Gills Joell J, Dennis Phillip A
Medical Oncology Branch, National Cancer Institute, NNMC Building 8, Room 5101, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
Curr Oncol Rep. 2009 Mar;11(2):102-10. doi: 10.1007/s11912-009-0016-4.
The PI3K/Akt/mTOR pathway is aberrantly active in most human cancers and contributes to cell growth, proliferation, and survival. Akt is a nodal regulator of cellular survival pathways and an attractive target in cancer therapy. Many inhibitors of Akt are being developed. Perifosine is an oral Akt inhibitor currently being tested in phase 2 clinical trials. Unlike most kinase inhibitors, which target the adenosine triphosphate-binding region, perifosine targets the pleckstrin homology domain of Akt, thereby preventing its translocation to the plasma membrane. Single-agent activity with perifosine has been observed in sarcoma and Waldenström macroglobulinemia patients. However, the disappointing response rates of common solid tumors to perifosine as a single agent have diminished expectations and prompted further investigation into its mechanism of action. Perifosine exerts Akt-dependent and Akt-independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. In this article, we review the clinical history of perifosine and discuss its many biologic activities.
PI3K/Akt/mTOR信号通路在大多数人类癌症中异常活跃，促进细胞生长、增殖和存活。Akt是细胞存活通路的关键调节因子，也是癌症治疗中一个有吸引力的靶点。许多Akt抑制剂正在研发中。哌立福新是一种口服Akt抑制剂，目前正处于2期临床试验阶段。与大多数靶向三磷酸腺苷结合区域的激酶抑制剂不同，哌立福新靶向Akt的普列克底物蛋白同源结构域，从而阻止其易位至质膜。在肉瘤和华氏巨球蛋白血症患者中观察到了哌立福新的单药活性。然而，常见实体瘤对哌立福新单药治疗的反应率令人失望，降低了人们的期望，并促使对其作用机制进行进一步研究。哌立福新具有Akt依赖性和Akt非依赖性作用，尽管许多临床前研究记录了哌立福新对Akt的抑制作用，但这些发现缺乏临床验证。在本文中，我们回顾了哌立福新的临床历程，并讨论了其多种生物学活性。
