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TARGETING STEM CELLS AND ERADICATING CML Pr A.G. Turhan, MD,PhD

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Presentation on theme: "TARGETING STEM CELLS AND ERADICATING CML Pr A.G. Turhan, MD,PhD"— Presentation transcript:

1 TARGETING STEM CELLS AND ERADICATING CML Pr A.G. Turhan, MD,PhD
TARGETING STEM CELLS AND ERADICATING CML Pr A.G. Turhan, MD,PhD Division of Laboratory Hematology and Oncology, Inserm U935 “Models of Malignant and Therapeutic Stem Cells” University of Poitiers / University Paris Sud 11, France

2 FROM « LEUCOCYTHEMIA » TO TARGETED THERAPIES
1996 Imatinib (IM) IRIS Complete Remissions Resistances Mutations BCR-ABL Novel TKI Dasatinib Nilotinib 1845 Bennett, Virchow 1974 t (9;22) J. Rowley 1960 Ph Chromosome Nowell & Hungerford 1984 BCR-ABL

3 HEMATOPOIETIC STEM CELLS (HSC)
Quiescence (G0) ASYMMETRICAL DIVISION Self-renewal Differentiation OU ProgenitorsP HSC Mature Cells: Red blood cells, Platelets, Granulocytes

4 HSC: MAJOR PROLIFERATIVE ACTIVITY
Granulocytes Red blood cells Platelets # of RBC produced / day (Adult 70kg)= ~ 10 Billion cells / hour

5 CML: A STEM CELL DISEASE WITH CLONAL EVOLUTION
Ph+ Quiescent Acquisition Of BCR-ABL Ph+ Ph+ Clonal Evolution Ph+/ACA Normal HSC Differentiation Arrest Blast Crisis Differentiation to terminal Progeny (Granulocytes, Erythro-Mega, B cells) Tough et al, Lancet 1963 Whange et al, Blood 1963 Fialkow et al PNAS 1967

6 NORMAL OR CML HSC CAN BE ASSAYED ONLY USING INDIRECT METHODS
Long-term Culture 6 Weeks culture: LTC-IC assay Human CD34+ cells 2-3 months: NOG-IC assay Bone marrow Spleen of mice Method 2: Engraftment In immunodeficient mouse Detection Of Human cells

7 DYNAMICS OF STEM CELL PROLIFERATION IN CML
Marrow Stem cells and Progenitors in permanent cycle Persistence of normal HSC Small numbers of leukemic stem cells Presence of a highly quiescent fraction At diagnosis Blood Mobilization of high numbers of leukemic progenitors and LTC-IC Into blood Coulombel et al NEJM 1983 Turhan et al, Blood 1989 Udomsakdi et al PNAS 1990 Holyoake et al, Blood 1999

8 CML STEM CELLS IN THE ERA OF TARGETED THERAPIES
WHY SOME PATIENTS IN COMPLETE MOLECULAR RESPONSE RELAPSE UPON IM DISCONTINUATION? Mahon et al, Lancet Oncol 2010

9 COEXISTENCE OF MULTIPLE MECHANISMS OF IMATINIB RESISTANCE IN Ph1+ STEM CELLS
CD34+ Ph1+ Diagnosis CD34+ Ph1+ Cell Separation Cell Separation DIVIDING QUIESCENT Primitive HSC Committed cells + GLEEVEC Expression BCR-ABL + GLEEVEC Expression MDR (Drug Resistance) Leukemic Cell death Leukemic cell Survival+++ Graham et al, Blood 2002 Jiang et al, Leukemia 2007

10 KINETICS OF LEUKEMIC CELL REDUCTION
IN CML ON TKI THERAPY 1012 BCR-ABL/ABL RATIO % Hematological Response 100 Cycling Amplified / Cells & Progenitors TKI-S 10 Ph1+ 1 MMR 0.1 RQ-PCR+ Active Stem 0.01 0.001 CMR 0.0001 106 RQ-PCR - Quiescent / Primitive Stem TKI-R 1 ?

