Tumor cells arise from normal cells in which multiple metabolic processes go awry. One of the most typical abnormalities in tumor cells is the control of protein metabolism, which includes synthesis, post-translational modification, and degradation. It is often observed that tumor cells are highly dependent on alterations in these processes to increase entry into the cell cycle and resistance to the normal process of cell death, or apoptosis. Our research focuses on targeting these protein metabolism processes, with the goal of preferentially initiating apoptosis of tumor cells versus normal cells. To this end we are investigating agents that specifically interfere with protein metabolism, either as research tools to better understand these pathways or as compounds for potential development as anti-cancer drugs in CLL and other B-cell malignancies. These agents include the translation initiation inhibitor silvestrol, the mTOR inhibitor rapamycin, the deacetylase inhibitor AR-42, and the proteasome inhibitor bortezomib.
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Lucas DM, Edwards RB, Lozanski G, West DA, Shin JD, Vargo MA, Davis ME, Rozewski DM, Johnson AJ, Su BN, Goettl VM, Heerema NA, Lin TS, Lehman A, Zhang X, Jarjoura D, Newman DJ, Byrd JC, Kinghorn AD, Grever MR. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood. 2009; 113:4656-4666
Lucas DM, Alinari L, West DA, Davis ME, Edwards RB, Johnson AJ, Blum KA, Hofmeister CC, Freitas MA, Parthun MR, Wang D, Lehman A, Zhang X, Jarjoura D, Kulp SK, Croce CM, Grever MR, Chen C-S, Baiocchi RA, Byrd JC. The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-cell Malignancies In Vitro and In Vivo. PLoS One 2010 Jun 3;5(6):e10941