Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension.

Pulmonary hypertension (PH) and cancer pathology share growth factor- and MAPK stress-mediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-beta, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxia-exposed control animals, four groups were maintained at 10% inspired O(2) fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]- and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change >1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target.

[1]  F. Grimminger,et al.  Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure , 2008, European Respiratory Review.

[2]  M. Gordon.  Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma , 2008 .

[3]  N. Voelkel,et al.  VEGF‐R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle‐like and neuronal‐like cells , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  Lee T. Sam,et al.  Use of consomic rats for genomic insights into ventilator-associated lung injury. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[5]  Yoon-Koo Kang,et al.  Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC) , 2007 .

[6]  F. Grimminger,et al.  126 Combined inhibition of tyrosine‐ and serine‐/threonine kinases in pulmonary hypertension: Sorafenib prevents vascular and myocardial remodeling , 2007 .

[7]  Jeffrey W. Clark,et al.  Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. , 2007, The oncologist.

[8]  B. Rini.  Vascular Endothelial Growth Factor–Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions , 2007, Clinical Cancer Research.

[9]  A. Blann,et al.  Detection of circulating endothelial cells: CD146-based magnetic separation enrichment or flow cytometric assay? , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  W. Rathmell,et al.  Biological Aspects and Binding Strategies of Vascular Endothelial Growth Factor in Renal Cell Carcinoma , 2007, Clinical Cancer Research.

[11]  D. Badesch,et al.  Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. , 2007, Chest.

[12]  D. Badesch,et al.  Evidence-Based Clinical Practice Guidelines Hypertension: Updated ACCP Medical Therapy for Pulmonary Arterial , 2007 .

[13]  S. Rosenkranz,et al.  Zukunftsaspekte der Therapie der pulmonalarteriellen Hypertonie , 2006 .

[14]  H. Ghofrani,et al.  [Treatment of pulmonary arterial hypertension: phosphodiesterase-5 inhibitors]. , 2006, Deutsche medizinische Wochenschrift.

[15]  M. Feldman,et al.  Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). , 2006, The American journal of pathology.

[16]  N. Morrell.  Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? , 2006, Proceedings of the American Thoracic Society.

[17]  S. Wilhelm,et al.  Discovery and development of sorafenib: a multikinase inhibitor for treating cancer , 2006, Nature Reviews Drug Discovery.

[18]  W. Seeger,et al.  Hypoxia- and non-hypoxia-related pulmonary hypertension - established and new therapies. , 2006, Cardiovascular research.

[19]  J. Cogan,et al.  High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. , 2006, American journal of respiratory and critical care medicine.

[20]  H. Tan,et al.  How valid are animal models to evaluate treatments for pulmonary hypertension? , 2006, Naunyn-Schmiedeberg's Archives of Pharmacology.

[21]  Meijing Wang,et al.  p38 mitogen-activated protein kinase mediates the sustained phase of hypoxic pulmonary vasoconstriction and plays a role in phase I vasodilation. , 2006, The Journal of surgical research.

[22]  H. Farber,et al.  Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. , 2006, Annals of internal medicine.

[23]  M. Maitland,et al.  Blood pressure (BP) as a biomarker for sorafenib (S), an inhibitor of the vascular endothelial growth factor (VEGF) signaling pathway. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  W. Seeger,et al.  [Reverse remodeling -- paradigm shift in the treatment of pulmonary hypertension]. , 2006, Deutsche medizinische Wochenschrift.

[25]  K. Flaherty,et al.  Mechanisms of hypertension associated with BAY 43-9006. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  M. Shibuya.  Vascular endothelial growth factor (VEGF)-Receptor2: its biological functions, major signaling pathway, and specific ligand VEGF-E. , 2006, Endothelium : journal of endothelial cell research.

[27]  M. Gore,et al.  The place of VEGF inhibition in the current management of renal cell carcinoma , 2006, British Journal of Cancer.

[28]  S. Salzberg,et al.  Physiogenomic resources for rat models of heart, lung and blood disorders , 2006, Nature Genetics.

[29]  J. SandovalZárate.  Pulmonary arterial hypertension , 2006 .

[30]  S. Rosenkranz,et al.  [Future aspects of the treatment of pulmonary arterial hypertension]. , 2006, Deutsche medizinische Wochenschrift.

[31]  R. Johns,et al.  Differential gene expression in chronic hypoxic pulmonary hypertension: effect of simvastatin treatment. , 2005, Chest.

[32]  R. Nemenoff,et al.  Prostacyclin synthase promoter regulation and familial pulmonary arterial hypertension. , 2005, Chest.

