Myeloproliferative disorders (MPDs) characterized by prominent myelofibrosis have a poor prognosis with no effective therapies outside of allogeneic stem cell transplantation. Recently, several groups identified a gain- of-function mutation in Janus Kinase 2 (JAK2 V617F) in the majority of patients with MPDs, suggesting that JAK2 is a potential therapeutic target in these diseases, including the myelofibrotic disorders. A primary in vitro kinase screen against purified JAK2 enzyme showed that the small-molecule multikinase inhibitor lestaurtinib (CEP-701) inhibits its activity with an IC50 of 1 nM. Based on these data, I found that CEP-701 selectively inhibits growth of primary cells from subjects with MPDs at doses that are clinically achievable. These studies led to the initiation of an MPD Research Consortium sponsored study, of which I am the study chair. The objectives of this proposal are first, to determine the safety and activity of CEP-701 in subjects with myelofibrosis;second, to use clinical samples obtained during this study to estimate optimal biologic dose and the relationship between inhibition of JAK2 mediated signaling and clinical response. Finally, to determine whether other previously identified disease modifiers are regulated by JAK2, I will test whether NF-E2 and Bcl-xL expression can be modified by JAK2 inhibition in primary patient cells. Together, these studies will provide a basis for predicting response and refining drug targets in the treatment of MPDs. This proposal outlines a 5 year plan for developing my independent career as a physician-scientist with an expertise in late preclinical testing and early phase studies of novel therapies for hematologic malignancies. It will be mentored by Dr. Martin Carroll, a leader both in the field of signal transduction in myeloid disorders and in related translational studies in experimental therapeutics. This award will allow me to complete a Master's Degree in Translational Research, and will provide the experience and formal training required to establish my career in translational medicine.
Approximately 15,000 new cases of myeloproliferative disorders are diagnosed in the United States each year. This research project focuses on novel, targeted therapies for this group of diseases, and may reveal key aspects of the biology of the disease and general principles of targeted therapy.
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