Glioblastomas (GBMs) are brain tumors of glial origin characterized by a heavy hypoxic microenvironment, which correlates with tumor aggressiveness. GBM cells abundantly express large-conductance, calcium-activated potassium (BK) channels and, since hypoxia modulates their activity in GBM cells, the aim of the present project is to explore their role in response to temozolomide (TMZ, the standard of care for all GBM patients) and to better understand the molecular mechanisms underlying the effect of the hypoxic microenvironment on BK channels-dependent drug resistance of GBM cells.
The present project is expected to gain a solid understanding on the role of BK channels in specific aspects of GBM aggressive behavior exacerbated under hypoxia and to give relevant indications for new therapeutic strategies based on the pharmacological inhibition of these ion channels. In particular, we expect to gain important evidences about the biological function that BK channels have in GBM cells exposed to chemotherapeutic agents. In fact, hypoxia is a relevant obstacle to conventional therapies for its capacity to induce resistance. There is an increasing need to find novel molecular targets to make this devastating tumor less aggressive. This is the first time that a possible mechanism of chemoresistance induced by hypoxia has been associated to BK channels. Our previous works demonstrated for the first time an association of BK channels with the stemness marker CD133, their fundamental role in glioblastoma stem-like cells migration and differentiation, and a role for these channels in the resistance induced by the hypoxic condition that exacerbates GBM aggressiveness. Thus, all these evidences may well be promising when thinking about BK channels as a new molecular target to consider for GBM management.
In conclusion our final aim is to develop novel tools to identify any possible therapy interfering with the activity of BK channels within the contest of the so-called precision medicine approach.
- This project has the main purpose of understanding the mechanisms of GBM cells resistance to conventional therapies which leads to tumor recurrence. The new evidences that we expect to produce will give precious information for the development of novel tools to make GBM less aggressive, as well as novel diagnostic and prognostic indications.
- The results that will be achieved with this project will help to stimulate the cooperation between diagnostics and pharmaceutical companies in order to develop new technologies with the intention to increase European industrial capabilities.
- The aims of the present project are ambitious and have the goal to bring together knowledge and resources for the health of population.