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76 ATTENUATION OF A RODENT MODEL OF PULMONARY HYPERTENSION: A NOVEL ROLE FOR SORAFENIB, A MULTIKINASE INHIBITOR.
  1. A. A. Desai,
  2. L. Moreno,
  3. M. M. Gomberg-Maitland,
  4. M. Maitland,
  5. K. Collins,
  6. S. Sammani,
  7. S. Ma,
  8. A. N. Husain,
  9. Y. Liu,
  10. L. Sam,
  11. R. M. Lang,
  12. M. J. Ratain,
  13. Y. A. Lussier,
  14. J. Garcia
  1. The University of Chicago, Chicago, IL.

Abstract

Drawing from new drug discovery studies is the observation that severe pulmonary hypertension (PH) and cancer pathophysiology share common signal transduction pathways leading to abnormal smooth muscle and endothelial cell (EC) interactions and angioproliferative vasculopathy. Sorafenib (Sor), a chemotherapeutic agent in clinical trials for the treatment of renal cell cancer, is an inhibitor of multiple kinases, including Raf-1 kinase, MAPK, VEGFR-2, and VEGFR-3, genes implicated in angiogenesis, proliferation, and the inhibition of apoptosis. We therefore tested the hypothesis that Sor will attenuate the development of PH using an established rodent model of the disease. We performed two 3-week hypoxia (FiO2 10%) and SU5416 (a selective VEGFR-2 inhibitor known to dramatically augment hypoxia-induced PH) studies to induce PH in Dahl salt-sensitive rats (SS). Rat groups were normoxia/vehicle (Norm), hypoxia/vehicle (H), H-Su, hypoxia/sorafenib (H-Sor), and hypoxia/sorafenib/ SU5416 (H-Su-Sor). Except for Norm, all rats were kept in hypoxia, whereas the H-Su group received SU5416 at day 1 (20 mg/kg, sc) and Sor was gavaged daily (2.5 mg/kg). Echocardiography, pulmonary artery pressures (PAPs), right ventricular pressures (RVPs), and lung gene microarray analyses were assessed at 3 weeks. Our results showed that H-Su rats developed severe PH compared with Norm, rats in the H alone group had mildly elevated pressures compared with Norm, and no changes were seen in pressures, weights, or remodeling in the H-Sor or H-SU-Sor groups compared with Norm. The H-Su-Sor rats showed significant reductions in PAP (56%), RVP (55%), and RV hypertrophy (52%). Gene expression profiling data were compared with Norm using GCRMA normalization in R and SAM (> .639, MFC > 1.7). With false discovery rates (FDRs) of 5.1% and 0.7%, respectively, 356 and 293 genes were up- or down-regulated. Forty-seven of the 356 H genes were recapitulated from previous H studies in the rodent model. In addition, 45 genes were differentially expressed between H-Su and H-Su-Sor (FDR 12%), with ECM, cytoskeleton, and angiogenesis gene ontologies, and 81 genes were changed in the H and H-Su groups but not in the H-Su-Sor group. These studies suggest Sor as a powerful novel treatment in PH.

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