Title | Combined targeting of PI3K and MEK effector pathways via CED for DIPG therapy. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Chang R, Tosi U, Voronina J, Adeuyan O, Wu LY, Schweitzer ME, Pisapia DJ, Becher OJ, Souweidane MM, Maachani UB |
Journal | Neurooncol Adv |
Volume | 1 |
Issue | 1 |
Pagination | vdz004 |
Date Published | 2019 May-Dec |
ISSN | 2632-2498 |
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. |
DOI | 10.1093/noajnl/vdz004 |
Alternate Journal | Neurooncol Adv |
PubMed ID | 32642647 |
PubMed Central ID | PMC7212917 |