2016年6月22日讯/生物谷BIOON/--Bellvige生物医学调查研究所(IDIBELL)的研究人员Mariona Graupera博士称：PI3蛋白激酶(PI3K)抑制剂对胰腺神经内分泌肿瘤(PanNETs)具有潜在的治疗希望。这项研究发表在《Clinical Cancer Research》杂志上，该研究为人们提供了PI3K作用于癌症的重要信息并开启了治疗胰腺神经内分泌肿瘤和其它类型癌症的新方法。
胰腺神经内分泌肿瘤通常被称为“胰岛细胞肿瘤”，是一种起源于胰腺的激素释放细胞的癌症，这种类型的癌症占了大约2%的胰腺癌病例。在过去的二十年里，几乎没有治疗这种癌症类型的有效方法，PanNETs的异质性需有较复杂的靶向治疗设计法。
众所周知，PI3K蛋白信号通路的突变发生在16%的PanNETs患者中；在目前的研究中，研究人员评估了40个人类肿瘤样本和患有PanNETs的小鼠模型中PI3K蛋白信号通路激活的频率，并研究了使用通用PI3K和同类的特殊抑制剂抑制小鼠模型中这种通路的治疗效果。
Graupera博士的研究小组发现，不管是通用PI3K还是称为p110α的特定PI3K同种类型的药物抑制剂都足以诱导肿瘤细胞死亡和阻碍血管生长，这可以阻止肿瘤的发展和转移。然而同种类型选择性抑制剂比通用抑制剂有更低的毒性，因此实现完全的通路抑制需要较高的p110α药物剂量，这样是可以接受的。
这些结果显示治疗这种恶性肿瘤的一种新型靶向疗法：PI3K抑制剂已经用于临床实践中。通过PI3K激酶在促进转移中的作用阐明了在肿瘤生物学中PI3K激酶的一种新功能。
Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors
Adriana Soler, Ana M Figueiredo, Pau Castel, Laura Martin, Erika Monelli, Ana Angulo-Urarte, Maria Mila-Guasch, Francesc Viñals, José Baselga, Oriol Casanovas, Mariona Graupera
Purpose: Mutations in the PI3-kinase (PI3K) pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacological intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown Experimental Design: In the present study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110αa selective (GDC-0326) inhibitors and isoform specific PI3K kinase-dead mutant mice Results: Human and mouse PanNETs showed enhanced pAKT, pPRAS40 and pS6 positivity compared to normal tissue. While treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110αa PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node (LN) metastasis compared to vehicle treated mice. We also demonstrated that tumor and stromal cells are implicated in the anti-tumor activity of GDC-0326 in RIP1-Tag2 tumors Conclusions: Our data provide a rationale for p110αa selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis.