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Preclinical Models for Developing Therapy for Pediatric Solid Tumors uses and limitations

Preclinical Models for Developing Therapy for Pediatric Solid Tumors uses and limitations. Peter J. Houghton, Ph.D. Solid Malignancies Program St. Jude Children’s Research Hospital. Problems in using Preclinical Data. Early drug discovery is conducted under defined/standardized environment.

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Preclinical Models for Developing Therapy for Pediatric Solid Tumors uses and limitations

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  1. Preclinical Models for Developing Therapy for Pediatric Solid Tumors uses and limitations Peter J. Houghton, Ph.D. Solid Malignancies Program St. Jude Children’s Research Hospital

  2. Problems in using Preclinical Data • Early drug discovery is conducted under defined/standardized environment. • Pediatric cancer models are not part of this process either in industry or NCI. • Preclinical data using pediatric models are generated in an uncontrolled or regulated environment. • Such data are derived from experimental systems that are not validated using experimental design and interpretation that lacks consistency or rigor.

  3. Informative Non-Clinical Data • Pharmacology and pharmacokinetics • Safety • Efficacy • Behaviour • Long term effects • Developmental aspects • Other? Pharmacodynamics

  4. Uses:Where Do Animal Models Fit in Drug Development for Childhood Cancer? Drug acquired NCI/Industry/Academia • Identification of active agents/analogs • Optimization of administration schedules and drug combinations. • Prioritization of agents for phase I Phase I • Rational decisions to advance/stop development • Potential to focus phase II trials Phase II • Potential to relate target inhibition to • biological response

  5. Models Identify Clinically Active Agents Prospectively RHABDOMYOSARCOMA COLON CARCINOMA

  6. SENSITIVITY OF WILMS TUMOR XENOGRAFTS

  7. Topotecan Lactone AUC Associated with Response in Neuroblastoma Xenografts 290 150 125 100 75 AUC (ng-hr/mL) 50 25 0 NB1382.2 NB1643 NBEB NB1771 NB1691 PR CR

  8. TPT AUC 100 ± 20 ng*hr/ml Targeted Topotecan Neuroblastoma Protocol NB97 Results • 28 evaluable patients • TPT median dose 3.0 mg/m2 • 17 partial responses (60%) • 11 stable disease • no tumor progressions Dose Adjustment Schema (100 ± 20 ng*hr/ml) Day 1 2 3 4 5 6 7 8 9 10 11 12 TPT TPT TPT TPT TPT X X TPT TPT TPT TPT TPT PK Studies Dose Adjust 113 Courses; 92% Targeting Success Santana et al.(submitted)

  9. Retrospective Analysis of Response-Exposure Relationships for Pediatric Tumors Xenografts Drugs that failed Drugs that worked

  10. Evaluation of MGI-114(Phase II in COG?) Systemic exposure is still > 10-fold higher than in children @MTD

  11. Schedule-dependent antitumor activity of topotecan Control TPT (daily x 5)every 21 daysTotal dose = 22.5 mg/kg TPT (daily x 5) x 2 every 21 daysTotal dose = 22.5 mg/kg 10 Tumor volume (cm3) 1 0.1 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Week Week Week

  12. Discriminating Between Analogs: Osteosarcoma Models Control Carboplatin Cisplatin Oxaliplatin

  13. The Challenge ofMolecularly-Targeted Drugs • Tumor models must accurately recapitulate activity of signal transduction pathways. -orthotopic or subcutaneous? - expression profiling - proteomics profiling

  14. WT6 vs parent XENOGRAFT PRIMARY TUMOR WT8 vs parent XENOGRAFT PRIMARY TUMOR

  15. P. Hedge et al. ASCO #535A GSK/Cytokinetics

  16. + + + + 5 / 5 0 / 5 2026 S J-W T 10 + + + + + + + + + 5 / 5 0 / 5 2034 S J-W T 10 + + + + +* 5 / 5 F L OO D 2061 S J-W T 8 + + + + 5 / 5 1 / 5 + + + + + +: CR w i t h o ut r e grow t h ( 12 we e k s ) ++ + + Evaluation of SB713489 S t ud y # T um or 15 mg /k g 10 mg /k g 5 mg /k g CR /P R Tox @ 15 d ea t h s m g / kg 1998 SK NE P + - - 0 / 5 0 / 5 1999 SK NE P + + + - - 2 / 5 1 / 5 2005 S J-W T 7 + + + + + + + + + 5 / 5 0 / 5 2009 S J-W T 7 + + + + + +: CR w i t h regrow th + + + +: a ll tum ors hav e p ar ti a l reg r es si on ( PR > 50% vo lum e r e d u c t i o n) + + + : s t a b l e di sea s e + +: grow th d e l ay ~ 2 t um or vol um e do ublin g ti m e s + : grow t h d e l ay ~ 1 tu mo r vo lu m e d o ub l in g t im e - : n o grow th inhib i ti o n

  17. Study 2026 SJ-WT10

  18. Informative Non-Clinical Data • Pharmacology and pharmacokinetics • Safety • Efficacy • Behaviour • Long term effects • Developmental aspects • Other? Pharmacodynamics

  19. Rheb Rheb 4E-BP1 eIF4E eIF4G eIF4E PHARMACOKINETICS IGF-II IRS-1 PI-3K Akt PTEN PDK1/2 Low Amino Acid Pools TSC1 TSC2 AMP mLST8 Low Energy (High AMP) AMPK mTOR Rapamycin (CCI-779) TARGET INHIBITION GDP GTP Raptor LKB1 GTP p70S6K ? Increased translation TOP Dependent Translation IGF-II Targets of Cap Dependent Translation Cyclin D1 ODC1 MYC HIF1a BIOLOGICAL READOUT

  20. Developing Initiatives for a National Consortium to Identify and Prioritize New Agents • RFA to systematically characterize models through genomic/proteomic screens to identify potential molecular targets (POPP-TAP). • RFP to establish preclinical screening program that will identify agents having high priority for pediatric Phase I testing through the Children’s Oncology Group.

  21. Effective use of Non-clinical Data • Standardization of experimental procedures: difficult, but a realistic goal. • Standardization of acceptable criteria for assessing drug activity. • GLP compliance: very expensive, most academic centers would be excluded.

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