Department of Pediatrics, Duke University, Durham, North Carolina, United States of America ; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, United States of America.
PLoS One. 2013 Oct 2;8(10):e77639. doi: 10.1371/journal.pone.0077639. eCollection 2013.
Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD-0332991 (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.
弥漫性内在脑桥神经胶质瘤（DIPG）是一种无法治愈的肿瘤，发生在儿童的脑干中。迄今为止，没有一种单一的批准药物可以有效地治疗这些肿瘤，因此急需新的治疗方法。最近的研究表明，这些肿瘤中的相当一部分包含细胞周期调节基因的改变，包括 D 型细胞周期蛋白和 CDK4/6 的扩增，以及不太常见的 Ink4a-ARF 的缺失，导致异常的细胞增殖。在这项研究中，我们评估了针对细胞周期蛋白-CDK-视网膜母细胞瘤（Rb）途径的治疗方法，该方法针对的是一种遗传工程 PDGF-B 驱动的脑干神经胶质瘤（BSG）小鼠模型。我们发现，PD-0332991（PD），一种 CDK4/6 抑制剂，在我们的 PDGF-B；Ink4a-ARF 缺陷型模型中，无论是在体外还是体内，都能诱导细胞周期停滞。相比之下，PDGF-B；p53 缺陷型模型对 PD 的治疗大多具有抗性。我们注意到，PD 的 7 天治疗疗程显著延长了 PDGF-B；Ink4a-ARF 缺陷型 BSG 模型的生存时间 12%。此外，与单独接受 RT 相比，单次 10 Gy 放射治疗（RT）后再接受 7 天 PD 治疗可使生存时间延长 19%。这些发现为评估 PD 在具有 Ink4a-ARF 缺陷型神经胶质瘤的儿童中的应用提供了依据。
