Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
Zachary Miklja, Viveka Nand Yadav, Rodrigo T. Cartaxo, Ruby Siada, Chase C. Thomas, Jessica R. Cummings, Brendan Mullan, Stefanie Stallard, Alyssa Paul, Amy K. Bruzek, Kyle Wierzbicki, Tao Yang, Taylor Garcia, Ian Wolfe, Marcia Leonard, Patricia L. Robertson, Hugh J.L. Garton, Daniel R. Wahl, Hemant Parmar, Jann N. Sarkaria, Cassie Kline, Sabine Mueller, Theodore Nicolaides, Chana Glasser, Sarah E.S. Leary, Sriram Venneti, Chandan Kumar-Sinha, Arul M. Chinnaiyan, Rajen Mody, Manjunath P. Pai, Timothy N. Phoenix, Bernard L. Marini, Carl Koschmann
Zachary Miklja, Viveka Nand Yadav, Rodrigo T. Cartaxo, Ruby Siada, Chase C. Thomas, Jessica R. Cummings, Brendan Mullan, Stefanie Stallard, Alyssa Paul, Amy K. Bruzek, Kyle Wierzbicki, Tao Yang, Taylor Garcia, Ian Wolfe, Marcia Leonard, Patricia L. Robertson, Hugh J.L. Garton, Daniel R. Wahl, Hemant Parmar, Jann N. Sarkaria, Cassie Kline, Sabine Mueller, Theodore Nicolaides, Chana Glasser, Sarah E.S. Leary, Sriram Venneti, Chandan Kumar-Sinha, Arul M. Chinnaiyan, Rajen Mody, Manjunath P. Pai, Timothy N. Phoenix, Bernard L. Marini, Carl Koschmann
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Research Article Oncology

Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma

Abstract

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor–bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

Authors

Zachary Miklja, Viveka Nand Yadav, Rodrigo T. Cartaxo, Ruby Siada, Chase C. Thomas, Jessica R. Cummings, Brendan Mullan, Stefanie Stallard, Alyssa Paul, Amy K. Bruzek, Kyle Wierzbicki, Tao Yang, Taylor Garcia, Ian Wolfe, Marcia Leonard, Patricia L. Robertson, Hugh J.L. Garton, Daniel R. Wahl, Hemant Parmar, Jann N. Sarkaria, Cassie Kline, Sabine Mueller, Theodore Nicolaides, Chana Glasser, Sarah E.S. Leary, Sriram Venneti, Chandan Kumar-Sinha, Arul M. Chinnaiyan, Rajen Mody, Manjunath P. Pai, Timothy N. Phoenix, Bernard L. Marini, Carl Koschmann

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Figure 3

Sustained exposure of everolimus improves dasatinib tumor concentration and efficacy in a mouse model.

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Sustained exposure of everolimus improves dasatinib tumor concentration ...
(A) PK data documenting an increase in dasatinib levels detected in tumors with an additional 24-hour everolimus pre-dasatinib dose of either 5 mg/kg or 10 mg/kg (*P ≤ 0.05, by Dunnett’s multiple comparisons test). n = 5 replicates. (B) Survival curve data for mice with PDGFRA-amplified HGG via IUE shows that the median survival for the control condition was 52 days after IUE injection (n = 10), 55 days for the everolimus condition (5 mg/kg, n = 9), 61 days for the dasatinib condition (10 mg/kg, n = 9), and 86 days for the dasatinib plus everolimus condition (10 mg/kg and 5 mg/kg, respectively, n = 9) (NS P = 0.3378, ***P ≤ 0.0005, and ****P ≤ 0.0001, by log-rank test). (C) Representative bioluminescence images of PPK mouse tumors (vehicle, n = 10; dasatinib, n = 9; everolimus, n = 9; dasatinib + everolimus, n = 10) 47 days after IUE injection, displaying lower average luminescence in the cotreatment group than in the 2 groups receiving monotherapy of dasatinib or everolimus. (D) IUE PPK bioluminescence tumor monitor growth data with statistical significance between dasatinib plus everolimus and DMSO treatment groups 47 days after IUE injection (****P ≤ 0.0001, by Tukey’s multiple comparisons test.). (E) In vivo IHC images of p-Src and p-S6 expression levels, documenting a reduction with everolimus and dasatinib treatment in comparison with nontreated tumors. Images are representative of 3 biological replicates. Original magnification, ×20. (F) IHC quantification data for treated PPK mice show statistical significance of p-Src and p-S6 expression levels between tumors treated with dasatinib and everolimus and nontreated tumors (**P = 0.0065 and ****P ≤ 0.0001, by Dunnett’s multiple comparisons test). n = 3 animals per treatment group and 4 images per animal. Data represent the mean ± SEM (A, D, and F).