Combined targeting of PI3K and MEK effector pathways via CED for DIPG therapy.

David J Pisapia,Julia Voronina,Linda Y Wu,Mark M Souweidane,Melanie E Schweitzer,Oluwaseyi Adeuyan,Oren J Becher,Raymond Chang,Uday B Maachani,Umberto Tosi

doi:10.1093/noajnl/vdz004

Abstract

BackgroundMidline gliomas like diffuse intrinsic pontine glioma (DIPG) carry poor prognosis and lack effective treatment options. Studies have implicated amplifications in the phosphatidylinositol 3-kinase (PI3K) signaling pathway in tumorigenesis; compensatory activation of parallel pathways (eg, mitogen-activated protein kinase [MEK]) may underlie the resistance to PI3K inhibition observed in the clinic.MethodsThree patient-derived cell lines (SU-DIPG-IV, SU-DIPG-XIII, and SF8628) and a mouse-derived brainstem glioma cell line were treated with PI3K (ZSTK474) and MEK (trametinib) inhibitors, alone or in combination. Synergy was analyzed using Chou-Talalay combination index (CI). These agents were also used alone or in combination in a subcutaneous SU-DIPG-XIII tumor model and in an intracranial genetic mouse model of DIPG, given via convection-enhanced delivery (CED).ResultsWe found that these agents abrogate cell proliferation in a dose-dependent manner. Combination treatments were found to be synergistic (CI < 1) across cell lines tested. They also showed significant tumor suppression when given systemically against a subcutaneous DIPG model (alone or in combination) or when given via direct intracranial injection (CED) in a intracranial DIPG mouse model (combination only, median survival 47 vs 35 days post-induction, P = .038). No significant short- or long-term neurotoxicity of ZSTK474 and trametinib delivered via CED was observed.ConclusionsOur data indicate that ZSTK474 and trametinib combinatorial treatment inhibits malignant growth of DIPG cells in vitro and in vivo, prolonging survival. These results suggest a promising new combinatorial approach using CED for DIPG therapy, which warrants further investigation.

Highlights

Midline gliomas like diffuse intrinsic pontine glioma (DIPG) carry poor prognosis and lack effective treatment options
We show that ZSTK474, a phosphatidylinositol 3-kinase (PI3K) inhibitor, and trametinib, a mitogenactivated protein kinase (MEK) inhibitor, synergistically inhibit DIPG cell proliferation in vitro and in vivo, prolonging survival in a genetically engineered mouse DIPG model following convection-enhanced delivery (CED) administration
There was a difference in relative cell viability only for SU-DIPG-IV when treated with selected PI3K inhibitors, as measured by estimated GI50 values (Figure 1B; Table 1)

Summary

Introduction

Midline gliomas like diffuse intrinsic pontine glioma (DIPG) carry poor prognosis and lack effective treatment options. Three patient-derived cell lines (SU-DIPG-IV, SU-DIPG-XIII, and SF8628) and a mouse-derived brainstem glioma cell line were treated with PI3K (ZSTK474) and MEK (trametinib) inhibitors, alone or in combination. Synergy was analyzed using Chou-Talalay combination index (CI). These agents were used alone or in combination in a subcutaneous SU-DIPG-XIII tumor model and in an intracranial genetic mouse model of DIPG, given via convection-enhanced delivery (CED). Combination treatments were found to be synergistic (CI < 1) across cell lines tested. They showed significant tumor suppression when given systemically against a subcutaneous DIPG model (alone or in combination) or when given via direct intracranial injection (CED) in a intracranial DIPG mouse model (combination only, median survival 47 vs 35 days post-induction, P = .038).

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Results

Conclusion