In recent years numerous targeted therapies have been identified for therapeutic application in the treatment[unreadable] of cancer. While Chronic Lymphocytic Leukemia (CLL) is an obviously important clinical challenge, it is also[unreadable] is a disease well-suited for the development of novel agents, as readily available tumor cells facilitate[unreadable] validation of specific mechanisms of action in vivo. However, lacking from CLL therapeutic development[unreadable] have been CLL-specific targets and an appropriate in vivo model to test new therapies before transitioning to[unreadable] clinical investigation. Project 6 investigators in conjunction with others in the CLL Research Consortium[unreadable] (CRC) have actively developed multiple new therapies for CLL, including fludarabine, rituximab, and most[unreadable] recently, flavopiridol, as discussed in the previous application. We have further validated the Tcl-1 transgenic[unreadable] mouse model of CLL generated by Project 1 and advanced it into a tool that can be used for investigating[unreadable] new therapeutic agents for subsequent clinical development in CLL. This work and the interactions that have[unreadable] come forth through the CRC have resulted in 23 peer-reviewed publications. Here, we propose to continue[unreadable] active pre-clinical and translational development of new therapeutic agents in CLL. In Aim 1, we will expand[unreadable] our preliminary work with flavopiridol by performing detailed pharmacokinetic, pharmacodynamic, and[unreadable] pharmacogenomic studies as part of our planned Phase II clinical trial, including assessment of efficacy in[unreadable] patients with high risk genetic features such as del(17p13) and mutated p53. Relevant to the development of[unreadable] any effective agent is achieving an understanding of resistance mechanisms, which we will pursue using[unreadable] both CLL patient cells and the Tcl-1 transgenic mouse model of CLL. In Aim 2, we will continue pre-clinical[unreadable] development of the PDK1/Akt inhibitor OSU-03012, now approved for clinical development in CLL by the[unreadable] NCI RAID program, by a) examining the relationship of apoptosis induced by OSU-03012 to inhibition of[unreadable] PDK1/Akt in primary CLL cells; b) examining alternative signaling pathways inhibited by OSU-03012 and the[unreadable] mechanism(s) by which it induces caspase- and Bcl-2-independent apoptosis in CLL cells; and c) exploring[unreadable] synergy of OSU-03012 with other agents used for CLL treatment. In Aim 3, we will use the Tcl-1 transgenic[unreadable] mouse as a pre-clinical tool for developing CLL therapies by performing in vivo studies with flavopiridol,[unreadable] OSU-03012, and other novel therapies. These experiments will also incorporate limited pharmacokinetics[unreadable] and pharmacodynamics. Additionally, we will use the Tcl-1 mouse model to identify relevant mechanisms of[unreadable] drug resistance in vivo for therapies employed in the treatment of CLL. Each of these projects will be[unreadable] performed in collaboration with Projects 1-5 of the CRC, continuing our extensive interactions with these[unreadable] investigators. Overall, this project seeks to continue the comprehensive drug development effort by physician[unreadable] scientists, pharmacologists, and medicinal chemists at Ohio State University and other CRC institutions.