AKT-independent Pathways of Phosphoinositide 3-kinase dependent transformation

总之，在PI 3 K的p110 cc催化亚基中发现功能获得性突变， PTEN脂质磷酸酶的功能缺失突变“证明”这一途径作为治疗靶点， 许多人类癌症。任何一种突变的结果都是PIPS稳态水平的增加， 其作为第二信使激活下游效应物途径。成功的治疗 靶向这一途径需要全面了解基本的信号事件 PIPS的下游。来自我们小组和其他人的许多数据支持Akt的关键下游作用 和mTOR，这导致了mTOR抑制剂在PI 3 K通路驱动的 在加州大学洛杉矶分校和其他地方。然而，有一些观察结果表明，其他PIP 3- 调节途径，与Akt结合，在介导完全转化中发挥关键作用， 表型。这个项目将解决这个问题，在前列腺癌，特别侧重于定义 MAP激酶JNK家族在PISK驱动的转化中的作用，并阐明了额外的PIP 3- 调节雄激素受体功能的依赖性、Akt非依赖性途径。在目标1和2中，我们将 评估JNK通路在PI 3 K通路驱动的前列腺癌进展中的功能作用，通过：（i） 在小鼠前列腺中表达JNK的活化等位基因，单独和与另外的损伤组合 如AKT，和（ii）靶向JNK途径（使用小分子抑制剂和RNA干扰）， 前列腺癌的条件性PTEN小鼠。目标3将建立在我们和其他人的观察基础上， 激酶途径和雄激素受体功能之间的串扰，通过定义PI 3 K依赖性途径 调节AR功能。这些实验将补充项目1中的工作，以确定直接 不同PI 3 K亚型的转化特性（Cantley/Roberts）和项目2（Sellers）中的努力， 表征小鼠前列腺中Akt活化与PTEN缺失的不同表型。总的来说， 这些研究将为未来临床试验的设计提供信息，着眼于合理的联合治疗。 PI 3 K通路驱动的前列腺癌。

Taken together, the discovery of either gain-of-function mutations in the p110cc catalytic subunit of PI3K or loss of function mutations in the PTEN lipid phosphatase 'credential' this pathway as a therapeutic target in many human cancers. The consequence of either mutation is an increase in the steady state level of PIPS, which functions as a second messenger to activate downstream effector pathways. Successful therapeutic targeting of this pathway requires a comprehensive understanding of the essential signaling events downstream of PIPS. Much data from our group and others supports the critical downstream roles of Akt and mTOR, which has resulted in translational clinical studies of mTOR inhibitors in PI3K pathway-driven tumors at UCLA and elsewhere. However, there are a number of observations that implicate other PIP3- regulated pathways, in conjunction with Akt, that could play critical roles in mediating the full transformation phenotype. This project will address this question in prostate cancer, with a particular focus on defining the role of the JNK family of MAP kinases in PISK-driven transformation and elucidating additional PIP3- dependent, Akt-independent pathways that regulate androgen receptor function. In Aims 1 and 2, we will evaluate the functional role of the JNK pathway in PI3K pathway-driven prostate cancer progression by: (i) expressing activated alleles of JNK in the mouse prostate, alone and in combination with additional lesions such as AKT, and (ii)targeting the JNK pathway (using small molecule inhibitors and RNA interference) in conditional PTEN mice with prostate cancer. Aim 3 will build upon observations by us and others showing crosstalk between kinase pathways and androgen receptor function, by defining PI3K-dependent pathways that regulate the AR function. These experiments will complement the efforts in Project 1 to define the direct transforming properties of distinct PI3K isoforms (Cantley/Roberts) and the efforts in Project 2 (Sellers) to characterize the distinct phenotypes of Akt activation versus PTEN loss in the mouse prostate. Collectively, these studies will inform the design of future clinical trials, with an eye toward rational combination therapy for PI3K pathway-driven prostate cancer.