La nicchia ipossica come target terapeu1co nel microambiente del mieloma mul1plo

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1 La nicchia ipossica come target terapeu1co nel microambiente del mieloma mul1plo Nicola Giuliani, PhD, MD Hematology, University of Parma

2 OSTEOBLAST NICHE: ROLE OF HYPOXIA

3 BONE MARROW (BM) MICROENVIRONMENT AND MULTIPLE MYELOMA (MM) CELLS Osteoblast Bone forma)on inhibi)on Osteoclast Bone resorp)on MM cell Stromal cells Cytokine produc)on Lymphocyte Immunosuppression Endothelial cell Angiogenesis

4 PATHOPHYSIOLOGY OF OSTEOBLAST SUPPRESSION IN MM MM cell IL- 7, IL- 3 MM cell Mesenchymal/ stromal cell VCAM- 1 VLA- 4 VLA- 4 VCAM- 1 COL I - ALP - OC - OPN - T cell Runx2/Cbfa1 IL- 3 DKK- 1, SFRP2, SFRP3 WNT? Immature Osteoblast COL I ++ ALP ++ OPN + OC + Mature Osteoblast Ehrlich LA-Giuliani N, Blood, 2005 Giuliani N et al Blood, 2006 Giuliani N et al Blood, 2005 Tian E et al. NEJM, 2003 Giuliani N et al. Cancer Res, 2007

5 MECHANISMS INVOLVED IN MULTIPLE MYELOMA ANGIOGENIC SWITCH IGF-1 IL-6 VEGF IL-6 OPN OPN HOXB7 ING4 MM cell VEGF IL-8 TGFβ HGF bfgf p0 2? ANG-1 OPN Stromal cells Giuliani N et al Blood 2003 Colla S et al. Leukemia 2005 Colla S et al Blood 2007 Storti P et al Leukemia 2011 VEGF bfgf TGFβ OPN TIE2 ANGIOGENESIS Blood vessel

6 HYPOXIA- INDUCIBLE FACTOR (HIF)- 1α: A KEY TRANSCRIPTION FACTOR NORMOXIA Angiogenesis HYPOXIA

7 PREVIOUSLY REPORTED The bone marrow microenvironment is hypoxic in MM pa)ents. 1 HIF- 1α is overexpressed by MM cells in the bone marrow. 1 Under normoxic condi)on, some HMCLs (JJN3, U266) and the 28% of CD138+ cells from MM pa)ents express HIF- 1α showing an oxygen- independent regula)on. 1, 2 Hif- 1α protein level and ac)vity in MM cells under normoxic HIF- 1α condi)ons modulates is regulated the pro- angiogene)c by oncogenic profile c- Myc of to MM influence cells. 1 VEGF secre)on and angiogenic ac)vity. Hypoxia and HIF- 1α expression leads to the forma)on of giant osteoclasts during mouse embryogenesis 3 and enhance osteoly)c bone metastases of breast cancer Colla S et al. Leukemia Zhang J et al. Cancer Res Bozec A et al. Nature Hiraga T et al. Cancer Res 2007

8

9 AIM OF STUDY Inves)gate the effect of a stable HIF- 1α inhibi)on in MM cells on cell prolifera)on, survival and on MM- induced angiogenesis and osteolysis either in vitro and in vivo.

10 LENTIVIRAL STABLE INHIBITION OF HIF- 1α JJN3/RPMI MISSION shrna anti HIF-1α Sigma-Aldrich RPMI +10% FBS + puromycin 4 ug/ml for 15 days

11 SPECIFICITY OF VECTORS ANTI- HIF1- α

12 EFFECT OF HIF1- α SUPPRESSION ON HMCLs PROLIFERATION AND SURVIVAL JJN3 RPMI JJN3 RPMI

13 DOWN- REGULATION OF PRO- ANGIOGENIC MOLECULES OF JJN3 BY HIF- 1α SUPPRESSION Modulated Genes Microarray data JJN3- an)- HIF- 1α vs JJN3- plko NORMOXIA COMMON HYPOXIA Pro- angiogenic genes down- regula)on VEGF IL8 CCL2 MMP9

14 DOWN- REGULATION OF PRO- ANGIOGENIC MOLECULES OF JJN3 BY HIF- 1α SUPPRESSION

15 EFFECT OF HIF- 1α INIBITION ON PRO- OSTEOCLASTOGENIC CYTOKINES PRODUCTION IN HMCLs

16 1. TUMOR GROWTH IN IN VIVO MODEL 1. Subcutaneous injec)on in NOD- SCID mice with JJN3 wt, JJN3- plko, JJN3- an)- HIF- 1α of three groups of 6 animals. 2. A`er 20 days the mice were sacrificed.

