Selected Articles from This Issue

Devimistat (CPI-613) is a novel inhibitor of key mitochondrial enzymes in the tricarboxylic acid cycle, but it failed to show an improvement in survival in pancreas cancer. Given the short half-life of devimistat, Mohan and colleagues conducted in vitro dose modeling experiments that demonstrate synergism of devimistat in combination with gemcitabine and cisplatin and, at higher doses or prolonged exposures to devimistat, a significant decrease in mitochondrial respiration. The phase Ib clinical trial supported by preclinical work evaluated higher doses at longer infusion times and demonstrates a favorable safety profile with promising initial efficacy, and it identified a recommended phase II dose currently under further investigation in a phase II randomized trial.

Tumor BRAFp.V600E mutation is responsible through the activation of the MAP kinase pathway for the loss of expression of proteins involved in the iodine metabolism in thyroid cancer. Leboulleux and colleagues explored the efficacy and safety of a 6-week treatment with a combination of dabrafenib-trametinib-¹³¹I in patients with metastatic and progressive radioactive iodine refractory BRAFp.V600E mutated thyroid cancer. The dabrafenib-trametinib combination restored ¹³¹I uptake in 95% of the patients and, 6 months after the administration of a high activity of ¹³¹I, a partial tumor response was observed in 38% of the patients. These favorable results open a new treatment opportunity.

Cisplatin-induced hearing loss (CIHL) results from oxidant-mediated damage to the cochlea. Sodium thiosulfate successfully reduced CIHL in recently concluded randomized trials, the first thiol-class agent to do so. N-acetylcysteine (NAC) is a strong thiol antioxidant, but also acts as a glutathione prodrug, stimulating glutathione production to restore innate resistance to oxidant damage. In this nonrandomized, controlled Phase Ia/Ib trial, Orgel and colleagues show that NAC demonstrated clear efficacy and safety signals as an otoprotectant, warranting further development in randomized trials. Although multiple otoprotective mechanisms have been proposed, NAC's recognized role in glutathione metabolism, reinforced by the serum and pharmacogenomics findings, support targeting the antioxidant pathway for otoprotection, including further investigation into glutathione's central role in CIHL and otoprotection. Moreover, with marked heterogeneity in tumor types treated and cisplatin-based chemotherapy regimens, this successful phase I trial highlights the critical importance of selecting clinically relevant tumors and infusion methods in developing novel otoprotectants.

Neural parameters besides perineural invasion, such as nerve density, could be important for treatment selection and response. However, this has not been investigated using a standardized approach or in pre-clinical models. Perez-Pacheco and colleagues developed normalized nerve density (NND) that integrates variations in innervation. High NND associates with poor survival in oral cancer. Moreover, NND impacts perineural invasion, nerve-tumor distance, and nerve diameter. Artificial intelligence and manual detection showed high concordance, important for clinical feasibility. Preclinical models established that increased nerve density enhances tumor growth. These findings open clinical possibilities that could reduce tumor recurrence.