Dddr-27. class i hdac inhibitor against tm-mediated network connectivity in glioblastoma

Abstract Tumor microtubes (TMs) are long thin cellular protrusions extended by one glioblastoma cell to connect to another and integrate into a communicating network that contributes to glioblastoma’s high therapy resistance. Understanding the biological functions of tumor cell connectivity and overcoming network resistance has emerged as a new therapeutic opportunity. The combinatorial treatment of an anti-TM compound with a cytotoxic treatment has come to focus after it was shown that non-connected glioblastoma cells are more vulnerable to cytotoxic therapy. Besides the development of therapies against specific proteins in TM function, other drugs have also been repurposed and tested for their anti-TM activity and potential additional benefits with radiotherapy. Among these, we tested histone deacetylase (HDAC) inhibitors regarding their potential to overcome TM mediated connectivity and thereby open vulnerabilities in glioblastoma. To investigate the drugs, we applied our drug testing pipeline in vitro and in vivo. Here, we observed fewer TMs in an in vitro monolayer of glioblastoma monoculture after treatment with a class I HDAC inhibitor as opposed to two other compounds from the HDAC inhibitor group. In a 3D co-culture model with human neuronal organoids, treatment with the most promising class I HDAC inhibitor showed a dose-dependent inhibitory effect on cell proliferation and TMs. We then continued to examine the HDAC inhibitor’s effect in our in vivo two photon microscopy model with radiotherapy as cytotoxic co-treatment. After the implantation and establishment of xenograft glioblastoma under a chronic cranial window in mice, treatment with the HDAC inhibitor was started and a course of radiotherapy was added. After six weeks after treatment start, tumors of the co-treated animals were smaller than in animals that were only irradiated. Further studies will involve the examination of the underlying biological mechanism of the anti-TM effects and continued long-term treatment to further improve overall anti-tumor effectivity.