Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to “Stupp protocol”, Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4–13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large “real-life” experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment.

The enzyme thioredoxin reductase (TrxR) is attracting much interest as a potential target for cancer therapy. The presence of a selenium atom in the catalytic site makes it sensitive to inhibition by electrophilic molecules, including the AuI complex auranofin [2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D‐glucopyranosato‐S‐(triethylphosphane)gold]. The reactions between auranofin and models of thiol and selenol nucleophiles present in TrxR (PhSH and PhSeH) have been investigated in chloroform and methanol by means of 1H, 31P, and 77Se NMR spectroscopy. In chloroform, auranofin undergoes ligand substitution of the tetraacetylthioglucose moiety by a PhS or PhSe group. The reaction is reversible in both cases, but it is characterized by widely different equilibrium constants (ca. 1 for S and at least 103 for Se). In polar solvents, such as methanol, the reaction is more complex, and the phosphane moiety also undergoes ligand exchange. Some features have been clarified through the investigation of Et3PAuCl. The elementary processes involved have been characterized by DFT calculations.

No abstract