Development of lysyl oxidase inhibitors for the treatment of fibrosis

SUMMARY Myeloproliferative disorders (MPD) are chronic myeloid blood disorders that present as clonal proliferation of one or more myeloid lineages, and are characterized by activating mutations in the JAK-STAT pathway. There are more than 175,000 MPD patients, such that these are the most common leukemias observed in the United States. MPD patients have an increased risk of thrombosis and bleeding, and progress to end stage bone marrow (BM) fibrosis or acute leukemia. The JAK inhibitors ruxolitinib and, more recently, fedratinib have been approved for the treatment of myelofibrosis (MF). JAK inhibitor therapy with ruxolitinib, fedratinib, or with other JAK inhibitors in clinical development ameliorates splenomegaly and constitutional symptoms in MF patients. However JAK inhibitor therapy does not lead to significant molecular or pathologic remissions in the majority of MPD patients. This is in contrast to the molecular responses seen with ABL kinase inhibitors in chronic myeloid leukemia. As such there is a pressing need for novel therapies to improve outcomes for MPD patients. This proposal is based on the hypothesis that lysyl oxidase (LOX)-mediated collagen crosslinking and LOX- driven megakaryocyte proliferation is involved in establishing a growth-permissive fibrotic microenvironment and that targeting LOX can abrogate the extent to which fibrosis manifests in MPD patients, and potentially in other diseases with a fibroproliferative component. The objective of this proposal is to evaluate whether targeting LOX is a potential novel therapeutic approach to reduce BM fibrosis in MPD patients by performing two specific aims: SA1: To elucidate cellular mechanisms by which LOX inhibition attenuates fibrosis in MPD. SA2: To assess the impact of different LOX and LOXL inhibitors on fibrosis, alone and in combination with JAK inhibitor ruxolitinib. In sum, this proposal aims to improve our understanding of the role of LOX enzymes in collagen formation in fibrotic BM diseases and to use that knowledge to develop a novel anti-fibrogenic therapeutic approach for a spectrum of human diseases associated with pathologic BM fibrosis.Project Narrative Allogeneic stem cell transplantation is currently the only therapeutic intervention leading to clonal eradication and reversal of bone marrow (BM) fibrosis in myeloproliferative disorders (MPD). BM fibrosis contributes to the impairment of the BM microenvironment facilitating malignant transformation over normal hematopoiesis in MPD. Hence, there is a pressing need for agents that either prevent BM fibrosis or reverse the pathological process allowing for physiologic resorption of fibrosis and improving outcomes in MPD.