Development of novel platinum-based prodrugs and combination therapies for Glioblastoma treatment

Glioblastoma (GBM) remains one of the most aggressive and difficult-to-treat brain tumors, presenting significant challenges in terms of therapeutic resistance and recurrence. The primary objective of this project was to identify novel therapeutic targets and develop innovative therapies for GBM by synthesizing, in collaboration with chemists from the University of Pavia and the University of Eastern Piedmont, and evaluating new platinum-based prodrugs. A critical component of this research involved the investigation of (OC-6-44)- acetatediaminedichlorido(2-(2-propynyl)octanoate)platinum(IV) (Pt(IV)Ac-POA), a platinum(IV) prodrug. This compound is characterized by the inclusion of a histone deacetylase inhibitor (HDACi) as an axial ligand, and its effects were compared to those of Cisplatin, a standard chemotherapeutic agent. The study also explored the therapeutic efficacy of combining these compounds with micotherapy, which is recognized for its antioxidant properties. A key focus was to elucidate the differential activation of cell death mechanisms, with particular attention given to the physiological processes involved in both programmed and non-programmed cell death. These processes are vital for development, tissue homeostasis, and defense mechanisms, and understanding them could provide insights into more effective GBM treatments. The promising synergistic effects observed from the combination therapies led to the development of a new prodrug called Pt(IV)-GA. This novel compound integrates the cytotoxic effectiveness and the innovative concepts of octahedral platinum-based compounds and natural adjuvants, potentially enhancing therapeutic outcomes. Further comparisons between Pt(IV)Ac-POA and Cisplatin highlighted the potential of Pt(IV)Ac-POA in overcoming therapeutic resistance mechanisms, a significant limitation in current GBM treatments. This finding prompted a deeper investigation into another innovative compound, (OC-6-44)-acetatediamminedichlorido (4,5- dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato)platinum(IV) (DB178). Both Pt(IV)Ac-POA and DB178 feature HDAC inhibitors as axial ligands (PropynylOctanoate in Pt(IV)Ac-POA and SuberoylAnilide Hydroxamic Acid in DB178). Notably, DB178 also includes Rhein, a naturally occurring compound known for its anti-inflammatory, antioxidant, and anticancer properties. By examining these novel compounds, the study aimed to identify and target vulnerable points within the molecular pathways of GBM that contribute to therapeutic resistance. Addressing these pathways could significantly improve the efficacy of platinum-based therapies, which are currently limited by resistance issues in GBM treatment. To ensure clinical relevance and potential applicability of these findings, preliminary data are being gathered using 3D tumor models and blood-brain barrier models, in addition to in vivo studies. These evaluations are crucial for providing a comprehensive understanding of the therapeutic potential and safety profiles of the three compounds of interest.