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Combined targeting of PI3K and MEK effector pathways via CED for DIPG therapy
Raymond Chang1, Umberto Tosi1, Julia Voronina1
1Department of Neurosurgery, Weill Cornell Medicine, New York, New York.
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.
Insights
Combinatorial treatment with PI3K (ZSTK474) and MEK (trametinib) inhibitors shows promise for diffuse intrinsic pontine glioma (DIPG). This combination therapy effectively inhibited DIPG cell growth in vitro and in vivo, prolonging survival in mouse models with no observed neurotoxicity.
Area of Science:
- Oncology
- Neuro-oncology
- Pharmacology
Background:
- Diffuse intrinsic pontine glioma (DIPG) and other midline gliomas have a poor prognosis and limited treatment options.
- The phosphatidylinositol 3-kinase (PI3K) signaling pathway is implicated in tumorigenesis, with compensatory activation of parallel pathways like mitogen-activated protein kinase (MEK) potentially causing resistance to PI3K inhibitors.
Purpose of the Study:
- To investigate the efficacy of combining PI3K (ZSTK474) and MEK (trametinib) inhibitors for treating diffuse intrinsic pontine glioma (DIPG).
- To evaluate the synergistic effects and therapeutic potential of this combination therapy in preclinical DIPG models.
Main Methods:
- Patient-derived and mouse-derived DIPG cell lines were treated with ZSTK474 and trametinib, alone and in combination.
- Synergy was assessed using the Chou-Talalay combination index (CI).
- Therapeutic efficacy was evaluated in subcutaneous and intracranial mouse models of DIPG using systemic administration or convection-enhanced delivery (CED).
Main Results:
- Combination treatment with ZSTK474 and trametinib demonstrated synergistic inhibition of DIPG cell proliferation in vitro (CI < 1).
- Significant tumor suppression was observed in both subcutaneous and intracranial DIPG mouse models with combination therapy.
- Intracranial combination therapy via CED significantly prolonged median survival (47 vs. 35 days, P = .038) without causing significant neurotoxicity.
Conclusions:
- Combined ZSTK474 and trametinib treatment effectively inhibits DIPG cell growth in vitro and in vivo, leading to prolonged survival.
- This combinatorial approach, particularly using convection-enhanced delivery (CED), represents a promising therapeutic strategy for DIPG that warrants further clinical investigation.
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