PKC-beta as a therapeutic target in B-CLL

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the west and is incurable with conventional therapy. B-CLL is a clonal lymphocytosis of CD5-expressing B-cells. Signalling through the B-cell receptor (BCR) plays an important role in B-CLL pathogenesis. PKC-beta is an important modulator of BCR- signalling. Moreover, PKC-beta deficient mice display a distinct loss of CD5+ B-cells. Thus, abolishing PKC-beta signals may have relevant effects on B-CLL pathophysiology. We propose to establish PKC-beta as a target for the treatment of B-CLL using the E-Tcl1 transgenic mice model. These mice develop a CD5+ CLL with striking similarities to human B-CLL and thereby represent the first relevant mouse model for B-CLL. We will cross Tcl1 transgenic mice onto a PKC-beta deficient background to assess the effects of a complete loss of PKC-beta on CLL progression. Furthermore, we will inhibit PKC-beta therapeutically in vivo using a novel PKC-beta specific inhibitor, Enzastaurin (Eli Lilly and Company). Finally, we will use our extensive base of CLL patient samples to establish a role for PKC-beta inhibition in human CLL using ex vivo short term cultures in the presence of Enzastaurin. Should we obtain promising results, we have agreed with Lilly to negotiate the terms of a clinical trial in our experienced institution.