11 EVALUATION OF BCR-ABL EXPRESSING LSC IN COMPLETE MOLECULAR RESPONSE
Bone Marrow Aspirate in CMR Induced by: IFN (n=3) (OFF Rx) IFN , IM (n=2) (OFF Rx) IM, then DASA (n=1) (ON Rx) Purification CD34+Cells MS5 LTC-IC HoxB4/MS5 (Amplification Of HSC) MED CHANGE LTC-IC DERIVED CFU-C 220 colonies / patient Analysis of Stem cell-derived colonies by PCR Chomel et al, Blood 2011

12 Week 5: LTC-IC-derived CFU
VARIABLE AMOUNTS OF BCR-ABL EXPRESSING STEM CELLS PERSIST IN COMPLETE REMISSION Pt Previous Therapies D0 : Clonogenic Week 5: LTC-IC-derived CFU CFU-Cs Pools de 10 CFU-Cs Individual Pools of 10 LTC-ICs MS-5 MS5/HOXB4 1 IFN-a 0/20 1/18 4/31 1/8 2 1/19 2/39 4/40 * 3 9/19 11/16 1/30 9/30 * 4 IFN-a; IM 2/20 0/19 5 1/20 2/17 * 6 IM, DASA 1/17 23/24 12/43 Chomel et al, Blood 2011

13 Vs DASATINIB / NILOTINIB
DO BCR-ABL EXPRESSING STEM CELLS PERSIST IN PATIENTS IN CMR ON IM vs TKI2 ? IMATINIB Vs DASATINIB / NILOTINIB « PERSISTEM » STUDY

14 PERSISTEM STUDY: (Jan 2012)
CMR > 1-2 YEARS INDUCED BY IM : 17 patients INDUCED BY DASATINIB 2 patients Goal: DETECTION & QUANTIFICATION OF BCR-ABL EXPRESSING LSC WHAT IS THE FREQENCY OF LSC MRI POST- IM VS TKI2 ? POST NILOTINIB VS DASATINIB ?

15 MECHANISMS OF SURVIVAL OF Ph1+ STEM CELLS IN THE PRESENCE OF TKI?
« Oncogene- Independence » ABL-K mutations Inefficent drug delivery (transport) Alternate mechanisms of survival Survival signals Quiescence signals « LEUKEMIC NICHE »

16 PRIMITIVE HSC IN CML SURVIVE DESPITE INHIBITION OF ACTIVITY OF BCR-ABL
CELL DEATH « Oncogene Addiction » + TKI BCR-ABL + HSC + TKI GROWTH FACTORS SURVIVAL CELLS DO NOT NEED BCR-ABL TO SURVIVE: « Oncogene Independence » HOW ? Corbin et al, JCI 2010

17 CML STEM CELLS: HOW TO BECOME « ONCOGENE-INDEPENDENT ? »
Compensation of TK-induced signalling by other pathways -Niche -Intrinsic signalling Down-regulation of BCR-ABL expression

18 BCR-ABL EXPRESSION IN PROGENITORS AND STEM CELLS AT DIAGNOSIS VS REMISSION
100 10 1 0.1 1000 0.01 p=0.0024 p<0.0001 BCR-ABL/ABL IS (%) TKI-resistant patient with a T315I mutation BCR-ABL-positive hematopoietic colonies CML patients in UMRD > 3years CFU-Cs n=163 median=52.1 LTC-ICs n=58 Median=51 n=13 Median=12 n=55 Median=0.7 Kumari et al Blood 2011 Chomel et al, Blood 2012

19 CML STEM CELL TARGETING
STRATEGIES CONDITIONS 1- IDENTIFICATION OF TARGETS WITH PREFERENTIAL EXPRESSION ON LEUKEMIC STEM CELLS (NO OR LITTLE EXPRESSION ON NORMAL CELLS) 2- DEVELOPMENT OF NOVEL COMPOUNDS 1- WAKE-UP of DORMANT CELLS ? G-CSF PLERIXAFOR 2- TARGET QUIESCENCE / SELF-RENEWAL PATHWAYS 3-IMMUNOMODULATION

