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04 Octobre 2012

Towards optimization of Acute Myeloid Leukemia treatment : a data- driven model of cell population dynamics. Annabelle Ballesta , Faten Mehri , Xavier Dupuis, Pierre Hirsh , Ruoping Tang, Jean-Pierre Marie, Jean Clairambault. 04 Octobre 2012. OUTLINE.

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04 Octobre 2012

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  1. Towardsoptimization of Acute MyeloidLeukemiatreatment: a data-driven model of cell population dynamics Annabelle Ballesta, FatenMehri, Xavier Dupuis, Pierre Hirsh, Ruoping Tang, Jean-Pierre Marie, Jean Clairambault 04 Octobre 2012

  2. OUTLINE Introduction on Acute MyeloidLeukemia • Cell Dynamics in the absence of drugs • Experimentalresults for Patient #7 • Time- and age-structuredmathematicalmodel • Fit to experimentalresults for Patient #7 • Cell Dynamics in presence of Anticancerdrugs (Aracytine and AC220) Annabelle Ballesta

  3. Normal Hematopoiesis Hematopoietic Stem Cell Annabelle Ballesta

  4. Acute MyeloidLeukemia Hematopoietic Stem Cell Annabelle Ballesta

  5. Acute MyeloidLeukemia Blockage in the differenciation of progenitors of the myeloidlinage. Cancer cellsproliferate in the bonemarrow and eventuallyinvade the blood and otherorgans. AMLs are the mostfrequentleukemias in adults. They are associated to a high mortality (40 000/year in Europe). -> optimizingtherapiesagainst AML still a clinical challenge Annabelle Ballesta

  6. 1 Cell Dynamics in the absence of drugs

  7. Experimentalprotocol Experiments on AML patient bloodsample. Assumption: only cancer progenitors in blood, healthyprogenitorsbeing in the bonemarrow. Three membrane markers to characterizecell populations: CD 34, CD 38 and CD 33 Surface marker Annabelle Ballesta

  8. ThreeCellcompartments Cancer Hematopoietic stem cells CD34+/CD38- CD38+/CD33- Cancer progenitors Mature cancer cells ”blast” CD38+/CD33+ Threecell population: from immature to mature cells Able to self-renew, to differenciate Able to differenciate Unable to differenciate Annabelle Ballesta

  9. Experimentalprotocol J0 8am: Blood sample collection J0: Sort white bloodcells by Ficoll J0: Sort CD34/38/33+ cell population by immunomagnetic technique J0 2pm to J5: cell culture in standard medium supplementedwithgrowthfactors (SCF, G-CSF, Il-3, Flt-3) Annabelle Ballesta

  10. Patient #7: Markers at J0 Markers: ->cellsorting of CD 38+ population Annabelle Ballesta

  11. Patient #7: Cell count Methods: count using the Malassezcell Average of 2 to 3 independantmeasurements Time (min) Annabelle Ballesta

  12. Patient #7: CellDeath Methods: Annexin/ Propidium iodure (PI) Average of 2 to 3 independantmeasurements Time (min) Annabelle Ballesta

  13. Patient #7: Cell cycle (PI+Ki67) J2 J1 J4 J3 Annabelle Ballesta

  14. Patient #7: CD 38 and CD 33 markers Time (min) Annabelle Ballesta

  15. Mathematical model One population : CD 38+ Model isstructured in time and age 4 phases: G0 (r), G1 (g), S (s), G2/M (m) NB: model incorporatescell cycle phases in view of modeling of phase-specificanticancerdrugs. Tr r Tg Ts Tm g s m γ γ γ γ Annabelle Ballesta

  16. Mathematical model Equation for g(t,a): Initial condition in age: Initial condition in time: Annabelle Ballesta

  17. Mathematical model Tr, Tg, Ts, Tm: Transitions functions in the form: -> 3 parameters to beestimated for each phase= 12 parameters Initial instant: cells in G0 and G1, sameageassumed for all cells,age to beestimated Annabelle Ballesta

