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

BASIC DATA OF THE RESEARCH PROJECT

• ARIS code: J3-50108
• TITLE: DEBIO 1143 has a potential to increase effectiveness of electrochemotherapy and radiotherapy in HPV positive and HPV negative Head and Neck Cancers
• PROJECT LEADER: Katarina Žnidar, PhD
• DURATION: : 1. 10. 2023 - 30. 9. 2026
• RESEARCH ORGANISATION: Institute of Oncology Ljubljana
• FINANCING: Slovenian Research Agency

ABSTRACT

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.

OBJECTIVE

The objective of the project is to evaluate therapeutic potential of antagonist of inhibitor of apoptosis proteins DEBIO 1143 in combination with RT and ECT in HNC. For RT we will use single dose 1x15 Gy and fractionated raditation 3x8 Gy. For ECT we will use BLM and CDDP that have different mode of action and lead to different types of cell death. We will use HPV positive and HPV negative HNC that respond different to therapy and usually HPV positive tumors have statistically significantly better overall survival than patients with HPV negative. We will investigate molecular changes induced by DEBIO 1143 in HPV positive and HPV negative HNC and evaluate expression of DNA sensors and cytokines to evaluate if the response of treatment is connected also to DNA sensing pathways in HPV positive and HPV negative HNC.

Furthermore, our in vitro results will disclose which combination of ECT with DEBIO 1143 is the most effective for treatment of HPV positive and HPV negative oral squamous cell carcinoma and the effectiveness of selected treatment will be evaluated in vivo on tumors. Due to different HPV statusof tumors we expect different response of HPV positive and HPV negative tumors. All the findings will contribute to more efficient RT and ECT treatment of HNC.

The proposed project will be divided into three work packages (WP) with specific tasks:

WP 1. Cytotoxic effect of DEBIO 1143, RT in combination with DEBIO 1143 and ECT in combination with DEBIO 1143 on HPV16 positive and HPV16 negative mouse oral carcinoma (MOC1) cell lines in vitro.

WP 2. Molecular mechanisms of combined treatment

WP 3. Potentiation of antitumor effectiveness of ECT with cisplatin or bleomycin in combination with DEBIO 1143 on HPV positive and HPV negative oral carcinoma in vivo.