Gliomas are tumors of glial origin and are the most frequent malignancies of the brain being associated with a dismal prognosis and life quality. Glioblastoma (GBM, WHO grade IV) is the most aggressive form of glioma, and despite the best of the cares, is still an untreatable tumor with a median survival of about 12-15 months. GBM is characterized by extensive hypoxic areas that strongly correlate with tumor malignancy. Hypoxia promotes stemness, migration, invasion, angiogenesis, radio- and chemoresistance, all responsible of the failure of current therapies. Thus, there is still an increasing need to find novel molecular targets and to understand how to limit GBM relapse.
Polysialic acid (PSA) is a carbohydrate composed of a linear polymer of ¿2,8-linked sialic acid. In neural cells, PSA is mainly attached to the Neural Cell Adhesion Molecule (NCAM). PSA is considered an oncodevelopmental antigen being highly expressed during development, downregulated in the adult, and re-expressed in tumoral cells. High levels of PSA-NCAM are associated with high-grade tumors with a low degree of differentiation and with the ability to spread aggressively.
In light of that, the aim of this study is to understand the effect of PSA inhibition in GBM cells. Targeting PSA could well be a promising strategy to manage a devastating tumor as GBM.
With this project we expect to gain a solid understanding on the role of PSA in specific aspects of GBM aggressive behavior exacerbated under hypoxia. The proposed experiments have the potential to provide relevant indications for new therapeutic strategies based on the pharmacological inhibition of this post-translational modification. In particular, we expect to gain important evidence about the biological function that PSA exert in GBM cells exposed to hypoxic microenvironments. Our previous works pointed to understand the role of BK channels in the migration, differentiation and chemoresistance of GBM cells.
Since low oxygen is a relevant obstacle to conventional therapies for its capacity to induce resistance, there is still an increasing need to find novel molecular targets to make this devastating tumor less aggressive.
Our preliminary data show a clear induction of PSA levels under hypoxia, and it would be extremely important to find novel ways to lower this post-translational modification in those cells. The possibility to extend our determinations to primary cultures and to analyze patient¿s tissues will be fundamental to understand whether our observations may have a pathophysiological relevance.
We believe that our proposal has the potential to clarify some still unexplored aspect of GBM and to identify novel and effective therapeutic strategies for it. The possibility to analyze patient-derived tissues will also provide the opportunity to develop a personalized approach and eventually identify novel diagnostic and prognostic indications. This will certainly stimulate the cooperation between diagnostics and pharmaceutical companies, increase the European industrial capabilities and produce tangible benefits for patients with more sustainable costs for the National Health Systems.