PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma.
PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma.
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DOI：
10.1371/journal.pone.0077639
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Becher OJ
中科院分区：
文献类型：
--
作者：
Barton KL;Misuraca K;Cordero F;Dobrikova E;Min HD;Gromeier M;Kirsch DG;Becher OJ
弥漫性固有桥脑胶质瘤(DIPG)是一种发生在儿童脑干的无法治愈的肿瘤。到目前为止，还没有一种被批准的药物可以有效地治疗这些肿瘤，因此迫切需要新的治疗方法。最近的研究表明，这些肿瘤中有很大一部分包含细胞周期调控基因的变化，包括D型细胞周期蛋白和CDK4/6的扩增，少数情况下，Ink4a-ARF的缺失会导致细胞异常增殖。在这项研究中，我们评估了在基因工程PDGF-B驱动的脑干胶质瘤(BSG)小鼠模型中靶向细胞周期蛋白-CDK-视网膜母细胞瘤(RB)通路的治疗方法。我们发现，PD-0332991(PD)，一种CDK4/6抑制剂，在体外和体内都能诱导我们的PDGFR-B；INK4A-ARF缺陷模型的细胞周期停滞。相比之下，PDGF-B；P53缺陷模型对PD治疗大多耐药。我们注意到，在PDGF-B；Ink4a-ARF缺乏的BSG模型中，7天的PD疗程显著延长了12%的存活率。此外，在PD治疗7天后进行单次10Gy射线治疗(RT)，与单独进行RT相比，存活率提高了19%。这些发现为评估Ink4a-ARF缺陷的儿童胶质瘤的PD提供了理论基础。
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.
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DOI：
10.1016/j.bbrc.2011.08.047
发表时间：
2011-09-16
影响因子：
3.1
作者：
Katsumi, Yoshiki;Iehara, Tomoko;Miyachi, Mitsuru;Yagyu, Shigeki;Tsubai-Shimizu, Satoko;Kikuchi, Ken;Tamura, Shinichi;Kuwahara, Yasumichi;Tsuchiya, Kunihiko;Kuroda, Hiroshi;Sugimoto, Tohru;Houghton, Peter J.;Hosoi, Hajime
通讯作者：
Hosoi, Hajime
在遗传学和组织学精确的脑干神经胶质瘤模型中，辐射和perifosine的临床前评估。
影响因子：
11.2
作者：
Becher OJ;Hambardzumyan D;Walker TR;Helmy K;Nazarian J;Albrecht S;Hiner RL;Gall S;Huse JT;Jabado N;MacDonald TJ;Holland EC
通讯作者：
Holland EC
影响因子：
50.3
作者：
Anders L;Ke N;Hydbring P;Choi YJ;Widlund HR;Chick JM;Zhai H;Vidal M;Gygi SP;Braun P;Sicinski P
通讯作者：
Sicinski P
影响因子：
45.3
作者：
Paugh, Barbara S.;Broniscer, Alberto;Baker, Suzanne J.
通讯作者：
Baker, Suzanne J.
影响因子：
11.5
作者：
Flaherty, Keith T.;LoRusso, Patricia M.;Schwartz, Gary K.
通讯作者：
Schwartz, Gary K.