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

TitleCombined targeting of PI3K and MEK effector pathways via CED for DIPG therapy.
Publication TypeJournal Article
Year of Publication2019
AuthorsChang R, Tosi U, Voronina J, Adeuyan O, Wu LY, Schweitzer ME, Pisapia DJ, Becher OJ, Souweidane MM, Maachani UB
JournalNeurooncol Adv
Volume1
Issue1
Paginationvdz004
Date Published2019 May-Dec
ISSN2632-2498
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, = .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.

DOI10.1093/noajnl/vdz004
Alternate JournalNeurooncol Adv
PubMed ID32642647
PubMed Central IDPMC7212917