Abstract
BACKGROUND
Pediatric-type diffuse high-grade gliomas (pHGGs) are a diverse group of central nervous system tumors in children and adolescents with typically fatal outcomes. Addressing this disease requires new treatment approaches to enhance both survival and quality of life for affected patients. Recently, targeting oncogenic receptor tyrosine kinases (RTKs) has provided promising initial responses in different pHGG subtypes. However, even in these cases, the disease invariably relapses.
METHODS
We utilized murine tumor cell cultures carrying oncogenic alterations in different RTKs, such as an NTRK fusion, an ALK fusion and activating FGFR1 mutations to evaluate the synergy of radiotherapy and a variety of specific small molecule inhibitors using viability and apoptosis assays. By conducting pharmacokinetic analyses in murine models, we quantified the availability of selected compounds in the mouse brain in vivo, informing downstream preclinical experiments.
RESULTS
We found that concomitant radiation potentiated the antitumor effect of all tested targeted compounds, mostly outperforming calculated additivity of single treatments. Of note, the level of potentiation was comparable between different inhibitors targeting the same RTK, but was highly dependent on the underlying tumor genotype. Using erdafitinib or futibatinib and a dose of 2 Gy in a FGFR1-driven pHGG model, the combined treatment resulted in a remarkably high late apoptosis rate of 90%, warranting ongoing in vivo studies. Through pharmacokinetic analyses, we identified that among all tested small-molecule-inhibitors, only lorlatinib and futibatinib reach clinically relevant concentrations in the murine brain.
CONCLUSIONS
Our preliminary data showed that the combination of targeted therapy and radiation elicits encouraging anti-tumor effects in different pHGG cultures. We are currently performing preclinical in vivo studies using immunocompetent orthotopic mouse models to evaluate benefits of combined treatment. Our data will inform future clinical trials and hopefully improve the prognosis and quality of life for a fraction of pediatric patients diagnosed with pHGG.