Combined targeting of PI3K and MEK effector pathways via CED for DIPG therapy. Issue 1 (28th May 2019)

• Record Type: Journal Article
• Authors: Chang, Raymond; Tosi, Umberto; Voronina, Julia; Adeuyan, Oluwaseyi; Wu, Linda Y; Schweitzer, Melanie E; Pisapia, David J; Becher, Oren J; Souweidane, Mark M; Maachani, Uday B
• Is Part Of: Neuro-oncology advances. Volume 1:Issue 1(2019)
• Publication Date: 2019-05-28
• Subjects: combinatorial therapy -- convection-enhanced delivery -- MEK -- midline glioma -- PI3K; 616.99481
• DOI: 10.1093/noajnl/vdz004
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: Background: Midline 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. Methods: 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 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). Results: We 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. Conclusions: Our 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.