Endocrine Abstracts

Astrocytomas are a subtype of malignant gliomas characterized by rapid growth and high diffusion through the brain. Based on the agresiveness features, they are stratified from low grades (I and II) to high grades (HGAs; III and IV), being grade-IV [glioblastoma multiforme (GBM)] the most aggressive and one of the most common malignant cancers in the brain, with an overall survival from diagnosis of ~14 months. Current standard therapies to treat HGAs are not efficient and therefore, identification of new therapeutic tools to tackle HGAs is urgently needed. In this sense, many metabolic drugs have emerged as antitumor agents for several endocrine-related cancers demostrating different pleiotropic anti-tumoral effects. Among them, metformin and simvastatin are currently prescribed to treat T2D patients and hypercholesterolemia, respectively. Thus, our aims were to evaluate: i) the putative in vivo association between metformin and/or simvastatin treatment and key clinical parameters in HGA patients, and ii) the direct effects of metformin, simvastatin and their combination, on key functional endpoints and associated signaling mechanisms in GBM-cells. Specifically, an exploratory/observational retrospective cohort of patients with HGAs (n = 61; mean age: 63.9 ± 5.5) was analyzed, and human GBM-cells (U-87 MG/U-118 MG cell lines and patient derived-HGA cell cultures) were used to measure a set of key functional parameters and signaling-pathways in response to metformin, simvastatin and their combination. We found that metformin/simvastatin combination showed an association to longer overall survival in vivo. Moreover, metformin and simvastatin exerted strong antitumor actions being able to inhibit proliferation, migration, tumorsphere/colony-formation, VEGF secretion and to induce apoptosis on HGA-cells in vitro. Notably, their combination further decreased, additively, these functional parameters compared with the individual treatments. These individual or combined actions were mediated through modulation of key oncogenic signaling-pathways (i.e. AKT/JAK-STAT/NFkB/TGFß pathways). Interestingly, an enrichment analysis uncovered an activation of TGFß pathway together with the AKT inactivation when metformin and simvastatin were administered in combination, which might promote to a senescence-associated secretory phenotype and then a senescence state transition. Altogether, our results demonstrate that metformin and simvastatin significantly reduce tumor aggressiveness features in HGAs, being this effect more potent (in vitro and in vivo) when both drugs are combined. Therefore, given the demonstrated clinical safety of biguanides (metformin) and statins (simvastatin), our results suggest a potential therapeutic role of these compounds, especially their combination, for the treatment and management of this devastating brain cancer.

Fundings

MINECO (PID2019–105564RB-I00/FPU16/05059), ISCIII (PI16–00264), Junta de Andalucía (BIO-0139) and CIBERobn.