MODL-08. Evaluation of Therapeutic Efficacy of Imipiridones in Lynch Syndrome-Associated High-grade Gliomas

Abstract Introduction Lynch Syndrome is a common hereditary cancer syndrome linked to DNA mismatch repair gene deficiency (MMRD) that predisposes individuals to various cancers, including high grade gliomas (Lynch-HGG). Lately, there has been increasing evidence suggesting the effectiveness of imipiridones as an anti-cancer treatment for high grade gliomas. In this study, we aimed to develop suitable preclinical Lynch-HGG models and evaluate the efficacy of imipiridones using these models. Methods In this study, we retrieved, cultured, and profiled a panel of Lynch-HGG patient-derived cell lines by Western blotting, Whole Exome Sequencing, and mRNASeq. The cells were then tested with increasing doses of imipiridones, ONC201 and ONC206, in both mono- and combination therapy regimen. Murine models were generated via intracranial injection of Lynch-HGG cells labelled with mCherry-luciferase. The murine models were then treated with ONC201 and ONC206 mono- and combination treatment. Results Our results indicated that all the tested Lynch-HGG cells showed a loss of MMRD protein, consistent with the primary mutation associated with lynch syndrome, and a constant loss of P53, a tumor suppressor protein. One of the Lynch-HGG, 7316-3058, exhibited an additional gene alteration, loss of NF1, another critical tumor suppressor protein. Transcriptomic analysis unveiled upregulation in cell cycle processes in all the Lynch-HGG cells. In vitro treatment with ONC201 and ONC206 demonstrated varying degrees of drug response, with 7316-3058 displaying high sensitivity to the targeted inhibitors. Unfortunately, this therapeutic efficacy did not translate to the in vivo murine model, suggesting potential underlying mechanisms that impede drug efficiency in vivo. Conclusion In summary, we developed Lynch-HGG preclinical models that can be utilized for drug screening to develop novel targeted therapies. Despite the promising in-vitro data, the limited efficacy of imipiridones in treating Lynch-HGG in vivo, emphasizes the challenges in translating in vitro findings to in vivo context. This study contributes valuable insights to the development of effective therapeutic strategies for Lynch-HGGs.