Unveiling the drug repurposing versatility of denosumab in the battle against human cervical cancer.

Cervical cancer (CC) remains a leading cause of cancer related deaths in women worldwide. Over the last decades, little progress has been made in the systemic treatment of patients with advanced or recurrent forms. To successfully battle this cancer and improve long-term benefits for the patient, anti-cancer responses need to be stimulated whereby the immune system eradicates all residual cancer cells and prevents disease outbreak by anti-tumor immunity. Since CC has shown to be immunogenic, a promising hot field of research in oncology that opens new perspectives for its treatments is immunotherapy. However, tumor cells seem to have multiple mechanisms for evading immune surveillance, which is believed to be a major confounding factor involved in failure of currently used immunotherapies, like immune checkpoint inhibitors (ICI). In recent years, the RANKL/RANK signaling pathway has been implicated as a key player in this tumor-induced immunosuppression, making it a very attractive target to reinvigorate the tumor susceptibility to checkpoint inhibition.Signaling between receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) is best described for its obligate role in the differentiation of bone-resorbing osteoclasts and consequential bone-derived diseases, such as postmenopausal osteoporosis and cancer-related bone destruction. This has led to the development of denosumab, a fully human monoclonal antibody that binds RANKL, thereby blocking the interaction with its receptor, RANK. Recently however, it has been shown that RANK and RANKL are commonly highly co- expressed on tumor cells and immune cells in their tumor microenvironment (TME). Accumulating evidence highlights the pivotal role that RANK/L signaling has in allowing tumor cells to evade immune surveillance by modulating the tumor immune environment, and in participating in every step of cancer progression, given its pleiotropic effects on tumor cells and its microenvironment. The primary objective of the proposed research project is to expose the functional mechanisms of the RANK/L signaling pathway in CC. The second objective is to exploit the effects of denosumab on the migratory and invasive features of cervical cancer cells. We hypothesize that RANK/L signaling plays a key role in both the metastatic as immune modulating features of CC, and therefore we see great potential in investigating the drug repurposing of denosumab in the battle against this type of cancer.

Keywords:CERVICAL CANCER

Disciplines:Cancer biology, Cancer therapy