Development of an oral anti-fibrotic drug for patients with myelofibrosis

Primary myelofibrosis (PMF) and myelofibrosis (MF) secondary to myeloproliferative neoplasms are life-threatening disorders, reversible only by allogeneic stem cell transplantation. The prevalence of these disorders is considerable with approximately 150,000 Americans affected. Although a gain-of-function mutation in JAK2V617 has been found commonly, the molecular basis of myelofibrosis remains elusive, and even with ruxolitinib, its management remains unsatisfactory. Recent findings in fibrotic diseases of the lung, heart, kidney, and liver have shown that hepatocyte growth factor (HGF) prevents the development of fibrosis and stimulates normal tissue repair. Of note, HGF levels are increased 3-fold in patients with PMF. We hypothesize that this reflects a partial compensatory response to PMF. We hypothesize that captopril can pharmacologically reverse MF by targeting the bone marrow microenvironment and resulting in decreased TGFß and increased HGF levels. To this hypothesis we propose the following specific aim: Determine the beneficial effects of captopril on two mouse models of marrow fibrosis (MPLW515L-induced and GATA-1 low) and validate a HGF-TGFß-Fibrocyte disturbances in humans with MF.