Abstract 5871: Efficacy and selectivity of novel dually targeted kinase inhibitors for therapy of adult and pediatric high-grade glioma
2018
High grade gliomas (HGGs) in adults and children confer very poor prognosis, with median survival rates under two years post diagnosis. Genetic alterations in receptor tyrosine kinases (RTKs) are seen in both adult and pediatric glioblastoma. Amplification of epidermal growth factor receptor (EGFR), as well as mutations in the PI3K/AKT/mTOR pathway, are frequent and can be targeted by kinase inhibitor based strategies. However, clinical trials singly targeting either EGFR or PI3K have had marginal impact on HGG patient outcomes. Given data showing that compensatory kinase activation is responsible for refractory disease, we developed therapeutics that target more than one kinase. Employing a computational modeling approach, we exploited the known binding modes of structurally related ATP binding site inhibitors of EGFR and PI3K to design small molecules that simultaneously and selectively inhibit both kinases. A panel of novel inhibitors has been synthesized, screened for metabolic stability and characterized with respect to kinase inhibition. Six compounds with varying degrees of inhibition for EGFR and PI3K were evaluated in the NCI-60 COMPARE cell line panel, whereupon two molecules, MTX-216 and MTX-241, exhibited strong in vitro activity against a series of human HGG cell lines. We further evaluated cytotoxicity in five human glioblastoma (GBM) lines, some of which bear EGFRvIII, the truncation mutation frequently seen, and in three patient-derived pediatric diffuse intrinsic pontine glioma (DIPG) cells. Treatment with either MTX-216 or MTX-241 resulted in potent growth inhibition relative to targeting of EGFR alone or PI3K alone using gefitinib, lapatinib or alpelisib. Cytotoxic activity against DIPG patient-derived cell lines was observed at lower concentrations compared to adult GBM cell lines, suggesting that dosing could be de-escalated in children, thereby reducing risks of toxicities. Importantly, selectivity of these compounds was demonstrated against malignant cells versus normal human astrocytes. Furthermore, we have identified unique metabolism targeting features of these compounds in GBM and DIPG lines, indicating suppression of both glycolytic pathways and oxidative phosphorylation, which is not seen with clinically relevant EGFR or PI3K inhibitors. Given the documented metabolic dependencies of brain tumor cells on glycolytic pathways, future studies will evaluate whether biomarkers of sensitivity to the dual inhibitors can be identified. Taken together, our findings point toward proof that a single small molecule inhibitor with dual specificity for EGFR and PI3K represents a rational and promising treatment strategy for recurrent adult and pediatric HGG. Despite the knowledge that HGG is associated with deregulated EGFR and PI3K activity, no current treatment exists targeting both of these critical oncogenes with a single molecule approach. Citation Format: Trever R. Carter, Cavan P. Bailey, Yusha Y. Sun, Alexsandra B. Espejo, Christopher E. Whitehead, Judith Leopold, Joya Chandra. Efficacy and selectivity of novel dually targeted kinase inhibitors for therapy of adult and pediatric high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5871.
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