Efficacious Intermittent Dosing of a Novel JAK2 Inhibitor in Mouse Models of Polycythemia Vera

Abstract

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.

JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation

“…Accordingly, whereas ruxolinitib, a JAK2 inhibitor used in clinics, induced thrombocytopenia in mice treated with high doses, the drug paradoxically increased the platelet count when used at suboptimal doses. An increased platelet count was also reported in mice treated with MRLB-11055, a highly potent inhibitor of JAK2, 35 whereas an increased platelet count was observed in some PMF patients treated with lower doses of ruxolitinib. 18 In conclusion, we propose that the expression level of JAK2 and MPL regulates the switch from proliferation to differentiation in the megakaryocytic lineage ( Figure 4B).…”

Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis

“…This finding suggests that thrombocytopenia observed with certain JAK2 inhibitors is due to JAK2 inhibition in more proximal stem/progenitor cells consistent with conditional Jak2 knockout studies in hematopoiesis, 15,16 or potentially due to inhibition of other targets. Analogous to genetic Jak2 loss, Jak2 inhibition in PLTs/MKs may actually enhance PLT production, 30 but may be overruled by the impact of Jak2 inhibition on stem/ progenitors. Complementary to previous studies on the role of Mpl in PLTs, [17][18][19] our results demonstrate an important role for PLT-specific Jak2 signaling in regulating TPO turnover, and show that PLT Jak2 signaling negatively regulates stem/progenitor cells, including MK-primed HSCs.…”

Current treatment strategies for inhibiting mTOR in cancer

“…Examples of how different schedules of drug administration could lead to different outcomes are documented by a study in which the effects of the g-secretase inhibitor MK-0752 were investigated in adults with advanced solid tumors and by the testing of intermittent doses of MRLB-11055, a JAK2 inhibitor, in a mouse model of polycythemia vera in which chronic, high-level inhibition of JAK2 would have been intolerable. In both cases, the intermittent schedule proved to be superior to daily administration in terms of clinical efficacy, pathway inhibition, and toxic side effects [107,108].…”