Bortezomib with concurrent radiation therapy in head and neck squamous cell carcinoma

Abstract

Problem: Head and neck squamous cell carcinomas (HNSCCs) exhibit constitutive activation of nuclear factor-kappa B (NF-kB), a transcription factor which regulates genes important in tumor progression. Bortezomib, a potent proteasome inhibitor shown to inhibit NF-kB activation in vitro, has not been studied in HNSCC patients. Methods: We initiated a phase I trial of bortezomib with concurrent radiation therapy in patients with recurrent/metastatic HNSCC. Patient biopsy specimens were stained for apoptotic cells and serum cytokines were measured pre- and posttreatment. To investigate the possible basis for differences in clinical response, we conducted real-time RT-PCR to examine gene expression in HNSCC cell lines treated with bortezomib. Results: Two of the 6 patients treated with 0.6 mg/m2/dose bortezomib with radiation at 1.8 Gy daily fractions to 60–72 Gy showed tumor reductions of more than 50%. Significant apoptosis was demonstrated by TUNEL in 1 patient who had a 50% tumor reduction by 3 weeks, whereas less apoptosis was observed in another patient clinically less responsive. A second patient, who experienced a 90% tumor reduction, had a greater than 90% decrease in levels of NF-kB-dependent serum cytokines IL-6, IL-8, VEGF, GRO-1. Patients not demonstrating marked tumor reductions did not show a significant decrease. In vitro studies revealed significant cell death and suppressed cyclin D1 and IAP-1 gene expression in UMSCC-11A and -11B lines treated with 10-7M bortezomib. Conclusion: In patients with clinically responsive tumors, bortezomib induces apoptotic effects and reductions in NF-kB-regulated cytokines in serum as early as 24 hours posttreatment. Suppression of IAP-1 and cyclin D1 gene expression in HNSCC cells may contribute to the antiproliferative and apoptotic effects of bortezomib. Significance: Further investigation of antiapoptotic and cell cycle genes in patient tissue with real-time RT-PCR is in progress to study the molecular mechanism of differential sensitivity of tumors in HNSCC patients to bortezomib. Understanding this mechanism may significantly improve the efficacy of this drug in HNSCC patients. Support: Intramural Project DC-00016 and NIH Clinical Research Training Program