Repurposing Barasertib for the Treatment of Pulmonary Fibrosis
Project Abstract:
Idiopathic Pulmonary Fibrosis IPF is a chronic fibrotic lung disease that involves the progressive accumulation of mesenchymal cells due to their excessive proliferation and survival Nintedanib and pirfenidone are two recently FDAapproved therapies that slow the rate of decline in lung function in patients with IPF but do not halt progression or reverse fibrosis thus newer therapies that inhibit fibroblast activation to reverse established and ongoing fibrosis would have significant advantages over these current agents Although multiple profibrotic growth factors intensively studied the molecular pathways that synergistically regulate fibroblast phenotypes have not been identified and constitute a fundamental knowledge gap in the field Our preliminary findings demonstrate that Aurora Kinase B AURKB represents a targetable downstream point where multiple upstream fibrogenic pathways converge to cause excessive proliferation and survival in fibroblasts The objective of the proposed study is to develop an effective formulation and aerosolized delivery methods to determine the efficacy of a highly selective AURKB inhibitor Barasertib AZD1152 that can prevent the progression and reverse fibrosis in mouse models of pulmonary fibrosis Barasertib is well tolerated in multiple cancers with favorable safety data and showed antitumor activity Importantly our new findings suggest that barasertib administered intraperitoneally IP attenuates fibroblast activation and pulmonary fibrosis in vivo Since IPF requires prolonged treatment IP administration is undesirable and impractical for patients Hence a targeted therapeutic pressurized aerosol delivery method that i can be given at smaller doses compared to systemic treatment ii has rapid onset of drug action and iii has lesser systemic side effects is proposed The proposed studies focusing on nebulization of barasertib are therefore important and critical in moving this lead compound to become a clinical candidate for IPF The major goals of this application are i to develop an optimal aerosol formulation of barasertib and to establish preclinical therapeutic dose for barasertib dry powder formulation in pulmonary fibrosis The culmination of this work will enable future innovative Phase III IPF clinical trials using barasertib
