Targeting PI3K in personalized treatment of BRAF-mutated pediatric low-grade gliomas
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Targeting PI3K in personalized treatment of BRAF-mutated pediatric low-grade gliomas

Abstract

Abstract Introduction: Pediatric low-grade gliomas (PLGG) constitute the most common group of central nervous system tumors in children. Although they exhibit rare malignant transformation and relatively slow growth, PLGGs pose great morbidity. Viewed as a chronic disease, ideal therapy for PLGG should carry limited side effects that can be best achieved through selective, personalized therapy. Despite the known heterogeneity of PLGGs and characterized driver mutations that together offer the perfect, timely platform for personalized approaches to therapy, most children are still treated with standard chemotherapy protocols in a “one treatment fits all” approach. Recent genomic studies have defined recurrent, diverse alterations driving WHO grade 1 and 2 PLGGs. Activation of mitogen protein kinase (MAPK) and phosphatidylinositol-3′ kinase (PI3K) in PLGGs suggests the potential efficacy of agents that target these key growth regulatory pathways. BRAF, a kinase within the MAPK pathway, is activated by missense mutation (V600E) in ∼20% of grade 2-4 pediatric gliomas or KIAA1549-BRAF fusion in ∼60% of pilocytic astrocytomas. In addition to RAS/MEK/MAPK/ERK, the PI3K/AKT/mTOR signaling cascade is activated in ∼half of PLGGs. We hypothesize that knowledge of individual tumor BRAF genotype can guide selection of PI3K/MAPK inhibitors as single agents and in combinations, to maximize efficacy of therapy and overcome innate and acquired resistance to targeted agents. Methods: We used human glioma cell lines containing BRAFV600E (AM38, DBT-RG, BT40), or wild-type BRAF (BRAFWT; SF188, SF9427, SF9402) and isogenic systems of KIAA1549:BRAF-expressing NIH3T3 cells and BRAFV600E-expressing murine brain tumors. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK). Cell cycle distribution and apoptosis were assessed using flow cytometry; proliferation was determined using an ATP-based assay (CellTiter-Glo). In vivo activity of these inhibitors was assessed in the BT40 PLGG xenograft mouse model. Results: In BRAFV600E cells, combination of PLX4720+everolimus and PLX4720+AZD6244 exhibited significantly greater effects on cell viability, apoptosis, and cell cycle than respective single agents. In BRAFWT cells, everolimus+AZD6244 was superior compared to respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF fusion cells, MEK inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the PLGG xenograft model BT40 showed the greatest survival advantage in mice treated with combination of AZD6244+PLX4720 or AZD6244+everolimus compared with respective monotherapies (p<0.01). Conclusions: For BRAFV600E tumors, combination of everolimus+MEK or PLX4720+MEK inhibitors is equally efficacious and superior to single agents, and the choice between these two might be dictated by clinical tolerability. For BRAFWT PLGGs, combination of everolimus+MEK inhibitor is superior to single agent therapies. Optimal treatment of KIAA1549:BRAF-expressing PLGGs is still under investigation as single agent MEK inhibition is extremely efficacious but mTOR inhibition may contribute to greater overall anti-neoplastic effects. Citation Format: Aleksandra K. Olow, Sabine Mueller, Xiaodong Yang, Rintaro Hashizume, William Weiss, Adam C. Resnick, Angela J. Sievert, Mitchel S. Berger, Nalin Gupta, David C. James, Daphne A. Haas-Kogan. Targeting PI3K in personalized treatment of BRAF-mutated pediatric low-grade gliomas. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B42.

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