Tyrosine Kinase Inhibitors

Transcription

1 European Society of Cardiology ESC CONGRESS 2011 aris, August 27-31, 2011 New Approaches to the Treatment of ulmonary Hypertension: Tyrosine Kinase Inhibitors Stephan Rosenkranz Klinik III für Innere Medizin Center for Molecular Medicine Cologne (CMMC) Herzzentrum der Universität zu Köln, Germany

2 Conflict of Interest - Disclosure Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationships Honoraria for lectures / Consulting / Advisory Board Acitivies / articipation in Clinical Trials: Actelion, BayerSchering, Gilead, GSK, Lilly, Novartis, fizer, United Therapeutics Research funding: Actelion, BayerSchering, fizer Financial shares and options: None.

3 Survival in atients with AH in the Modern Management Era REVEAL French Registry One year survival 91% ~10% Benza-RL et al., Circulation 2010; 122: Humbert-M et al., Circulation 2010; 122:

4 Survival in atients with AH in the Modern Management Era REVEAL French Registry One year survival 91% ~10% AH remains a progressive, fatal disease Benza-RL et al., Circulation 2010; 122: Humbert-M et al., Circulation 2010; 122:

5 Current Limitations in AH Treatment Improvement of pulmonary hemodynamics (VR, CO), quality of life, and survival, but.. No profound reduction of vascular remodeling No significant reduction of the mean A RV dysfunction remains major problem Disease progression is only delayed No causal treatment Mortality remains unacceptably high

6 ulmonary Arterial Hypertension: Modern Therapeutic Concepts Is this the right approach? ulmonary Vasodilators Courtesy of N. Galiè

7 roliferative Vascular Disease: Anti-Remodeling Strategies Rosenkranz S. ulmonale Hypertonie. In: Harrison s rinciples of Internal Medicine, 17 th ed Rosenkranz S. ulmonary hypertension. Clin. Res. Cardiol. 2007; ; Rosenkranz S. DMW 2008

8 Selected Tyrosine Kinase Inhibitors: Overview Grimminger F, Schermuly RT, Ghofrani HA, Nat Rev Drug Discov 2010; 9:

9 Signaling athways of the DGF b Receptor in Vascular Smooth Muscle Cells (VSMC) DGF DGF-BB DGFR (RTK) Kinase activity low Kinase activity high Src ACTIVATION OF SIGNALING ATHWAYS Grb2 740/51 RasGA 716 I3K 771 ROLIFERATION CHEMOTAXIS AOTOSIS / SURVIVAL? SH LCg bdgfr

10 Chimeric (c-fms/βdgfr) Receptor Mutants / bdgfr CSF1R M-CSF Src 740/ X X X X X X I3K RasGA SH-2 LCg Chimeric Receptor Mutants (ChiR) (c-fms / bdgfr) A. Subtraction anel: Name: roperties: S r c I3K RasGA SH-2 579/81 740/ J M K I B. Add-back anel: 579/81 740/ L C g WT F40/51 Tail S r c I3K RasGA SH L C g 1021 F79/81 F771 F1009 F1021 F6 F5 Y40/51 Y771 Y1009 Y1021 Binds / activates all signaling molecules Does not bind / activate Src Does not bind / activate I3K Does not bind / activate RasGA Does not bind / activate SH-2 Does not bind / activate LCg Binds / activates none of signaling molecules Binds / activates only Src Binds / activates only I3K Binds / activates only RasGA Binds / activates only SH-2 Binds / activates only LCg g J M K I Tail Vantler M et al., J Biol Chem 2005; 280: Caglayan E, Vantler M et al., JACC 2011; 57:

11 BrdU Incorporation Fold increase DGF-dependent roliferation and Migration Are Blunted in VSMCs from F3/F3 Mice Chemotaxis fold-increase S r c I3K RasGA SH-2 L C g F3 (F40/51-F1021) DGFR F3/F3 roliferation ( BrdU incorporation ) Chemotaxis 5 4 MASMC F Control DGF-BB MASMC F3/F3 DGF-BB [ng/ml] Caglayan et al., JACC 2011; 57:

