Low Molecular Weight Heparins In Cancer Present Future and Beyond. I. ELALAMY Service d Hématologie Biologique HOPITAL TENON - UPMC PARIS INSERM U938

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1 Low Molecular Weight Heparins In Cancer Present Future and Beyond I. ELALAMY Service d Hématologie Biologique HOPITAL TENON - UPMC PARIS INSERM U938

2 Disclosures Conferences Clinical Studies Board Daiichi-Sankyo NovoNordisk Mitsubishi Pharma Shire Boehringer-Ingelheim Celgene Pfizer Bayer HealthCare Astra-Zeneca Sanofi-Aventis BMS GSK LFB Leo-Pharma x x x

3 AGENDA 1. Cancer an acquired hypercoagulable state with multicellular interactions? 2. Missing link between tumour angiogenesis and coagulation? 3. LMWH heterogeneity and structure-activity relationship? 4. LMWH anti-tumoral potency? 5. LMWH and survival benefit?

4 Contribution of Cell Interaction to Tumour Progression investigation of platelets, their surface receptors, released products and their critical influence on coagulation pathways, will help to elucidate the mechanisms of tumour metastasis, as well as vascular development and stability that support metastatic growth. GP: glycoprotein; ICAM: intercellular adhesion molecule; PAR: protease-activated receptor; PSGL1: P- selectinglycoprotein ligand 1; slea: sialyl Lewis a antigen; slex: sialyl Lewis x antigen; VCAM: vascular cell adhesion molecule; VWF: von Willebrand factor Gay L et al, Nature Rev Cancer 2011; 11:

5 Thrombin and Angiogenesis Prothrombin Thrombin Angiogenesis Shape Change Permeability Proliferation Proteolysis bfgf: basic fibroblast growth factor; MMP: matrix metalloproteinase; MAPk: mitogen-activated protein kinase; PAR: protease-activated receptor; PKC: protein kinase C; TF: tissue factor; TFPI: tissue factor pathway inhibitor; VEGF: vascular endothelial growth factor Rickles et al, Chest 2003;124: 28S-38S

6 Coagulation and Angiogenesis Prothrombin Thrombin Angiogenesis Proangiogenic Fragments Proliferation Migration Metastasis bfgf: basic fibroblast growth factor; FPA: fibrinopeptide A; FPB: fibrinopeptide B; PDGF: plateletderived growth factor; VEGF:vascular endothelial growth factor Rickles et al, Chest 2003;124: 28S-38S

7 LMWH Production Natural GAG Porcine mast cells UFH LMWH *Depolymerisation VERY LMWH Pentasaccharide domain Polysaccharide chains ULTRA LMWH GAG: glycosaminoglycan; LMWH: low molecular weight heparin; UFH: unfractionated heparin

8 BUT, does it mean 70% of the chains are useless? Pharmacological Activities Clinical Impact 30% Anticoagulant? Anti-a Anti-IIa TFPI?? Venous thrombosis Arterial thrombosis 70% Nonanticoagulant??? P-selectin inhibition VEGF, TGF Other (anti-inflammatory, antiplatelet) In addition depending of the GAG chains length and composition they interact with other components They exchange with natural GAG of the receiver endothelium They bind to receiver molecules They bind to receiver cells??? Angiogenesis Bleeding Immunogenicit y GAG: glycosaminoglycan; TFPI: tissue factor pathway inhibitor; TGF: transforming growth factor; VEGF: vascular endothelial growth factor Adapted from Lovenox pharmacopeia

9 LMWH heterogeneity Heparin Mean MW (Da) Anti-a/ anti-iia Anti-a activity/ mg UFH UI Tinzaparin IU Dalteparin IU Enoxaparin IU Nadroparin IU Bemiparin IU Anti-IIa activity/ mg UI 50 IU IU IU IU 5-10 IU LMWH: low molecular weight heparin; MW: molecular weight; UFH: unfractionated heparin European Pharmacopoeia 2010 Fareed et al Chest 2008

10 Thrombin Generation and Cancer Cell Lines Platelet poor plasma with 100 cancer cells/ml BPC3 (pancreas cancer) control MCF7 HT29 (colon cancer) A549 (lung cancer) MCF7 (breast cancer) thrombin (nm) BPC3 A549 HT time (min) Gerotziafas GT et al. Thromb Res Jun;129(6):779-86

11 Differential Effect of LMWH on Thrombin Generation Rate in the Presence of BPC3 in Plasma 0.40 BPC3 (pancreas) Velocity index IC50 (anti-a IU/ml) Tinzaparin Enoxaparin Nadroparin BPC 3 ( cells / µl ) Gerotziafas GT et al Curr Vasc Pharmacol. 2012

12 Heparin-Induced Endothelial TFPI Release UFH or LMWH TF-VIIa TFPI TFPI Pro-coagulant Effects Non-Coagulant Effects Thrombosis Inflammation, Angiogenesis LMWH: low molecular weight heparin; TF: tissue factor; TFPI: tissue factor pathway inhibitor; UFH: unfractionated heparin Moussa SA amd Petersen LJ, Thromb Haemost 2009;102(2):258-67

13 LMWH and angiogenesis Chick embryo aortic ring model 1 HUVEC model 2 Control D5 LMWH D5 HUVEC: human umbilical vein endothelial cells; LMWH: low molecular weight heparin 1. Fernandez PM et al. Semin Thromb Hemost Feb;30(1): Mousa SA & Mohamed S. Thromb Haemost 2004;92:627 33

