Clinical and translational evidence of metformin and simvastatin additive antitumor effects in glioblastoma via senescence-state

ME. G-Garcia*^a (Mr), AC. Fuentes-Fayos^a (Dr), J. Pérez-Gómez^a (Mr), R. Sanchez-Sanchez^b (Mr), JM. Jimenez-Vacas^a (Dr), M. Tena-Sempere^a (Prof), M. Lopez^c (Mr), J. Solivera^d (Dr), MD. Gahete^a (Prof), RM. Luque^a (Prof)

^a IMIBIC/Univeristy of Cordoba, Córdoba, SPAIN ; ^b Reina Sofia University Hospital/Pathoogy Service, Córdoba, SPAIN ; ^c CiMUS/University of Santiago, Santiago De Compostela, SPAIN ; ^d Reina Sofia University Hospital/Neurosurgery Department, Córdoba, SPAIN

* miedu1998gargar@gmail.com

Glioblastoma (GBM) is one of the most devastating and incurable neuroendocrine-related cancers due to its aggressive behavior and lack of therapies available, being its overall-survival from diagnosis ~14 months [1]. Thus, identification of new therapeutic tools is urgently needed. Interestingly, metabolism-related drugs [e.g., biguanides (i.e. metformin) and statins (i.e. simvastatin)] are emerging as efficient antitumor agents for several endocrine-related cancers [2]. Therefore, we aimed to evaluate the in vivo and in vitro antitumor effects of metformin and simvastatin alone, or in combination, in GBM patients and in different GBM preclinical models. Specifically, an exploratory-observational-randomized retrospective GBM patient cohort (n=85), human GBM-cells (cell-lines and patient-derived cell-cultures), mouse astrocytes progenitor cell-cultures, and a preclinical xenograft GBM mouse-model were used to measure key clinical/functional/molecular/signaling-parameters and tumor-progression treating with metformin and/or simvastatin. Metformin and simvastatin exerted strong antitumor actions in vitro (i.e., proliferation/migration/tumorsphere/colony-formation/VEGF-secretion inhibition and increased apoptosis) in GBM-cells, but not in non-tumor brain cells. Notably, their combination additively decreased these functional parameters compared to individual treatments. Moreover, we demonstrated that metformin, simvastatin, and especially their combination, significantly decreased mouse astrocytes progenitor cells proliferation (a model focused on GBM-malignancy and therapeutic-resistance). These antitumor actions of metformin, simvastatin, and especially their combination, were mediated by the modulation of key oncogenic signaling-pathways (i.e., AKT/JAK-STAT/NF-κB/TGFß-pathways). Interestingly, an enrichment analysis uncovered a TGFß-pathway activation, together with AKT-inactivation, in response to metformin+simvastatin combination, which might promote a senescence-state linked to a secretory-phenotype, and to the dysregulation of oncogenic spliceosome components. Finally, the antitumor actions of metformin+simvastatin were also observed in vivo [i.e., association with longer overall-survival in GBM-patients, and reduction in tumor-progression in a GBM mouse-model (significant reduction in tumor size, weight, mitosis-number, and increased apoptosis)]. Altogether, metformin and simvastatin reduce aggressiveness features in GBM, being this effect significantly more effective when both drugs are combined, offering a clinically relevant therapeutic opportunity that should be tested in humans.

Bibliography:

[1] Ostrom QT, et al. 2021. Neuro-Oncol 23(12 Suppl 2):iii1-iii105

[2] León-González AJ, et al. 2021. Curr Opin Pharmacol 60:17-26

The author has declared no conflict of interest.