Development of lysyl oxidase inhibitors for the treatment of fibrosis

总结 骨髓增生性疾病（MPD）是慢性骨髓性血液疾病，表现为克隆性骨髓增生异常。 一种或多种骨髓谱系的增殖，并且特征在于活化突变， JAK-STAT途径。有超过175，000名MPD患者，因此这些是 是美国最常见的白血病MPD患者的风险增加， 血栓形成和出血，并进展到终末期骨髓（BM）纤维化或急性 白血病JAK抑制剂鲁索利替尼和最近的非德拉替尼已被批准用于 骨髓纤维化（MF）的治疗。JAK抑制剂与鲁索替尼、非德拉替尼或与 临床开发中的其他JAK抑制剂改善了脾肿大和体质性 MF患者的症状。然而，JAK抑制剂治疗不会导致显著的分子生物学效应。 或病理缓解。这与分子生物学相反， ABL激酶抑制剂治疗慢性粒细胞白血病的疗效观察因此， 迫切需要新的疗法来改善MPD患者的结局。这项建议是 基于赖氨酰氧化酶（LOX）介导的胶原交联和LOX- 驱动的巨核细胞增殖参与建立生长许可的纤维化 微环境和靶向LOX可以消除纤维化表现的程度， MPD患者，并可能在其他疾病与纤维增生成分。的 本提案的目的是评估靶向LOX是否是一种潜在的新型治疗方法 通过执行两个特定目标减少MPD患者BM纤维化的方法：SA 1： 阐明LOX抑制减弱MPD中纤维化的细胞机制。SA 2：至 评估不同LOX和LOXL抑制剂单独和联合对纤维化的影响 JAK抑制剂ruxolitinib。总括而言，这项建议旨在加深我们对 LOX酶在纤维化BM疾病中胶原形成中的作用，并利用这些知识 为一系列人类疾病开发一种新的抗纤维化治疗方法 与病理性骨髓纤维化相关。

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.