A first-in-class small-molecule inhibitor targeting AVIL exhibits safety and antitumor efficacy in preclinical models of glioblastoma.

Glioblastoma (GBM) is the most common and deadliest malignancy of the brain. Despite decades of intense research, there has been little change to the overall survival of patients with GBM. Our laboratory recently identified the actin-binding protein advillin (AVIL) as being overexpressed, oncogenic, and necessary for tumorigenesis in GBM. Here, we further examined AVIL expression in GBMs and found that it was enriched across molecular subtypes and states, including GBM stem cells and temozolomide-resistant samples. In contrast, we found that AVIL was scarcely expressed in normal human brain tissue. In addition, Avil knockout in mice had no adverse effects, suggesting that there may be a wide therapeutic window for therapies targeting AVIL. Using high-throughput small-molecule screening, we identified a direct inhibitor of AVIL that bound to the protein and also blocked AVIL binding to its substrate, actin. It induced a transcriptome profile similar to that of AVIL silencing by siRNA and caused down-regulation of FOXM1 and LIN28B, two known downstream targets of AVIL. Moreover, it exhibited selectivity toward tumor cells, sparing astrocytes and neural stem cells in vitro. In vivo, we found that the compound readily crosses the blood-brain barrier and could be delivered orally. We then demonstrated efficacy in five GBM mouse models without evidence of side effects. In summary, we have identified an efficacious first-in-class compound targeting an oncogene in GBM. Further optimization of the molecule may offer an effective therapeutic intervention for GBM.