17 IMMUNOHISTOCHEMISTRY

18 2. TUMOR GROWTH IN IN VIVO MODEL 1. Intra- )bial injec)on in SCID and NIH- III nude mice with saline solu)on, JJN3- plko, JJN3- an) HIF- 1α. 2. A`er 3-4 weeks the mice were sacrificed.

19 HIF- 1α SUPPRESSION BLUNTS ANGIOGENESIS IN THE IN VIVO MODEL

20 HIF- 1α SUPPRESSION INHIBITS BONE DESTRUCTION IN THE IN VIVO MODEL

21 SUMMARY We show that: A selec)ve and stable HIF- 1α inhibi)on did not directly induce a significant effect on MM cell prolifera)on and survival in vitro. HIF- 1α suppression modified the pro- angiogenic and osteoclastogenic profiles of MM cells either under normoxic or hypoxic condi)ons.

22 SUMMARY A strong effect on tumor growth in both models (subcutaneous and intra- )bial) by HIF- 1α suppression mainly due to the inhibi)on of angiogenesis. In the intra- )bial bone model, HIF- 1α suppression affects MM- induced in vivo forma)on of osteoly)c bone lesions. These results suggest that HIF- 1α is a poten)al therapeu)c target in MM microenvironment.

23 HIF- 1α AND DRUGS v The sulfonanilides ELR510490, ELR510444, ELR and ELR completely inhibit prolifera)on of all tested MM cell lines at nm concentra)ons. The compounds show a pronounced effect on the HIF1A signaling pathway. v EZN- 2968: a RNA antagonist that specifically binds and inhibits the expression of HIF- 1A mrna. Ongoing phase I studies in adults with advanced solid tumors.

24 MM MICROENVIRONMENT AND NEW DRUGS IN MM THERAPY CYTOTOXICITY ThaI / Len. CTL NK cells IL-2 IFNγ GROWN INHIBITION AND APOPTOSIS PBMC CITOKINES INHIBITION ThaI / Len. Bortezomib Len. Bortezomib MM CELLS ADHESION INHIBITION ThaI / Len. Bortezomib IL-6 IGF-1 VEGF SDF-1α IL-1β VEGF bfgf ThaI / Len., Bortezomib Blood Vessels STROMAL cells ANTI-ANGIOGENIC

25 HIF- 1α AND THE NEW ANTI- MM DRUGS v BORTEZOMIB Repressed HIF- 1a ac)vity by inhibi)ng the recruitment of p300 coac)vator à VEGF down- regula)on. v LENALIDOMIDE Shin Dh et al. Blood 2008 An)oxidants protect MM cells from bortezomib- mediated cell death. GCLM and HMOX1 are upregulated a`er treatment with Bortezomib. Tight links between sensi)vity to proteasome inhibi)on and redox homeostasis in MM cells. Nerini-Molteni S et al. Br J Haematol 2008 Strong inhibitory effect on hypoxia- induced endothelial cell forma)on of cords and HIF- 1α expression. Lu L et al. Microvasc Res 2009

26 EFFECT OF HIF1- α INHIBITION AND DRUGS ON HMCLs PROLIFERATION AND SURVIVAL

27 ONGOING STUDY In vivo mouse model in NOD- SCID mice Subcutaneous injec)on with JJN3wt, JJN3 plko and JJN3 an)- HIF1α Mice treatment with Lenalidomide and other IMIDs Synergis)c/addi)ve effects on tumors development?

28 EMATOLOGIA E CTMO, PARMA (Dir. Franco Aversa) LABORATORY STAFF Paola Stor) Marina Bolzoni Denise Toscani Daniela Guasco CLINICAL STAFF Benedeia Dalla Palma Dipar)mento di Salute Animale, PARMA Gaetano Donofrio U.O. di Anatomia Patologica, PARMA Eugenia Martella Cris)na Mancini THANKS TO Ematologia, IRCCS POLICLINICO, MILANO Luca Agnelli Ka)a Todoer) Antonino Neri MD Anderson Cancer Center, TX, USA Simona Colla Hematology, University of Indiana, USA G. Dave Roodman Laboratorio AIRC, Oncologia, G. Gaslini, Genova Irma Airoldi

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