Abstract 4942: Variations in HPV function are associated with patient outcome and identify new candidate therapeutic approaches
Authors: Gleber-Netto Frederico O. , Gao Meng , Rao Xiayu , Vellano Christopher P. , Marszalek Joseph R. , Wang Jing , Johnson Faye M. , Pickering Curtis R. 
Published: August 2019

Abstract
Human papilloma virus (HPV) is an oncogenic driver for a subset of head and neck squamous cell carcinomas (HNSCC), primarily from the oropharyngeal tissue subsite (OPSCC). These tumors are increasing in incidence and have recently surpassed cervical cancer as the most common HPV-driven malignancy in the United States. Fortunately, these tumors generally respond well to radiation-based therapy (XRT), and long-term (5 yr) survival is around 85%. However, the XRT treatment can generate significant morbidity, including problems with speech and swallowing. There is a clinical effort to reduce the treatment-related morbidity without compromising survival outcomes, through de-escalation treatment protocols. However, there is a subset of HPV+ OPSCC patients who do not respond to the current therapies and should not be given less intense treatment. This has generated the need to stratify patients based on their risk of recurrence or death, but currently no molecular biomarkers are available for risk assessment in OPSCC. By analyzing genomic data from The Cancer Genome Atlas (TCGA) we have identified a gene expression signature associated with expression of HPV genes. This signature identified 2 groups within the HPV+ tumors that demonstrate different levels of HPV function. One group seems to have reduced HPV function and present with intermediate phenotypes between HPV+ and HPV- tumors. Importantly, this signature is also highly prognostic in HPV+ OPSCC (p&lt;0.0001) and significant on multivariate analysis (p&lt;0.01). With the tumors showing reduced HPV function having worse outcomes. This prognostic signature was validated in independent OPSCC (p&lt;0.0001) and cervical cancer cohorts (p&lt;0.0026). The signature is most strongly associated with differential expression in the HPV gene E1^E4 but not with expression of the oncogenic driver genes of E6 and E7 genes. In vitro, we have associated the signature with sensitivity to XRT, suggesting a mechanism for the differences in patient outcome. An in vitro high throughput drug screen has identified candidate druggable targets in both the high and low risk groups, with 2 key pathways being cellular metabolism and proteasome function. Single agent and combination treatments targeting these pathways are currently being evaluated. In conclusion, we have identified a novel prognostic signature for HPV+ tumors that is associated with variations in HPV function among patients. This has the potential to translate into a biomarker assay for risk stratification, for use with de-escalation treatment protocols. Additionally, it has identified key functions of HPV that appear to be targetable and could lead to new therapeutic approaches for the subset of HPV+ patients who do not respond to XRT treatment.
Citation Format: Frederico O. Gleber-Netto, Meng Gao, Xiayu Rao, Christopher P. Vellano, Joseph R. Marszalek, Jing Wang, Faye M. Johnson, Curtis R. Pickering. Variations in HPV function are associated with patient outcome and identify new candidate therapeutic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4942.