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
Department of Neurosurgery, Weill Cornell Medicine, New York, New York.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
Neurooncol Adv. 2019 May 28;1(1):vdz004. doi: 10.1093/noajnl/vdz004. eCollection 2019 May-Dec.
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.
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).
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.
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.
中线胶质瘤如弥漫性脑桥内在型胶质瘤（DIPG）预后较差且缺乏有效的治疗方案。研究表明磷脂酰肌醇3激酶（PI3K）信号通路的扩增参与肿瘤发生；平行通路（如丝裂原活化蛋白激酶[MEK]）的代偿性激活可能是临床上观察到的对PI3K抑制产生耐药性的原因。
用PI3K抑制剂（ZSTK474）和MEK抑制剂（曲美替尼）单独或联合处理三种患者来源的细胞系（SU-DIPG-IV、SU-DIPG-XIII和SF8628）以及一种小鼠来源的脑干胶质瘤细胞系。使用Chou-Talalay联合指数（CI）分析协同作用。这些药物还单独或联合用于皮下SU-DIPG-XIII肿瘤模型和DIPG的颅内基因小鼠模型，通过对流增强递送（CED）给药。
我们发现这些药物以剂量依赖性方式消除细胞增殖。在所测试的细胞系中，联合治疗具有协同作用（CI<1）。当全身给药用于皮下DIPG模型（单独或联合）或通过颅内直接注射（CED）用于颅内DIPG小鼠模型（仅联合用药，诱导后中位生存期47天对35天，P = 0.038）时，它们也显示出显著的肿瘤抑制作用。未观察到通过CED递送的ZSTK474和曲美替尼有明显的短期或长期神经毒性。
我们的数据表明，ZSTK474和曲美替尼联合治疗在体外和体内均能抑制DIPG细胞的恶性生长，延长生存期。这些结果提示一种使用CED进行DIPG治疗的有前景的新联合方法，值得进一步研究。
