AKT-independent Pathways of Phosphoinositide 3-kinase dependent transformation

综上所述，在PI3K的p110cc催化亚基中发现功能增益突变或 PTEN脂磷酸酶功能突变的丧失将这一途径作为治疗的靶点 许多人类癌症。任何一种突变的结果都是PIP稳态水平的增加， 其功能是作为第二信使激活下游效应器通路。成功的治疗 靶向这条通路需要全面了解基本的信号事件 在点子的下游。来自我们团队和其他人的大量数据支持Akt的关键下游角色 和mTOR，这导致了PI3K途径驱动的mTOR抑制剂的翻译临床研究 加州大学洛杉矶分校和其他地方的肿瘤。然而，有一些观察结果暗示了其他PIP3- 调节通路，与Akt一起，可能在调节完全转化过程中发挥关键作用 表型。这个项目将解决前列腺癌的这个问题，特别关注定义 JNK蛋白家族在Pisk驱动的转化中的作用及额外的PIP3- 调节雄激素受体功能的依赖的、不依赖Akt的通路。在目标1和目标2中，我们将 通过以下方法评价JNK通路在PI3K通路驱动的前列腺癌进展中的功能作用： JNK激活等位基因在小鼠前列腺中的单独表达及与其他病变的联合表达 例如AKT，以及(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 通过定义依赖于PI3K的信号通路，信号通路与雄激素受体功能之间的串扰 来调节AR的功能。这些实验将补充项目1中定义直接 不同PI3K亚型的转化性质(坎特利/罗伯茨)和项目2(Sellers)中的努力 描述小鼠前列腺中Akt激活与PTEN缺失的不同表型。总而言之， 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。 用于PI3K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.