12 Reverse Remodeling: Reversal of Experimental ulmonary Hypertension by DGF Inhibition DGF-B-Expression Mediadicke Muskularisierung Tag 0 Tag 42 Tag 42 + STI571 Schermuly RT et al., J Clin Invest 2005; 115:

13 Reverse Remodeling: Reversal of Experimental ulmonary Hypertension by DGF Inhibition Reversibility of AS Increase Improved Survival Schermuly RT et al., J Clin Invest 2005; 115:

14 fold increase fold increase Hypoxia enhances DGF-dependent roliferation and Migration of hasmc roliferation (BrdU incorporation) Chemotaxis (modified Boyden chamber) 3,5 3 * * * 6 5,5 5 * 2,5 2 1,5 * * * 4,5 4 3,5 3 2,5 2 * * * * * DGF-BB (ng/ml) 1, DGF-BB (ng/ml) Normoxia Hypoxia *p<0,05 vs. buffer p<0,05 vs. normoxia ten Freyhaus H et al., Am J Respir Crit Care Med 2011; 183:

15 Hypoxia enhances DGFR hosphorylation RasGap 116 kd I:βDGFR WB: βdgfr 190 kd βdgfr Hypoxia - 24h 48h 190 kd I:βDGFR WB:-Y DGF-BB Hypoxia kd RasGap 116 kd p-y kd p-y kd p-akt 62 kd p-erk 44 kd 42 kd DGF-BB Hypoxia ten Freyhaus H et al., Am J Respir Crit Care Med 2011; 183:

16 Hypoxia enhances DGF signaling in the ulmonary vasculature DGF-BB chronic hypoxia βdgfr I3K + LCγ Ts HIF-1 HIF-1 ULMONARY VASCULAR REMODELING ten Freyhaus H et al., Am J Respir Crit Care Med 2011; 183:

17 Imatinib in AH with Inadequate Response to Established Therapy hase II Trial Ghofrani HA et al., Am J Respir Crit Care Med 2010; 182:

18 Imatinib in AH with Inadequate Response to Established Therapy hase II Trial 6MWD and ulmonary Hemodynamics at Baseline and at End of Study Ghofrani HA et al., Am J Respir Crit Care Med 2010; 182:

19 Imatinib in AH with Inadequate Response to Established Therapy hase II Trial 6MWD and ulmonary Hemodynamics at Baseline and at End of Study Ghofrani HA et al., Am J Respir Crit Care Med 2010; 182:

20 Imatinib in AH with Inadequate Response to Established Therapy hase II Trial All atients Subgroup Analysis Ghofrani HA et al., Am J Respir Crit Care Med 2010; 182:

21 Imatinib in atients with Advanced AH IMRES hase III Study Randomized, double-blind, placebo-controlled, multicenter phase III study 200 patients with advanced AH (VR > 800 dyn*s*cm -5 ) revious treatment with at least two targeted AH drugs Intervention: Imatinib mesylate ( mg/day) or placebo for 24 weeks rimary endpoint: Change in the 6 minute walking distance (6MWD) Secondary endpoints: Change in pulmonary hemodynamics (mean A, VR) Change in cardiac output (CO) Time to clinical worsening harmakokinetics otential interactions with AH drugs (sildenafil, bosentan) etc.

22 6-minute walk distance (m) Imatinib in atients with Advanced AH IMRES hase III Study 500 Imatinib lacebo hase III: Baseline Month 6 Jan 2009 Jul 2009 Jan 2010 Core IMRES study Extension study (extension participants) (all patients on active treatment)

23 Current Questions about TKIs in (A)H EFFICACY: TKIs (Imatinib) only effective in advanced AH? otential limitations of effectiveness? A role for TKIs in other forms of H? SAFETY: Cardiotoxicity? Induction of AH by TKIs?

24 Current Questions about TKIs in (A)H EFFICACY: TKIs (Imatinib) only effective in advanced AH? otential limitations of effectiveness? A role for TKIs in other forms of H? SAFETY: Cardiotoxicity? Induction of AH by TKIs?

