Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors.
Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors.
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DOI：
10.1158/1535-7163.mct-12-0015
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发表时间：
2012-08
影响因子：
5.7
通讯作者：
Lev D
中科院分区：
文献类型：
--
作者：
Ghadimi MP;Lopez G;Torres KE;Belousov R;Young ED;Liu J;Brewer KJ;Hoffman A;Lusby K;Lazar AJ;Pollock RE;Lev D
迫切需要有效的治疗策略来改善恶性周围神经鞘瘤(MPNST)患者的预后。多条证据表明，放松调控的PI3K/mTOR信号在MPNST中发挥了作用，使这个轴成为治疗操作的一个有吸引力的靶点。在以往体外实验观察的基础上，我们旨在评估PI3K/mTOR阻断对MPNST体内生长的影响。在两个人MPNST异种移植模型(STS26T和MPNST724)和一个肺转移实验模型(STS26T)上测试了XL765的抗MPNST作用。XL765是一种正在进行人类癌症临床试验的PI3K/mTOR双重抑制剂。XL765抑制人MPNST在SCID小鼠体内的局部和转移生长。值得注意的是，这种治疗方法未能诱导MPNST细胞凋亡，而是导致了显著的生产性自噬。重要的是，基因和药物上的自噬阻断逆转了对凋亡的抵抗，并导致了显著的PI3K/mTOR抑制诱导的MPNST细胞死亡。在用XL765预处理后，在MPNST异种移植的治疗方案中加入自噬抑制剂氯喹，与单独使用任何一种药物相比，都能产生更好的抗肿瘤效果。总之，这里描述的临床前研究扩展了我们之前的发现，并表明单独抑制PI3K/mTOR以及(最重要的)结合自噬阻断可能构成一种针对携带MPNST的患者的新的有效治疗方法。
There is a critical need for efficacious therapeutic strategies to improve the outcome of patients afflicted by malignant peripheral nerve sheath tumors (MPNST). Multiple lines of evidence suggest a role for deregulated PI3K/mTOR signaling in MPNST, making this axis an attractive target for therapeutic manipulation. Based on previous observations obtained from in vitro experimentation, here we aimed to assess the effects of PI3K/mTOR blockade on MPNST growth in vivo. The anti-MPNST impact of XL765, a dual PI3K/mTOR inhibitor currently being evaluated in human cancer clinical trials, was tested in two human MPNST xenograft models (STS26T and MPNST724) and an experimental model of pulmonary metastasis (STS26T). XL765 abrogated human MPNST local and metastatic growth in SCID mice. Notably, this therapeutic approach failed to induce apoptosis in MPNST cells but rather resulted in marked productive autophagy. Importantly, genetic and pharmacologic autophagy blockade reversed apoptotic resistance and resulted in significant PI3K/mTOR inhibition-induced MPNST cell death. The addition of the autophagy inhibitor, chloroquine, to the therapeutic regimen of MPNST xenografts after pre-treatment with XL765 resulted in superior anti-tumor effects as compared to either agent alone. Together, pre-clinical studies described here expand our previous findings and suggest that PI3K/mTOR inhibition alone and (most importantly) in combination with autophagy blockade may comprise a novel and efficacious therapy for patients harboring MPNST.