Chronic lymphocytic leukemia (CLL) has long been incorrectly labeled “the good leukemia” due to the age of onset and the low incidence of detectable symptoms. No leukemia; however, is “good,” and CLL is no exception. CLL is the most common type of adult leukemia in the United States and yet remains incurable by traditional therapies; this provides strong justification for developing additional types of therapeutics. Of particular interest are therapies that target signal transduction pathways essential to CLL cell survival mechanisms that are known to be aberrantly activated as these contribute not only to the inherent survival of transformed cells but also contribute to survival signaling received from the microenvironment.
The focus of the work presented here is on altering kinase signaling in either the cancerous B-cell or the surrounding microenvironment to alter disease progression, duration, or state. Chapter one is a general introduction into B-cell biology and CLL: biology, diagnosis and treatment. The dependence of CLL cells on microenvironmental signaling is discussed with particular attention given to the bone marrow stroma and T-lymphocytes. In addition, key signaling pathways involved in B-cell survival and potential target kinases are discussed. Chapter two discusses the effects of inhibiting Phosphatidylinositol 3-Kinase (PI3-Kinase) for the treatment of CLL using a novel drug, CAL-101. We found that inhibition of PI3-Kinase signaling using a selective inhibitor resulted in not only direct cytotoxicity to CLL cells, but also altered the microenvironment in a way that was unfavorable to CLL cell survival. Chapter three discusses the effects of inhibition of B-cell receptor (BCR) signaling via inhibition of Tec family kinases (specifically BTK) using a novel drug, PCI-32765. Similarly to PI3-Kinase, we again found that inhibition of BCR signaling resulted in the induction of apoptosis in CLL cells and an alteration of microenvironmental signaling. Chapter four discusses the affects of activating PI3-Kinase for the treatment of CLL using the novel compound lenalidomide. The focus of this chapter; however, is on the contradictory roles of two therapies for the treatment of CLL and the potential downfalls of their combination. Chapter five discusses the conclusions and implications of our work; specifically the balance of kinase signaling involved in maintaining a disease state in CLL. In addition, chapter five discusses questions left unanswered and the future directions of this work.
Together, 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 as it suggests that inhibition or activation of any particular kinase may only be half the answer – with evidence suggesting a need for a set balance in kinase signaling.