25 AH: Early Intervention and Treat-to-Target Sitbon & Galiè, Eur Respir Rev 2010; 19:

26 AH: Early Intervention and Treat-to-Target Sitbon & Galiè, Eur Respir Rev 2010; 19:

27 Relationship between ulmonary Microcirculation Loss and ulmonary Artery ressure at Rest mean A Modified from Lau et al., Eur Heart J 2011; published on-line May 26

28 NTproBN Levels (ng/l) 7000 Imatinib min walk distance (m) Time (Months) Ten Freyhaus H et al., Clin Res Cardiol 2009; 98:

29 NTproBN Levels (ng/l) 7000 Imatinib min walk distance (m) Time (Months) Ten Freyhaus H et al., Clin Res Cardiol 2009; 98:

30 Systole Diastole RA RV RVEF (%) LA LV Baseline Imatinib 0 Baseline Imatinib Ten Freyhaus H et al., Clin Res Cardiol 2009; 98:

31 Current Questions about TKIs in (A)H EFFICACY: TKIs (Imatinib) only effective in advanced AH? otential limitations of effectiveness? A role for TKIs in other forms of H? SAFETY: Cardiotoxicity? Induction of AH by TKIs?

32 athogenesis of AH ULMONARY VASCULAR REMODELING Inflammation, Growth Factors Cellular & Molecular Basis Hassoun-M et al., JACC 2009; 54(Suppl S): S10-S19 Morrell-N et al., JACC 2009; 54(Suppl S): S20-S31

33 Tyrosine Kinase Signaling in ulmonary Vascular Remodeling DGF I3K Src Grb2 LCg Ras Barst RJ, J Clin Invest 2005;115: Schermuly R et al., J Clin Invest 2005; 115:

34 Multiple Growth Factors are Important for ulmonary Vascular Remodeling DGF Insulin b-fgf IGF-1 I3K Src EGF Grb2 LCg Ras Barst RJ, J Clin Invest 2005;115: Schermuly R et al., J Clin Invest 2005; 115: Izikki M et al., J Clin Invest 2009; 119: Merklinger S et al., Circulation 2005;112: Dahal BK et al., Am J Respir Crit Care Med 2010;181:

35 Multiple Growth Factors are Important for ulmonary Vascular Remodeling DGF Insulin b-fgf IGF-1 I3K Src EGF Grb2 LCg Ras I3K Barst RJ, J Clin Invest 2005;115: Schermuly R et al., J Clin Invest 2005; 115: Izikki M et al., J Clin Invest 2009; 119: Merklinger S et al., Circulation 2005;112: Dahal BK et al., Am J Respir Crit Care Med 2010;181:

36 Growth Factor-Induced roliferation of hasmcs Depends on I3K subunit p110 Activity BrdU Incorporation (fold increase) BrdU incorporation (fold increase) BrdU incorporation (fold increase) DGF-BB 30ng/ml 3nM 10nM 30nM 100nM 300nM 1µM 3µM 10µM Imatinib * * * Growth factor mixture (DGF- BB 30ng/ml, FGF 2ng/ml, EGF 0,5 ng/ml, Insulin 0,5µg/ml, FCS 5%) Sorafenib Imatinib MGFs (DGF-BB 30ng/ml, FGF 2ng/ml, EGF 0,5 ng/ml Insulin 0,5µg/ml FCS 5%) * 0 30 nm 100 nm 300 nm 1 µm 3 µm 300 nm 3 µm 300 nm 3 µm IK 75 TGX-221 IC Berghausen E et al., unpublished

37 Growth Factor-Induced roliferation of hasmcs Depends on I3K subunit p110 Activity BrdU Incorporation (fold increase) BrdU incorporation (fold increase) BrdU incorporation (fold increase) DGF-BB 30ng/ml 3nM 10nM 30nM 100nM 300nM 1µM 3µM 10µM Imatinib * * * Growth factor mixture (DGF- BB 30ng/ml, FGF 2ng/ml, EGF 0,5 ng/ml, Insulin 0,5µg/ml, FCS 5%) Sorafenib Imatinib MGFs (DGF-BB 30ng/ml, FGF 2ng/ml, EGF 0,5 ng/ml Insulin 0,5µg/ml FCS 5%) 6 Berghausen E: 4 The I3 kinase isoform p110 alpha is essential * for growth factor induced 2 vascular remodelling in pulmonary hypertension 0 Monday, Aug , 16:30 h, room Beirut Zone E 30 nm 100 nm 300 nm 1 µm 3 µm 300 nm 3 µm IK 75 TGX nm 3 µm IC Berghausen E et al., unpublished

38 Current Questions about TKIs in (A)H EFFICACY: TKIs (Imatinib) only effective in advanced AH? otential limitations of effectiveness? A role for TKIs in other forms of H? SAFETY: Cardiotoxicity? Induction of AH by TKIs?

