Identification of common pathogenic mechanisms driving squamous cell carcinomas of the anogenital tract and head&neck region to develop overarching therapeutic strategies

Squamous cell carcinomas (SCC) originating from the mucosal epithelium of the anogenital tract and head and neck region (particularly oral and oropharyngeal tract) share common cancerous pathways that are primarily triggered by a panel of risk factors, e.g. aging, smoking, alcohol consumption, and, to a lesser extent, the human papillomavirus (HPV) infection. Currently, the standard treatments for these tumors involve radiotherapy, chemotherapy, or surgery, all with devastating effects on the targeted anatomical sites. Thus, alternative therapies with higher efficacy and fewer side effects are urgently needed to improve patient outcomes. The proposing group has recently observed that activating mutations in the telomerase reverse transcriptase promoter (TERTpm) are frequent in this setting and cause enhanced TERT expression in both oral (60%) and genital (20%-60%) SCC. High expression levels of endogenous TERT in cancer cells can trigger extra-telomeric oncogenic pathways and tumorigenesis, which demand new combined therapeutic approaches, including telomerase inhibitors. They have also recently shown that HPV-related SIRT1 upregulation in oropharyngeal SCC, characterized by dysregulated TERT expression and wild-type p53, causes p53 deacetylation and enhanced stabilization. Inhibition of SIRT1 with the small molecule EX527 determines p53 restoration in cervix and oropharynx SCC rendering tumor cells more sensitive to either genotoxic agents or ionizing radiation. In addition, a novel approach of gene editing, more effective than CRISPR/Cas9, has also been developed by the proposing group to target neoplastic cells bearing specific mutations. Thus, we propose to identify common molecular pathways underlying SCC development in the anogenital tract and head and neck region and to develop host-targeted therapeutic interventions against these cancers.