  18. Parameter estimation 16 parameters to beestimated in total: 12 for transition functions, age in G0 and G1 at t=0, 2 deathrates gamma and delta. Least square approach, minimizationtaskperformedwith the CMAES algorithm Annabelle Ballesta

  19. Results for Patient #7: cellnumber Annabelle Ballesta

  20. Results for Patient #7: celldeath Annabelle Ballesta

  21. Results for Patient #7: cell cycle G0 G1, S , G2/M Annabelle Ballesta

  22. Results for Patient #7: parameter values a0_G0= 53 h a0_G1= 235 h γ=0.002 h-1 δ=0 h-1 a_min_r= 30.2 h µ_r= 53 σ_r= 7.1 a_min_g= 18.9 h µ_g= 27.7 σ_g=7 a_min_s= 28.3 h µ_s=39.9 σ_s=-=6.59 a_min_m= 0.9 h µ_m=0.16 σ_m=0.05 Annabelle Ballesta

  23. Conclusions and Perspectives Experimentalcharacterization of celldynamicsin control conditions for Patient #7, mathematical model calibrated to data achieve a satisfying fit. Perspective: model two populations (CD 38+/CD 33- and CD38+/33+) to improve fit. Samemodelingapproach for other patient data (10 patients) Annabelle Ballesta

  24. 2 Cell Dynamics in presence of Aracytin (ARA-C) and FLt 3 inhibitor AC220

  25. AML therapeutics Aracytine (ARA-C) widelyused in clinicsagainst AML. Aracytinetargetscells in S-phase. Annabelle Ballesta

  26. Celldynamics: cell count Patient #7: CD38+ population Temps (min) Annabelle Ballesta

  27. Celldynamics: Annexin/PI Patient #7: CD38+ population % de cellules Annexin-/IP- Temps (min) • Forte mort cellulaire due à l’ARA-C, dépendante du temps d’exposition (pas de la dose pour ce patient) Annabelle Ballesta

  28. Celldynamics: cell cycle analysis Patient #7: CD38+ population, ARA-C 0.5ng/mL J2 J1 J3 Annabelle Ballesta

  29. Celldynamics: differenciation Patient #7: CD38+ population, ARA-C 0.5ng/mL Temps (min) Annabelle Ballesta

  30. Celldynamics in presence of Flt3 inhibitor AC220 Flt 3 isatyrosine kinase whichisoftenmutated in AML cells, giving a proliferativeadvantage AC220 inhibits Flt3 activty. Annabelle Ballesta

  31. Cell dynamics : cell count Patient #8 (53LAM2012), polpulation CD38+/33- Temps (min) Annabelle Ballesta

  32. Celldynamics : Annexin/PI Patient #8 (53LAM2012), population CD38+/33- Temps (min) Annabelle Ballesta

  33. Celldynamics: cell cycle analysis Patient #8 (53LAM2012), Flt3-, polpulation CD38+/33- Normal conditions AC-220, 1000µM Annabelle Ballesta

  34. Conclusions and Perspectives Cytotoxicactivity of ARA-C on AML cells Cytostaticactivity of AC220 on AML cells Next: Mathematically Model ARA-C and AC220 activities. Performoptimizationprocedure to optimizeco-administration. Annabelle Ballesta

  35. Thankyou • www.inria.fr

  36. M0 M4 M5a M6 M7 M1 M5b M2 M3 AML: FAB Classification Expression des antigènes: CD33, CD13, CD117, CD65, CD14, MPO Annabelle Ballesta

  37. Experimentalprotocol Ficoll on bloodsamples to isolate white bloodcells: Annabelle Ballesta

  38. Experimentalprotocol Cell sorting by immunomagnetic technique: Antibody against CD 34, CD38 and CD33 Specific antibody Surface antigen Magnetic particule Annabelle Ballesta

  39. Introduction rates:  functions Adimy et al., J of Biologicalsystems, 2008 : Annabelle Ballesta

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