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.
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