Dissecting NF-kB pathway in HPV-associated head and neck cancer

点击翻译按钮获取中文摘要

Project summary The incidence of HPV-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) has dramatically increased over the last few decades and continues to rise. Despite the magnitude of this epidemic, mechanisms of HPV-driven carcinogenesis in HPV+ HNSCC have not been thoroughly investigated. Compared to patients with tobacco-associated HNSCC, those with HPV+ HNSCC have increased overall survival and higher response to treatment, which usually consists of chemo- and radiation therapy; however, survivors frequently suffer from treatment’s toxic side effects, such as swallowing and speech dysfunction. In addition, approximately 25% of HPV+ HNSCC patients develop recurrent or metastatic disease, for which there are limited treatment options. A pressing goal in head and neck oncology is to decrease the morbidity of therapy for HPV+ HNSCC through treatment de-escalation. However, biomarkers that identify HPV+ patients with good prognosis, who may be appropriate for de-escalation therapy, are lacking. Using three independent cohorts, we found that constitutively active NF-κB (usually arising from genetic defects in NF-κB regulators, including TRAF3 and CYLD) correlates with survival and should be explored as a prognostic biomarker in HPV+ HNSCC. Our preliminary data suggest that survival benefits of patients, whose tumors harbor overactive NF-κB, are attributed to better tumor response to therapy and that both, inherent NF-κB-driven tumor characteristics (e.g. downregulated expression of oxidative stress response, NRF2 target genes), as well as a distinct tumor microenvironment (e.g. elevated number of tumor infiltrating CD4+ T cells), may contribute to increased sensitivity of NF-κB active tumors to radiation. We previously reported that mutations in TRAF3 and CYLD were associated with a lack of HPV integration, leading us to hypothesize that NF-κB activation may enable cells to maintain HPV episomes. Since the canonical HPV carcinogenesis model depends on HPV integration, we also hypothesize that activation of NF-κB may be critical for an alternative mechanism of HPV carcinogenesis driven by HPV episomal maintenance. To explore our hypothesis, in Specific Aim 1, we will investigate the impact of NF-κB signaling on HPV gene expression and episomal maintenance. In Specific Aim 2, we will explore the significance of NF-κB pathway on cellular proliferation, survival, and cellular transformation in response to HPV. Finally, Specific Aim 3 will explore mechanisms of NF-κB mediated radiation sensitivity in HPV+ HNSCC.