Targeting the PI3K Pathway in Ovarian Cancer

磷脂酰肌醇3-激酶（PI 3 K）途径在许多关键的生物过程中起核心作用， 包括细胞增殖、细胞周期进程、存活力、运动性、侵袭、新血管形成，以及 转移PI 3 K信号级联的多个组分在卵巢癌的DMA中是异常的， RNA和蛋白质水平。PI 3 K通路中的这些异常导致PI 3 K通路的激活， 大多数卵巢癌可能有助于患者的结果。我们已经证明， PI 3 K抑制剂LY 294002显著降低细胞增殖、新血管形成因子的产生， 运动和体外卵巢癌细胞的侵袭以及生长，产生新血管形成因子， 体内异种移植物中的新血管形成。此外，PI 3 K或AKT的过表达使卵巢癌 对紫杉醇（一种用于治疗卵巢癌的主要药物）具有抗性的细胞。抑制 PI 3 K在体外和体内均能使卵巢癌细胞对紫杉醇敏感。然而，LY 294002并不是一种 良好的药效团，不会在临床上向前推进。我们以前的研究表明，催化剂 PI 3 K下游的AKT的抑制剂具有非常窄的治疗指数。最近， 我们已经证明了两种新型的PI 3 K通路抑制剂哌立福新，它阻断了PI 3 K的PH结构域， AKT和SF 1126，SF 1126是PI 3 K抑制剂LY 294002抑制剂的优化前药 增殖、新生血管形成因子的产生、运动性和侵袭，并使细胞对紫杉醇敏感， 体外哌立福新在原位移植模型中显著降低卵巢癌细胞的生长。 根据我们的新数据，我们将追求以下具体目标： 目的1：确定用SF 1126靶向PI 3 K和用哌立福新靶向AKT的PH结构域的功效，以确定在治疗中的作用。 卵巢癌异种移植物。 目的2：开发和验证用于确定生物学相关有效剂量和生物学标记物的方法。 可以转化为临床试验的早期治疗反应。 目的3：研究ILK和PDK 1在卵巢癌细胞中的作用。 目的4：评估靶向药物的分子药效学临床试验中的生物学和临床活性。 pi 3 k途径

The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in many critical biological processes, including cellular proliferation, cell cycle progression, viability, motility, invasion, neovascularization, and metastasis. Multiple components of the PI3K signaling cascade are aberrant in ovarian cancer at the DMA, RNA, and protein levels. These abnormalities in the PI3K pathway result in activation of the PI3K pathway in most ovarian cancers likely contributing to patient outcome. We have demonstrated that treatment with the PI3K inhibitor LY294002 markedly decreases cell proliferation, production of neovascularizing factors, motility, and invasion of ovarian cancer cells in vitro and growth, production of neovascularizing factors and neovascularization in xenografts in vivo. Further, overexpression of PI3K or AKT renders ovarian cancer cells resistant to the effects of paclitaxel, a major drug used in the management of ovarian cancer. Inhibition of PI3K sensitizes ovarian cancer cells to paclitaxel both in vitro and in vivo. LY294002 is, however, not a good pharmacophore and will not move forward clinically. Our previous studies suggest that catalytic inhibitors of AKT, which is downstream from PI3K, have a prohibitively narrow therapeutic index. Recently, we have demonstrated that two novel PI3K pathway inhibitors¿perifosine, which blocks the PH domain of AKT, and SF1126, which is a pharmacologically optimized prodrug for the PI3K inhibitor LY294002¿inhibit proliferation, production of neovascularizing factors, motility, and invasion and sensitize cells to paclitaxel in vitro. Perifosine markedly decreases growth of ovarian cancer cells in an orthotopic transplantation model. Based on our new data, we will pursue the following Specific Aims: Aim 1: To determine the efficacy of targeting PI3K with SF1126 and the PH domain of AKT with perifosine in ovarian cancer xenografts. Aim 2: To develop and validate methods to determine biologically relevant effective dose and markers of early therapeutic response that can be translated to clinical trials. Aim 3: To determine the efficacy of targeting ILK and PDK1 in ovarian cancer cells. Aim 4: To assess biologic and clinical activity in molecular pharmacodynamic clinical trials targeting the PI3K pathway