[33]  N. Voelkel,et al.  Microarray analysis of peripheral blood cells in pulmonary arterial hypertension, surrogate to biopsy. , 2005, Chest.

[34]  W. Seeger,et al.  Reversal of experimental pulmonary hypertension by PDGF inhibition. , 2005, The Journal of clinical investigation.

[35]  S. Dudek,et al.  Regulation of sphingosine 1‐phosphate‐induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and α‐actinin , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  W. Seeger,et al.  Imatinib for the treatment of pulmonary arterial hypertension. , 2005, The New England journal of medicine.

[37]  K. Stenmark,et al.  Vascular remodeling versus vasoconstriction in chronic hypoxic pulmonary hypertension: a time for reappraisal? , 2005, Circulation research.

[38]  N. Voelkel,et al.  Initial apoptosis is followed by increased proliferation of apoptosis‐resistant endothelial cells , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  R. Glenny,et al.  Global gene annotation analysis and transcriptional profiling identify key biological modules in hypoxic pulmonary hypertension. , 2005, Physiological genomics.

[40]  Claes Wahlestedt,et al.  Considerations when using the significance analysis of microarrays (SAM) algorithm , 2005, BMC Bioinformatics.

[41]  Dirk Strumberg,et al.  Raf Kinase Inhibitors in Oncology , 2005, Oncology Research and Treatment.

[42]  S. Archer,et al.  Hypoxic pulmonary vasoconstriction. , 2005, Journal of applied physiology.

[43]  D. Auclair,et al.  BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis , 2004, Cancer Research.

[44]  Rafael A. Irizarry,et al.  A Model-Based Background Adjustment for Oligonucleotide Expression Arrays , 2004 .

[45]  D. Mccrory,et al.  Medical Therapy For Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines , 2004 .

[46]  Manabu Iwasaki,et al.  Prolonged nitric oxide inhalation fails to regress hypoxic vascular remodeling in rat lung. , 2004, Chest.

[47]  Chao-shu Tang,et al.  Effects of endogenous carbon monoxide on collagen synthesis in pulmonary artery in rats under hypoxia. , 2004, Life sciences.

[48]  R. Budhiraja,et al.  Endothelial Dysfunction in Pulmonary Hypertension , 2004, Circulation.

[49]  Tiffani J. Bright,et al.  PubMatrix: a tool for multiplex literature mining , 2003, BMC Bioinformatics.

[50]  R. Johns,et al.  Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. , 2003, American journal of physiology. Heart and circulatory physiology.

[51]  Shokei Kim,et al.  Stress and vascular responses: mitogen-activated protein kinases and activator protein-1 as promising therapeutic targets of vascular remodeling. , 2003, Journal of pharmacological sciences.

[52]  I. Adatia.  Recent advances in pulmonary vascular disease. , 2002, Current opinion in pediatrics.

[53]  P. Khatri,et al.  Profiling gene expression using onto-express. , 2002, Genomics.

[54]  G. Semenza,et al.  Expression of angiogenesis‐related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis , 2001, The Journal of pathology.

[55]  D. Welsh,et al.  Chronic hypoxia induces constitutive p38 mitogen-activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries. , 2001, American journal of respiratory and critical care medicine.

[56]  N. Voelkel,et al.  Genomic approaches to research in pulmonary hypertension , 2001, Respiratory research.

[57]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[58]  N. Voelkel,et al.  Gene Expression Patterns in the Lungs of Patients With Primary Pulmonary Hypertension: A Gene Microarray Analysis , 2001, Circulation research.

[59]  P. Hirth,et al.  Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[60]  RyuichiMorishita,et al.  Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats , 2000 .

[61]  T. Ogihara,et al.  Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats , 2000, Circulation.

[62]  N. Voelkel,et al.  Severe pulmonary hypertensive diseases: a perspective. , 1999, The European respiratory journal.

[63]  G. Neufeld,et al.  Vascular endothelial growth factor (VEGF) and its receptors , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[64]  D. Welsh,et al.  Hypoxia enhances cellular proliferation and inositol 1,4, 5-triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery. , 1998, American journal of respiratory and critical care medicine.

[65]  T. Higenbottam,et al.  Acute and chronic hypoxic pulmonary hypertension. , 1993, The European respiratory journal.

[66]  J. F. Keane,et al.  Vascular structure in lung tissue obtained at biopsy correlated with pulmonary hemodynamic findings after repair of congenital heart defects. , 1984, Circulation.

[67]  C. Hales,et al.  Impairment of hypoxic pulmonary artery remodeling by heparin in mice. , 2015, The American review of respiratory disease.