Translating science from bench to bedside is critical for advancing the treatment of CLL. Molecular Phamacology examines promising new treatments developed by pharmaceutical companies, at OSU and by collaborators with the intention of elucidating mechanism of action and optimizing clinical outcomes before going to clinical trials. Molecular pharmacology has recently been focusing on cyclin-dependent kinase inhibition with the success of flavopiradol, the role of PI3K in the CLL tumor cell as well as microenvironment, and the use of lenalidomide in the treatment of CLL. This work provides valuable insight into the potential use of both kinase inhibitors and kinase activators for the treatment of CLL. This is important as unlike diseases such chronic myeloid leukemia (CML) which displays a targetable aberrant fusion protein kinase, CLL displays no such target, but does display altered kinase signaling as compared to normal B-cells. By utilizing the known differences between normal B-cells and transformed cells such as CLL we have been able to predict new target kinases. This work adds to our ability to develop new therapeutics .
Byrd JC, Lin TS, Dalton JT, Wu D, Phelps MA, Fischer B, Moran M, Blum KA, Rovin B, Brooker-McEldowney M, Broering S, Schaaf LJ, Johnson AJ, Lucas DM, Heerema NA, Lozanski G, Young DC, Suarez JR, Colevas AD, Grever MR. (2007), “Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia”, Blood. 109:399-404
Awan FT, Johnson AJ, Lapalombella R, Hu W, Lucas M, Fischer B, and Byrd JC. (2010) “Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia”. Leuk Lymphoma. 51(1):27-38
Lapalombella R, Andritsos L, Liu Q, May SE, Browning R, Pham LV, Blum KA, Blum W, Ramanunni A, Raymond CA, Smith LL, Lehman A, Mo X, Jarjoura D, Chen CS, Ford R, Jr, Rader C, Muthusamy N, Johnson AJ*, and Byrd JC*. (2010) “Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B Cells through a PI3-kinase dependent pathway”. Blood. 115(13):2619-2629
Herman SEM, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, Jones J, Andritsos L, Puri KD, Lannutti BJ, Giese NA, Zhang X, Wei L, Byrd JC, Johnson AJ. (2010) “The phosphatidylinositol 3-kinase- inhibitor CAL-101 demonstrates promising pre-clinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.” Blood. 2010 Sep 23;116(12):1999-2000