Our long-range goal is to improve the therapy of Myeloma. The central hypothesis for the proposed research is that inhibition of specific gene targets will modulate the sensitivity of Myeloma cells to bortezomib and other proteasome inhibitors. Our objective in this proposal is to apply advanced functional genomic strategies to identify and rapidly validate the critical role of candidate genes in drug performance and advance this information clinically.
Specific Aim 1 will address the influence of recently-identified promiscuous mutations of NFKappaB in Myeloma and their relationship to proteasome inhibitor sensitivity.
Aim 2 will utilize an innovative high-throughput siRNA screen to identify critical genes or pathways which sensitize or protect Myeloma cells from bortezomib- or PR-171-induced cell death. A library of 10,000 siRNA targeting the druggable genome will be applied.
Specific Aim 3 is structured to enable rapid validation of the hypothesis that the candidate genes prioritized in Specific Aim 2 are functionally relevant as sensitizing targets in Myeloma cells.
In Specific Aim 4, we will use tissues and genetic data from clinical trials and clinical databases to rapidly validate the clinical importance of prioritized candidates, and previously-described targets of bortezomib. The ultimate goal of our entire study will be to generate new sensitizer drugs to be used in combination therapy to increase the clinical success rate of bortezomib or other PI therapy.
|Tiedemann, Rodger E; Zhu, Yuan Xao; Schmidt, Jessica et al. (2012) Identification of molecular vulnerabilities in human multiple myeloma cells by RNA interference lethality screening of the druggable genome. Cancer Res 72:757-68|
|Zhu, Yuan Xiao; Tiedemann, Rodger; Shi, Chang-Xin et al. (2011) RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. Blood 117:3847-57|
|Tiedemann, Rodger E; Zhu, Yuan Xiao; Schmidt, Jessica et al. (2010) Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. Blood 115:1594-604|
|Chesi, Marta; Robbiani, Davide F; Sebag, Michael et al. (2008) AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 13:167-80|