39 Diagnostic Algorithm Common causes of H: Left Heart Disease Chronic Lung Disease CTEH ulmonary Arterial Hypertension (Group 1) Galiè et al., Eur Heart J 2009; 30:

40 ulmonary Vascular Remodeling in Some atients with H owing to Left Heart Disease LHI + H LHI - H Delgado, Rev Esp Cardiol 2010; 63:

41 Increased Expression of DGF Receptors in Endarterectomy Tissue of atients with CTEH Ogawa A et al., Am J hysiol Cell Mol hysiol 2009; 297: L666-L676

42 Current Questions about TKIs in (A)H EFFICACY: TKIs (Imatinib) only effective in advanced AH? otential limitations of effectiveness? A role for TKIs in other forms of H? SAFETY: Cardiotoxicity? Induction of AH by TKIs?

43 Cardiotoxicity of Imatinib Mesylate in Animal Models and Humans Mice Humans Kerkelä R et al., Nat Med 2006; 8:

44 Cardiotoxicity associated with the Tyrosine Kinase Inhibitor Sunitinib Change in LVEF (n=36) LVEF Chu TF et al., Lancet 2007; 370:

45 reliminary Clinical Data on Sorafenib in atients with AH Gomberg-Maitland M et al., Clin harmacol Ther 2010; 87:

46 reliminary Clinical Data on Sorafenib in atients with AH Gomberg-Maitland M et al., Clin harmacol Ther 2010; 87:

47 Imatinib in AH with Inadequate Response to Established Therapy hase II Trial All atients Subgroup Analysis Ghofrani HA et al., Am J Respir Crit Care Med 2010; 182:

48 Tyrosine Kinase Inhibitors and Cardiotoxicity TKIs: Cardiotoxicity remains a concern with TKIs Cardiotoxic effects not due to inhibiton of DGF signaling With regard to imatinib: CHF is a rare event in patients receiving imatinib as anti-cancer agent, but occurs more frequently in patients with pre-existing cardiac conditions (Druker et al., NEJM 2006; Atallah et al., Blood 2007) No signals indicating detrimental effects on cardiac function in case studies and in phase II study in AH (Ghofrani et al., Am J Respir Crit Care Med 2010) Close monitoring of cardiac function is warranted

49 Current Questions about TKIs in (A)H EFFICACY: TKIs (Imatinib) only effective in advanced AH? otential limitations of effectiveness? A role for TKIs in other forms of H? SAFETY: Cardiotoxicity? Induction of AH by TKIs?

50 Fully Reversible AH Associated with Dasatinib Treatment for CML Dumitrescu D et al., Eur Respir J 2011; 38:

51 Fully Reversible AH Associated with Dasatinib Treatment for CML Hennigs JK, Keller G, Baumann HJ, Honecker F, Kluge S, Bokemeyer C, Brümmendorf TH, Klose H. Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension? BMC ulmonary Medicine 2011; 11: 30 Rasheed W, Flaim B, Seymour JF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res 2009; 33: Mattei D, Feola M, Orzan F, Mordini N, Rapezzi D, Gallamini A. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient Bone Marrow Transplant 2009; 43: Dumitrescu D et al., Eur Respir J 2011; 38:

52 Tyrosine Kinase Inhibitors TAKE HOME GF signaling by RTKs identified as critical therapeutic target (hypoxia!) Reverse Remodeling TKIs are potential additional treatment option in AH (anti-proliferative) Thus far, only shown in severe AH earlier stages of the disease (time?) other forms of H (eg. CTEH) better define the role of different RTKs Future: downstream targets otential problems: Cardiotoxicity Tolerability Induction of AH Kinase profile of TKIs!

53 Tyrosine Kinase Inhibitors ulmonary hypertension: The future has just begun... Horst Olschewski