RESUMEN
Glioblastoma (GBM) is a rare brain cancer with an exceptionally high mortality rate, which illustrates the pressing demand for more effective therapeutic options. Despite considerable research efforts on GBM, its underlying biological mechanisms remain unclear. Furthermore, none of the United States Food and Drug Administration (FDA) approved drugs used for GBM deliver satisfactory survival improvement. This study presents a novel computational pipeline by utilizing gene expression data analysis for GBM for drug repurposing to address the challenges in rare disease drug development, particularly focusing on GBM. The GBM Gene Expression Profile (GGEP) was constructed with multi-omics data to identify drugs with reversal gene expression to GGEP from the Integrated Network-Based Cellular Signatures (iLINCS) database. We prioritized the candidates via hierarchical clustering of their expression signatures and quantification of their reversal strength by calculating two self-defined indices based on the GGEP genes' log 2 foldchange (LFCs) that the drug candidates could induce. Among eight prioritized candidates, in-vitro experiments validated Clofarabine and Ciclopirox as highly efficacious in selectively targeting GBM cancer cells. The success of this study illustrated a promising avenue for accelerating drug development by uncovering underlying gene expression effect between drugs and diseases, which can be extended to other rare diseases and non-rare diseases.
RESUMEN
In laboratory animals, there are numerous demonstrations that past exposure to drugs of abuse can lead to devaluation impairments weeks after the final drug exposure, with the majority of these demonstrations examining effects of exposure to psychostimulants. There has been minimal investigation into whether prior exposure to opiates can lead to devaluation impairments. Here, we first trained female rats that two separate cuelights predicted two different foods and measured Pavlovian goal-tracking responses (Experiment 1) or trained female rats to press two levers to earn two different foods and measured this operant response (Experiment 2). In both experiments, we subsequently gave the rats injections of fentanyl twice daily for 6 days, and then tested rats for conditioned responses after satiation on one of the foods 48-h after the final injection. We found that rats were impaired in the expression of devaluation in the Pavlovian task after fentanyl exposure, but were unimpaired in the expression of devaluation in the operant task. The pattern of results is most consistent with an impairment in lateral orbitofrontal cortex function, but additional research is needed to determine the neurobiological cause of this pattern of results.