14 Hetero-Complexes and Endothelial Rolling = Hypercoagulability Inducers Neutrophil Polymorphonuclear Monocytes Ac1va1on Ac1va1on PSGL- 1 CD62 PAF PSGL- 1 CD62 CD40L Endothelium Ac1vated platelet Adapted from Gawaz M. Thieme Verlag 2001

15 Variable in vitro Selectin-Blocking Activities of LMWH Percent of control binding An1- a IU/ml UFH UFH Fondaparinux Fondaparinu x Enoxaparin Dalteparin Enoxaparin Dalteparin Tinzaparin Tinzaparin LMWH: low molecular weight heparin; UFH: unfractionated heparin Adapted from Stevenson JL et al. Clin Cancer Res 2005;11:

16 CRP Levels in Cancer Patients Treated with Enoxaparin 10 7,5 CRP (mg/ml) 5 n=101 2,5 0 ONCENObaseline ONCENO- 3 months Normal Controls CRP: C reactive protein Mousa SA. Methods Mol Med. 2004;93: Deitcher SR et al..clin Appl Thromb Hemost. 2006;12(4):389-96

17 IL6 Levels in Cancer Patients Treated with Enoxaparin IL-6 (pg/ml) n=101 0 ONCENObaseline ONCENO- 3 months Normal Controls IL: interleukin Mousa SA. Methods Mol Med. 2004;93: Deitcher SR et al..clin Appl Thromb Hemost. 2006;12(4):389-96

18 Heparanase-Mediated Extravasation of Blood-Borne Cells T-lymphoma cells without (top) or with (bottom) platelets ECM: extracellular matrix; HS: heparan sulfate; HSPG: HS-proteoglycan Vlodavsky I & Friedmann Y. J Clin Invest 2001;108:341 7

19 LMWH and Extracellular Matrix Proteases Modelling of extracellular matrix Endo-β glycosidases ( cysteine or serine proteases, MMPs) Heparan sulfate proteoglycan degradation and tumour invasion Aggrecanases and heparanases modulation by LMWH => reduction of metastatic potential Tinzaparin most potent inhibitor of aggrecanase (tinzaparin >> nadroparin >> enoxaparin) LMWH: low molecular weight heparin MMP: matrix metalloproteinase Arvatz G et al. Cancer Metastasis Rev 2011;30(2): Vlodavsky I et al. Thromb Res 2007;120(Suppl. 2):S112 20

20 LMWH Multifocal Anti-Tumoral Actions Page content LMWH: low molecular weight heparin; P:platelets; TC: tumour cells Prandoni P et al. Lancet Oncol 2005;6:401 10

21 LMWH Poly-Pharmacological Impact Site of actions Pharmacological impact AT-dependent plasmatic effects AT-independent vascular effects Cell adhesion molecules Fibrinolytic system Inflammation Matrix-degrading enzymes Anti-a, Anti-IIa, modulation of procoagulant factors TFPI, NO, vwf Selectins (P,L,E), ICAM-1, VCAM-1 tpa, PAI-1 TNFα, IL-6 Heparanases, aggrecanases AT: antithrombin; ICAM: intercellular adhesion molecule; IL:interleukin; LMWH: low molecular weight heparin; NO: nitric oxide; PAI-1: plasminogen activator inhibitor-1; TFPI: tissue factor pathway inhibitor; tpa: tissue plasmiogen activator; TNFα: tumour necrosis factor α; VWF: von Willebrand factor Mousa SA & Petersen LJ. Thromb Haemost 2009;102:258 67

22 LMWH Heterogeneity and Multi-Target Agents

23 LMWH and Survival CI: confidence interval; M-H: Mantel Haenszel; SCLC: small cell lung cancer Akl EA et al. Cochrane Database of Systematic Review 2011:CD006652

24 LMWH and Survival Therapy Median survival, months p Overall population Good prognosis population FAMOUS 1 (2002) Dalteparin Placebo SCLC study 2 (2003) Dalteparin Placebo MALT 3 (2003) Nadroparin Placebo CLOT 4 (2003) Dalteparin OAC HR = hazard ratio; OAC = oral anticoagulant 1Kakkar AK, et al. J Clin Oncol. 2004;22:1944-8; 2Altinbas M, et al. J Thromb Haemost. 2004;2: ; 3Klerk CP, et al. J Clin Oncol. 2005;23:2130-5; 4Lee AY, et al. N Engl J Med. 2003;349:146-53

25 Do LMWH have an Anti-Myeloma Effect? Analysis On Individual Data From Three Randomized Studies: GIMEMA, Nordic and Turkish Myeloma Study Groups MPT MPT+LMWH p n Age y 73 (55-89) 72 (63-89) Male 52.3% 55.3% 0.58 Survival Median y 31 (24-39) 45 (38-52) Survival at 1 Year 65.9% 70.5% Survival at 5 Years 18.5% 47.7% GIMEMA: Gruppo Italiano Malattie EMatologiche delladulto (Italian Group for Haematological Diseases in Adults) LMWH: low molecular weight heparin; MPT: melphalan, prednisone and thalidomide Beksac M & al. Abstract 3970 : ASH 2011

26 Conclusion Cancer => Induced-Prothrombotic Disease Thrombotic Process <=> Tumour Proliferation LMWH: first line and long term strategy Dissemination and implementation of good clinical practice for VTE management, 2nd cause of death in cancer patients, is a major public health priority. Facing all Faces

27 «Thrombosis and Cancer» STAY AWARE!