THERAPEUTICALLY TARGETING NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE NAMPT. Iris Gehrke, PDF Dr. Versha Banerji s lab CancerCare Manitoba Winnipeg

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1 THERAPEUTICALLY TARGETING NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE NAMPT Iris Gehrke, PDF Dr. Versha Banerji s lab CancerCare Manitoba Winnipeg

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3 Nicotinamide phosphoribosyltransferase NAMPT Alternative names: Pre B-cell colony enhancing factor (PBEF), Visfatin NAD salvage synthesis NMN NA NAD-using enzymes NAD NAD: nicotinamide adenine dinucleotide NMN: nicotinamide mononucleotide NMNAT: NMN adenylyltransferase Involved in: aging, atherosclerosis, diabetes, acute lung injury, sepsis, circadian rhythm

4 NAMPT dysregulation in cancer NAD: nicotinamide adenine dinucleotide NMN: nicotinamide mononucleotide NMNAT: NMN adenylyltransferase MTHFD2: Methylen tetrahydrofolate dehydrogenase Sirt11: Silent information regulator 1 upregulated in several cancers and confers drug resistance NAMPT as negative prognostic indicator in glioblastoma inhibition of NAMPT has anti-cancer effects

5 NAMPT-inhibitor FK866 substrate-competitive no cell intoxication leads to depletion of energy stores safe, well tolerated in clinical studies Hasman M et al Cancer Research 2003, Holen K et al Invest New Drugs 2008

6 NAMPT inhibition in hematopoietic malignancies Cancer Cell Line Profiling FK866 GMX-1778 hematopoietic and lymphoid tissue FK866 sensitive GMX-1778 unresponsive Basu A et al, Cell, 2013 CLL sensitive unresponsive Herishanu Y et al, Blood, 2011 NAMPT

7 Objective To evaluate FK866 as potential treatment option for CLL patients including those with high risk features

8 NAMPT is upregulated in PB CLL cells Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

9 FK866 selectively reduces viability in CLL cells ~ 37 fold CLL Ctrl PBMCs Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

10 FK866 reduces cellular energy content Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

11 On target effect of FK866 n=3 n=11 n=6 Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

12 FK866 response is dependent on CD38 and LDT Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

13 FK866 activity in CLL cells from high risk patients I Treatment resistant/relapse r = relapsed p = CD38 Dose Reduction Index Chou TC, Talalay P. Adv Enzyme Regul 1984 Chou TC. Pharmacol Rev 2006 Fraction Dead Cells Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

14 FK866 activity in CLL cells from high risk patients II del17p (n=5) (n=11) Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

15 FK866 activates apoptotic signaling Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

16 FK866 induces mitochondrial dysfunction Mitochondrial Membrane Potential Reactive Oxygen Species Poster by Eric Bouchard Gehrke I, Bouchard ED, Beiggi S, et al. Clin Cancer Res, 2014 Sep 15;20(18):

17 Effect of FK866 on DNA damage signaling < < H. Niiada et al, Mutagenesis, 2005 Work in progress

18 Combination treatment strategies with FK866 CI Bendamustine Chlorambucil Fludarabine FK866 [nm] [µm] [µm] [µm] CI < 0.80 Synergy 2.5 CI Additivity 5 CI > 1.20 Antagonism 10 Chou TC, Talalay P. Adv Enzyme Regul 1984 Chou TC. Pharmacol Rev 2006 n=6 CI: combination index Work in progress

19 Summary and conclusions I CLL cells overexpress the FK866 target NAMPT CLL cells are ~37fold more sensitive to FK866 than PBMCs from control donors FK866 reduces cellular energy levels in an on-target manner FK866 induces apoptotic signaling FK866 leads to mitochondrial dysfuntion FK866 promotes ROS generation and DNA damage response

20 Summary and conclusions II FK866 neither induces p21, nor is influenced by Nutlin and may therefore act independent of p53 FK866 is highly effective in vitro in samples with del17p adverse prognostic markers in vitro Fludarabine-resistance FK866 may sensitize CLL cells to standard drugs FK866 may be suitable for (combination) therapy of CLL patients including those with high risk features

21 Acknowledgments V. Banerji Lab Versha Banerji Eric Bouchard Armando Poeppl Cheryl Peltier CLL Group Spencer Gibson James Johnston Sara Beiggi DNA Damage and Repair Sachin Katyal Tumor Bank Donna Hewitt Mandy Squires Michelle Queau Kristin Hunt Thanks to all patients, who donated their blood! MERGE

22 Thank you for your attention!

23 CLL microenvironments, future directions Bone marrow p= * Lymph node Nurse like cells NLCs Work in progress

24 Patient characteristics