DEBIO 1143 has a potential to increase effectiveness of electrochemotherapy and radiotherapy in HPV positive and HPV negative Head and Neck Cancers

Treatment for advanced cancer of the head and neck cancer (HNC) is still challenging, due to the previous irradiation failure or when the site has already been operated and additional surgery would affect quality of life, loss of function and cosmetic disfigurement. Electrochemotherapy (ECT) is a possible option for patients with HNC where with local application of electric pulses we improve drug diffusion into the cells. The two drugs that have been used most often in ECT are bleomycin (BLM), and cisplatin (CDDP), that with electroporation easier cross cell membrane and reach their target molecule DNA. In our research we want to improve treatment with radiotherapy (RT) and ECT in with adding a molecule DEBIO 1143, that promotes apoptosis in tumor cells via restoration of caspase activity through blockade of Inhibitors of apoptosis proteins (IAP). In experiments where we will use RT in combination with DEBIO 1143 as a treatment of HNC we will use single and fractionated doses of irradiation. For ECT we will use BLM and CDDP that have different mode of action and lead to different types of cell death. We will search for the best therapeutic combination in HNC specifically, in HPV positive and HPV negative oral carcinoma tumors, that are two distinct entities with molecular, histological, epidemiological and prognostic differences. HPV positive and HPV negative HNC respond to therapy different and HPV positive HNC have better overall survival. Mechanisms for this are still not fully understood, but the ongoing research is focusing on HPV genes E6 and E7 and activation of DNA sensors. Expression of HPV genes E6- and E7-and their mode of action in degradation of tumor suppressor protein p53 and retinoblastoma proteins, leads to fundamental cellular events, such as cell cycle, apoptosis, DNA repair, senescence, and differentiation, facilitating the accumulation of DNA damage and the progression towards malignancy. DNA sensors are activated when DNA is present inside the cytosol and their activation leads to upregulation of cytokines such as type I interferons and IL-1β and can induce different types of cell death (apoptosis, pyroptosis, and necroptosis). We will determine different types of cell death and evaluate if also DNA sensors contribute to the cell death.