In recent years numerous targeted therapies have been identified for therapeutic application in the treatmentof cancer. While Chronic Lymphocytic Leukemia (CLL) is an obviously important clinical challenge, it is alsois a disease well-suited for the development of novel agents, as readily available tumor cells facilitatevalidation of specific mechanisms of action in vivo. However, lacking from CLL therapeutic developmenthave been CLL-specific targets and an appropriate in vivo model to test new therapies before transitioning toclinical investigation. Project 6 investigators in conjunction with others in the CLL Research Consortium(CRC) have actively developed multiple new therapies for CLL, including fludarabine, rituximab, and mostrecently, flavopiridol, as discussed in the previous application. We have further validated the Tcl-1 transgenicmouse model of CLL generated by Project 1 and advanced it into a tool that can be used for investigatingnew therapeutic agents for subsequent clinical development in CLL. This work and the interactions that havecome forth through the CRC have resulted in 23 peer-reviewed publications. Here, we propose to continueactive pre-clinical and translational development of new therapeutic agents in CLL.
In Aim 1, we will expandour preliminary work with flavopiridol by performing detailed pharmacokinetic, pharmacodynamic, andpharmacogenomic studies as part of our planned Phase II clinical trial, including assessment of efficacy inpatients with high risk genetic features such as del(17p13) and mutated p53. Relevant to the development ofany effective agent is achieving an understanding of resistance mechanisms, which we will pursue usingboth CLL patient cells and the Tcl-1 transgenic mouse model of CLL.
In Aim 2, we will continue pre-clinicaldevelopment of the PDK1/Akt inhibitor OSU-03012, now approved for clinical development in CLL by theNCI RAID program, by a) examining the relationship of apoptosis induced by OSU-03012 to inhibition ofPDK1/Akt in primary CLL cells; b) examining alternative signaling pathways inhibited by OSU-03012 and themechanism(s) by which it induces caspase- and Bcl-2-independent apoptosis in CLL cells; and c) exploringsynergy of OSU-03012 with other agents used for CLL treatment.
In Aim 3, we will use the Tcl-1 transgenicmouse as a pre-clinical tool for developing CLL therapies by performing in vivo studies with flavopiridol,OSU-03012, and other novel therapies. These experiments will also incorporate limited pharmacokineticsand pharmacodynamics. Additionally, we will use the Tcl-1 mouse model to identify relevant mechanisms ofdrug resistance in vivo for therapies employed in the treatment of CLL. Each of these projects will beperformed in collaboration with Projects 1-5 of the CRC, continuing our extensive interactions with theseinvestigators. Overall, this project seeks to continue the comprehensive drug development effort by physicianscientists, pharmacologists, and medicinal chemists at Ohio State University and other CRC institutions.
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