Preclinical evaluation of the combination of mTOR and proteasome inhibitors with radiotherapy in malignant peripheral nerve sheath tumors.
Preclinical evaluation of the combination of mTOR and proteasome inhibitors with radiotherapy in malignant peripheral nerve sheath tumors.
复制标题
MTOR和蛋白酶体抑制剂与放射疗法在恶性周围神经鞘肿瘤中的组合的临床前评估。
DOI：
10.1007/s11060-014-1422-5
复制
发表时间：
2014-05
影响因子：
3.9
通讯作者：
Riggins, G. J.
中科院分区：
文献类型：
--
作者：
Yamashita, A. S.;Baia, G. S.;Ho, J. S. Y.;Velarde, E.;Wong, J.;Gallia, G. L.;Belzberg, A. J.;Kimura, E. T.;Riggins, G. J.
大约一半的恶性外周神经鞘瘤（MPNST）具有神经纤维蛋白1（NF1）突变。NF 1是一种对RAS信号负调节至关重要的肿瘤抑制基因。MPNST患者的生存率很低，我们试图确定一种有效的联合治疗。从mTOR抑制剂雷帕霉素和依维莫司开始，我们使用在两个等位基因中都具有天然NF 1损失的MPNST细胞在542种FDA批准的化合物中筛选协同作用。进一步分析了细胞周期和信号转导。在MPNST异种移植物中评估了药物与局部放射治疗组合的体内生长作用。mTOR抑制剂与硼替佐米的协同组合产生MPNST细胞增殖的减少。mTOR抑制剂和硼替佐米的组合也增强了体外辐射的抗增殖作用。在体内，mTOR抑制剂（依维莫司）和硼替佐米与放射疗法的组合降低了肿瘤生长和增殖，并增加了细胞凋亡。批准的mTOR和蛋白酶体抑制剂与放射的组合显示出在动物模型中肿瘤生长的显著减少，并且应该进一步研究和优化MPNST治疗。
About one half of malignant peripheral nerve sheath tumors (MPNST) have Neurofibromin 1 (NF1) mutations. NF1 is a tumor suppressor gene essential for negative regulation of RAS signaling. Survival for MPNST patients is poor and we sought to identify an effective combination therapy. Starting with the mTOR inhibitors rapamycin and everolimus, we screened for synergy in 542 FDA approved compounds using MPNST cells with a native NF1 loss in both alleles. We further analyzed the cell cycle and signal transduction. In vivo growth effects of the drug combination with local radiation therapy were assessed in MPNST xenografts. The synergistic combination of mTOR inhibitors with bortezomib yielded a reduction in MPNST cell proliferation. The combination of mTOR inhibitors and bortezomib also enhanced the anti-proliferative effect of radiation in vitro. In vivo, the combination of mTOR inhibitor (everolimus) and bortezomib with radiation therapy decreased tumor growth and proliferation, and augmented apoptosis. The combination of approved mTOR and proteasome inhibitors with radiation showed a significant reduction of tumor growth in an animal model and should be investigated and optimized further for MPNST therapy.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-10-2120
发表时间：
2011-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Sano D;Matsumoto F;Valdecanas DR;Zhao M;Molkentine DP;Takahashi Y;Hanna EY;Papadimitrakopoulou V;Heymach J;Milas L;Myers JN
通讯作者：
Myers JN
影响因子：
11.5
作者：
Murphy, James D.;Spalding, Aaron C.;Hamstra, Daniel A.
通讯作者：
Hamstra, Daniel A.
DOI：
10.3324/haematol.2010.026997
发表时间：
2011-01-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Saunders, Philip;Cisterne, Adam;Bendall, Linda J.
通讯作者：
Bendall, Linda J.
影响因子：
8
作者：
Olaussen, K. A.;Commo, F.;Kroemer, G.
通讯作者：
Kroemer, G.
影响因子：
64.8
作者：
Garnett, Mathew J.;Edelman, Elena J.;Heidorn, Sonja J.;Greenman, Chris D.;Dastur, Anahita;Lau, King Wai;Greninger, Patricia;Thompson, I. Richard;Luo, Xi;Soares, Jorge;Liu, Qingsong;Iorio, Francesco;Surdez, Didier;Chen, Li;Milano, Randy J.;Bignell, Graham R.;Tam, Ah T.;Davies, Helen;Stevenson, Jesse A.;Barthorpe, Syd;Lutz, Stephen R.;Kogera, Fiona;Lawrence, Karl;McLaren-Douglas, Anne;Mitropoulos, Xeni;Mironenko, Tatiana;Thi, Helen;Richardson, Laura;Zhou, Wenjun;Jewitt, Frances;Zhang, Tinghu;O'Brien, Patrick;Boisvert, Jessica L.;Price, Stacey;Hur, Wooyoung;Yang, Wanjuan;Deng, Xianming;Butler, Adam;Choi, Hwan Geun;Chang, JaeWon;Baselga, Jose;Stamenkovic, Ivan;Engelman, Jeffrey A.;Sharma, Sreenath V.;Delattre, Olivier;Saez-Rodriguez, Julio;Gray, Nathanael S.;Settleman, Jeffrey;Futreal, P. Andrew;Haber, Daniel A.;Stratton, Michael R.;Ramaswamy, Sridhar;McDermott, Ultan;Benes, Cyril H.
通讯作者：
Benes, Cyril H.