20 HOW TO TARGET SELF-RENEWAL / QUIESCENCE PATHWAYS CML STEM CELLS ?
SHH /SMO Gli,Ptch Self-renewal Expression Increased in CML AHI-1 Jak2 STAT5 SIRT Complex BCR-ABL PML FOXO Quiescence TGF-b FOXO Wnt/b-catenin Maintenance Of LSC Alox5a Expression induced In CML HSC DRUGGABLE TARGETS Naka et al, Nature 2010 ; Zhao et al, Cancer Cell 2007; Dierks et al, Cancer Cell 2008; Ito et al, Nature 2008; Chen Y et al, Nat Genet 2009; Zhao et al, Nature 2009 Zhou et al, J Exp Med 2008;

21 TARGETING STAT5 IN CML EFFECTS ON STEM CELLS ? Pimozide
Differential effect On Normal Versus Leukemic progenitors EFFECTS ON STEM CELLS ? Nelson et al, Blood 2011

22 TARGETING AUTOPHAGY IN CML STEM CELLS Can we Inhibit Autophagy
A cell survival mechanism Under stress CD34+ CML cells (n=3) Leukemic cell TKI TKI Majority Of cells: DEATH SOME CELLS: SURVIVAL BY AUTOPHAGY Can we Inhibit Autophagy To kill CML stem cells ? Bellodi; JCI (2009):

23 NOVELS DRUGS TARGETING POTENTIALLY TARGETING CML STEM CELLS
CLINICAL STUDY SHH/ SMO SMO INHIBITORS BMS ALOX5a ZILEUTON UNIV MASS HDAC LBH 589 NOVARTIS PML ARSENIC TRIOXIDE ? STAT5 PIMOZIDE

24 CONCLUSIONS & QUESTIONS
1- CML STEM CELLS: LONG-TERM PERSISTENCE AND QUIESCENCE -Low BCR-ABL in persistent cells: Potential Protective Factor from genetic instability and progression -Elucidation of the mechanisms of « dormancy »: -Novel strategies of targeting residual cells are in development

25 QUESTIONS (2) 2-WHAT ARE THE EFFECTS OF TKI2 AS A FIRST LINE THERAPY ON LSC ? 3- WHAT IS THE DYNAMICS OF Ph+ LSC: -On TKI therapy ? -Off TKI therapy? Stem cell monitoring is required as a decisional tool in TKI discontinuation trials

26 TKI alone -Single agent TKI +
PERSPECTIVES DECADE: CURATIVE STRATEGIES TKI alone -Single agent -Multi-target/Anti Mutants (T315I) IFN-a Anti-SMO ? Anti-PML « Niche »therapy Arsenic TO ? Autophagy TKI + Heterogenity of the disease Predictive tests Stem cell Monitoring and follow-up in CMR

27 UNIVERSITY OF POITIERS
DIVISION OF LABORATORY HEMATOLOGY-/ INSERM U935 A.G.Turhan JC Chomel ML Bonnet N Sorel A Le Corf MC Meunier D Aggoune C. Bouneau M. Voldoire UNIVERSITY PARIS11 DEPARTMENT of HEMATOLOGY INSERM U 935 Human IPS /ES Core Facility A.Bennaceur-Griscelli M. Mitjavila F Griscelli E. Oberlin I Sloma S. Flamant L Tosca O. Feraud E.Gobbo D.Divers S. El Marsafy N Oudrhiri G Tachdjian COLLABORATIONS P. Rousselot Versailles A.Guerci CHU Nancy D Rea St Louis S. Ame Strasbourg A.Marfaing, CHU Paris Sud 11 JH Bourhis IGR CIC U802 Poitiers F. Guilhot J Guilhot L. Roy

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