Tyrosine kinase inhibition in pulmonary hypertension: experimental and clinical studies
Final Report Abstract
Pulmonary arterial hypertension (PAH) is a severe disease characterized by a marked and sustained elevation of pulmonary artery pressure and right heart hypertrophy. If untreated, the disease results in right ventricular failure and death. Pulmonary vascular remodeling, the key pathological feature of PAH, is attributable to the increased proliferation, resistance to apoptosis, and migration of pulmonary vascular cells. We have recently shown that inhibition of the PDGF receptor improves remodeling and survival of animals with severe experimental PH. In addition, clinical case reports, first initiated by this group, have demonstrated efficacy of the tyrosine kinase inhibitor Imatinib in PAH. Our findings showed that other tyrosine kinase inhibitors also demonstrate strong reverse remodelling potency in experimental pulmonary hypertension. Interestingly, the multikinase inhibitors Sunitinib (targeting PDGFR, VEGFR, c-Kit) and Sorafenib (targeting PDGFR, VEGFR, Raf1) reverse RV remodelling and improve RV function in experimental RV hypertrophy. Further, two novel PDGFR inhibitors, Nilotinib (targeting PDGFR, Abl) and Dasatinib (targeting PDGFR, Abl, Src), represent a therapeutic approach for PH. We further investigated the safety, tolerability, and efficacy of the PDGFR inhibitor Imatinib in patients with PAH. These data from a phase II study are consistent with Imatinib being well tolerated in patients with PAH, and provide proof of concept for further studies. In a phase III study, Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, Imatinib was evaluated in patients with pulmonary vascular resistance ≥800 dyne * s * cm -5 symptomatic on ≥2 PAH therapies. Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the longterm safety and efficacy of Imatinib in patients with PAH.
Publications
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Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1171-7
Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, Pascoe S
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Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med. 2010; 181(2):158-67
Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, Ghofrani HA, Weissmann N, Voswinckel R, Banat GA, Seeger W, Grimminger F, Schermuly RT
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Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev Drug Discov. 2010; 9(12):956-70
Grimminger F, Schermuly RT, Ghofrani HA
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Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-β. Pulm Circ. 2011;1(2):259-68
Dahal BK, Heuchel R, Pullamsetti SS, Wilhelm J, Ghofrani HA, Weissmann N, Seeger W, Grimminger F, Schermuly RT
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Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol. 2011;8(8):443-55
Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F
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Effects of multi-kinase inhibitors on pressure overload-induced right ventricular remodelling. Int J Cardiol. 2012 Jul 30. [Epub ahead of print]
Kojonazarov B, Sydykov A, Pullamsetti SS, Luitel H, Dahal BK, Kosanovic D, Tian X, Majewski M, Baumann C, Evans E, Phillips P, Fairman D, Davie N, Wayman C, Kilty I, Weissmann N, Grimminger G, Seeger W, Ghofrani HA, Schermuly RT
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Role of Src tyrosine kinases in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2012; 32(6):1354-65
Pullamsetti SS, Berghausen EM, Dabral S, Tretyn A, Butrous E, Savai RK, Butrous G, Dahal BK, Brandes RP, Ghofrani HA, Norbert W, Friedrich G, Werner S, Rosenkranz S and Schermuly RT
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Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013 Mar 12;127(10):1128-38
Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, Gómez-Sánchez MA, Grimminger F, Grünig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA
