scholarly journals Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 282
Author(s):  
W. Quinn O’Neill ◽  
Xiujie Xie ◽  
Shanying Gui ◽  
Heping Yu ◽  
Jacqueline Davenport ◽  
...  

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV− HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.

2019 ◽  
Vol 26 (6) ◽  
pp. 1474-1485 ◽  
Author(s):  
Janis V. de la Iglesia ◽  
Robbert J.C. Slebos ◽  
Laura Martin-Gomez ◽  
Xuefeng Wang ◽  
Jamie K. Teer ◽  
...  

2021 ◽  
Vol 27 (17) ◽  
pp. 4941-4941
Author(s):  
Janis V. de la Iglesia ◽  
Robbert J.C. Slebos ◽  
Laura Martin-Gomez ◽  
Xuefeng Wang ◽  
Jamie K. Teer ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jili Cui ◽  
Lian Zheng ◽  
Yuanyuan Zhang ◽  
Miaomiao Xue

AbstractHead and neck squamous cell carcinoma (HNSCC) is the sixth most common type of malignancy in the world. DNA cytosine-5-methyltransferase 1 (DNMT1) play key roles in carcinogenesis and regulation of the immune micro-environment, but the gene expression and the role of DNMT1 in HNSCC is unknown. In this study, we utilized online tools and databases for pan-cancer and HNSCC analysis of DNMT1 expression and its association with clinical cancer characteristics. We also identified genes that positively and negatively correlated with DNMT1 expression and identified eight hub genes based on protein–protein interaction (PPI) network analysis. Enrichment analyses were performed to explore the biological functions related with of DNMT1. The Tumor Immune Estimation Resource (TIMER) database was performed to explore the relationship between DNMT1 expression and immune-cell infiltration. We demonstrated that DNMT1 gene expression was upregulated in HNSCC and associated with poor prognosis. Based on analysis of the eight hub genes, we determined that DNMT1 may be involved in cell cycle, proliferation and metabolic related pathways. We also found that significant difference of B cells infiltration based on TP 53 mutation. These findings suggest that DNMT1 related epigenetic alterations have close relationship with HNSCC progression, and DNMT1 could be a novel diagnostic biomarker and a promising therapeutic target for HNSCC.


2019 ◽  
Vol 1866 (4) ◽  
pp. 623-637 ◽  
Author(s):  
Amanda Tomie Ouchida ◽  
Valéria Tudella Uyemura ◽  
André Lima Queiroz ◽  
Verônica Soares Brauer ◽  
Marinaldo Pacífico Cavalcanti-Neto ◽  
...  

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