1. Inhibition of mTOR Signaling and Clinical Activity of Rapamycin in Head and Neck Cancer in a Window of Opportunity Trial
- Author
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Day, Terry A, Shirai, Keisuke, O'Brien, Paul E, Matheus, Maria Gisele, Godwin, Kristina, Sood, Amit J, Kompelli, Anvesh, Vick, Julie A, Martin, Daniel, Vitale-Cross, Lynn, Callejas-Varela, Juan Luis, Wang, Zhiyong, Wu, Xingyu, Harismendy, Olivier, Molinolo, Alfredo A, Lippman, Scott M, Van Waes, Carter, Szabo, Eva, and Gutkind, J Silvio
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Dental/Oral and Craniofacial Disease ,Rare Diseases ,Clinical Trials and Supportive Activities ,Cancer ,Orphan Drug ,Digestive Diseases ,Clinical Research ,Health Disparities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Animals ,Apoptosis ,Cell Line ,Tumor ,Class I Phosphatidylinositol 3-Kinases ,Female ,Gene Expression Regulation ,Neoplastic ,Head and Neck Neoplasms ,Humans ,Male ,Mice ,Middle Aged ,Neoadjuvant Therapy ,Neoplasm Staging ,Phosphorylation ,Positron Emission Tomography Computed Tomography ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Sirolimus ,Squamous Cell Carcinoma of Head and Neck ,TOR Serine-Threonine Kinases ,Exome Sequencing ,Xenograft Model Antitumor Assays ,Whole Exome Sequencing ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeWe studied the impact of mTOR signaling inhibition with rapamycin in head and neck squamous cell carcinoma (HNSCC) in the neoadjuvant setting. The goals were to evaluate the mTOR pathway as a therapeutic target for patients with advanced HNSCC, and the clinical safety, antitumor, and molecular activity of rapamycin administration on HNSCC.Patients and methodsPatients with untreated stage II-IVA HNSCC received rapamycin for 21 days (day 1, 15 mg; days 2-12, 5 mg) prior to definitive treatment with surgery or chemoradiation. Treatment responses were assessed clinically and radiographically with CT and FDG-PET. Pre- and posttreatment biopsies and blood were obtained for toxicity, immune monitoring, and IHC assessment of mTOR signaling, as well as exome sequencing.ResultsSixteen patients (eight oral cavity, eight oropharyngeal) completed rapamycin and definitive treatment. Half of patients were p16 positive. One patient had a pathologic complete response and four (25%) patients met RECIST criteria for response (1 CR, 3 PR, 12 SD). Treatment was well tolerated with no grade 4 or unexpected toxicities. No significant immune suppression was observed. Downstream mTOR signaling was downregulated in tumor tissues as measured by phosphorylation of S6 (P < 0.0001), AKT (P < 0.0001), and 4EBP (P = 0.0361), with a significant compensatory increase in phosphorylated ERK in most patients (P < 0.001). Ki67 was reduced in tumor biopsies in all patients (P = 0.013).ConclusionsRapamycin treatment was well tolerated, reduced mTOR signaling and tumor growth, and resulted in significant clinical responses despite the brief treatment duration, thus supporting the potential role of mTOR inhibitors in treatment regimens for HNSCC.
- Published
- 2019