Abstract The network of cells and blood vessels that act as a filter to protect the brain from harmful substances constitutes the BBB. The ability to get effective treatment into the brain to treat a variety of diseases has taken many approaches to breach this constraint, including invasive strategies, direct injection, administering hyperosmolar solutions or using ultrasound waves and microbubbles (which transiently open the BBB), inhibition of efflux transporters, nanoparticles, and viral vectors. However, the prognosis for patients with diffuse midline gliomas, other high-grade gliomas (HGGs), and most recurrent pediatric brain tumors remains poor since current therapeutic strategies are unable to extend survival by more than a few months in most patients. We have developed approaches that utilize structural chemistry to modify standard chemotherapeutic agents to cross the BBB. These are based on drugs that have been important in treating multiple systemic diseases, including breast cancer and leukemia/lymphoma. We have demonstrated that both molecules (Berubicin and TPi 287) have activity in glioblastoma (GBM), Berubicin is a derivative of Doxorubicin, and TPI 287 is a derivative of paclitaxel, both of which have shown potent activity against WHO Grade 4 GBM. We have now embarked on evaluating these compounds in preclinical models of pediatric diffuse midline gliomas, including H3K27M. This type of tumor is often invasive with limited treatment options, for which a brain penetrant, active chemotherapy might be relevant. We are currently exploring their impact on H3K27M tumors in a program utilizing preclinical in vitro and in vivo models of pediatric diffuse midline gliomas with two different H3K27 mutations as well as the wild-type (unmutated) cells and also combination strategies with ONC201 (dordaviprone) to evaluate additive or synergistic activity. The outcome of these studies could warrant clinical trials in pediatric midline diffuse gliomas and provide treatment options for these patients.
Silberman et al. (Fri,) studied this question.
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