation was assessed using quantitative tumor lactate bioluminescence and assessment of cell-mediated immunity using E6/E7-vaccinated mouse splenocytes. Rapamycin alone inhibited mTOR signaling of all cancer cell lines tested in vitro and in vivo. Furthermore, rapamycin administered alone significantly prolonged survival in vivo but did not result in any long-term cures. Given concurrently, CRT/rapamycin significantly enhanced direct cell killing in clonogenic assays and prolonged survival in immunocompromised mice. However, in immunocompetent mice, concurrent CRT/rapamycin increased long-term cures by 21%. Preliminary findings suggest that improved survival involves increased cell killing and enhanced immune-mediated clearance in part due to decreased lactate production. The results may provide rationale for the clinical evaluation of mTOR inhibitors concurrent with standard-of-care CRT for treatment of HPV-positive HNSCC.

Prevention of Tumor Growth Driven by PIK3CA and HPV Oncogenes by Targeting mTOR Signaling with Metformin in Oral Squamous Carcinomas Expressing OCT3

“…Hence metformin represents an attractive drug candidate to prevent the development of cancer lesions that involved mTOR activity. These include HNSCCs, in which multiple molecular mechanisms converge on the stimulation of mTORC1 and the consequent accumulation of the phosphorylated form of ribosomal protein S6 (pS6) and other mTORC1 targets (10, 11, 27). …”

“…Most HNSCC and cervical SCC lesions exhibit strongly elevated activity of the PI3K and mammalian target of rapamycin (mTOR) signaling pathway (10–13). The activation of the mTOR pathway renders these cancers sensitive to the inhibition of mTOR by rapamycin and related rapalogs and new mTOR kinase inhibitors, as revealed in multiple pre-clinical animal models and experimental systems (14).…”

Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

“…We found that mTOR inhibitors can also interfere with the prosenescent activity of CT. Currently, mTOR inhibitors are under investigation in clinical studies as anticancer agents and are showing growth-inhibiting effects in preclinical models, including xenografts of HPV-positive cancer cells (41)(42)(43). The antitumorigenic effects of mTOR inhibitors in the clinic have often been unsatisfying when given as a monotherapy, however (44,45).…”

Upregulation of pAKT(Ser473) expression in progression of HPV‐positive oropharyngeal squamous cell carcinoma

“…In regard to HPV‐related oropharyngeal SCC, patients are younger and have a higher lifetime risk for radiation and medication‐associated complications. Among others, we could show that targeting the PI3K and mTOR axis can lead to enhanced radiosensitivity . Therefore, a potential future application of mTOR or combined AKT/mTOR inhibitors could reduce the radiation dose in HPV‐related oropharyngeal SCC and prevent secondary therapy‐related complications in the long term.…”