The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges.
The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges.
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DOI：
10.5732/cjc.014.10289
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发表时间：
2015-01
影响因子：
--
通讯作者：
Leary A
中科院分区：
文献类型：
--
作者：
Cheaib B;Auguste A;Leary A
磷脂酰肌醇3激酶（PI3K）通路在包括卵巢癌（OC）在内的癌症中经常发生改变。不幸的是，尽管在临床前模型中有良好的生物学原理和令人鼓舞的活性，第一代哺乳动物雷帕霉素靶点（mTOR）抑制剂在OC中的试验显示出负面结果。缺乏患者选择以及对选择性mTOR复合物-1 （mTORC1）抑制剂的耐药性可以解释迄今为止令人失望的结果。尽管如此，一些新型药物正在研究中，包括双重mTORC1/mTORC2、Akt和PI3K抑制剂。虽然抑制PI3K/Akt/mTOR通路可能对未选择的OC患者影响不大，但某些组织学类型，如透明细胞或子宫内膜样OC，频繁出现磷脂酰肌醇-4,5-二磷酸3激酶、催化亚基α (PIK3CA)和/或磷酸酶和紧张素同源物（PTEN）改变，可能特别适合这种方法。考虑到PI3K信号网络的复杂性和冗余性，在适当选择的OC患者中，PI3K途径抑制可能与化疗或其他靶向治疗（如MEK抑制剂、抗血管生成治疗和激素治疗）联合使用最有用。在这里，我们讨论了PI3K通路在OC中的相关性，并提供了新的PI3K抑制剂单独或与细胞毒素和新疗法联合治疗OC的临床试验的最新综述。此外，还讨论了耐药性和预测性生物标志物的挑战。
The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.
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影响因子：
4.7
作者：
Fu S;Hennessy BT;Ng CS;Ju Z;Coombes KR;Wolf JK;Sood AK;Levenback CF;Coleman RL;Kavanagh JJ;Gershenson DM;Markman M;Dice K;Howard A;Li J;Li Y;Stemke-Hale K;Dyer M;Atkinson E;Jackson E;Kundra V;Kurzrock R;Bast RC Jr;Mills GB
通讯作者：
Mills GB
影响因子：
5.7
作者：
Breuleux M;Klopfenstein M;Stephan C;Doughty CA;Barys L;Maira SM;Kwiatkowski D;Lane HA
通讯作者：
Lane HA
影响因子：
11.2
作者：
Buck, Elizabeth;Eyzaguirre, Alexandra;Ji, Qun-Sheng
通讯作者：
Ji, Qun-Sheng
影响因子：
45.3
作者：
Burger, Robert A.;Sill, Michael W.;Sorosky, Joel I.
通讯作者：
Sorosky, Joel I.
影响因子：
8.8
作者：
Campone, M.;Levy, V.;Bourbouloux, E.;Rigaud, D. Berton;Bootle, D.;Dutreix, C.;Zoellner, U.;Shand, N.;Calvo, F.;Raymond, E.
通讯作者：
Raymond, E.