The Texas Pediatric PDX Core. Peter J. Houghton, Ph.D., Director Greehey Children s Cancer Research Institute UT Health Science Center San Antonio
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1 The Texas Pediatric PDX Core Peter J. Houghton, Ph.D., Director Greehey Children s Cancer Research Institute UT Health Science Center San Antonio
2 GOALS To successfully heterograft and propagate new Patient Derived Xenograft (PDX) preclinical models from Hispanic and underserved children in Texas. To molecularly characterize each model and provide annotated deidentified patient demographic data associated with each tumor model. To establish a database web portal to allow Core users to access patient demographic, genomic and other data associated with individual models. To provide well-characterized, annotated, cryo-preserved xenograft tissues to researchers in Texas and beyond. To provide a Training Course for interested researchers interested in developing and using PDX models in research. Develop a novel zebrafish xenograft bioassay. In years 3-5, we will develop and validate a novel metastasis bioassay using the zebrafish model system.
3 ORGANIZATION De-identified Patient Database UTHSCSA -Tomlinson UHS/Methodist Sample acquisition Blood/Tumor/Shipping UTSWMC Skapek Sample acquisition Blood/Tumor/Shipping TPPDX Core Houghton/Kurmasheva Heterografting Coding Website Cryo-preservation Characterization Distribution Committee Exome sequence RNASeq Immunophenotype (leukemias) Research Laboratories
4 Leukemia PDX Models Established Specimen ID/Source Gende r Race/Ethnicity Age Diagnosis Relapse Y/N Germline DNA, Y/N/P , UT Health/UHS M White/Hispanic 16 years Pre B ALL N Y , UT Health/UHS F White/Hispanic 25 years Pre BALL N Y , UT Health/UHS F White/Hispanic 7 y 2 m B Cell, ALL Y (2nd) Y , UT Health/UHS M White/Hispanic 19 y 8 m Pre B ALL N N , UT Health/UHS F White/Hispanic P AML, secondary to treatment for Ewing's sarcoma N N , UT Health/UHS M White/Hispanic 2 y 1 m B Cell, ALL N Y MCH 0026, Methodist CH M White/Hispanic 2 years Pre B ALL N N MCH 0027, Methodist CH M White/Hispanic 19 y 10 m T- cell ALL Y N MCH 0029, Methodist CH F White/Not Hispanic 27 y 3 m AML N N MCH 0030, Methodist CH F Not White/Not Hispanic 13 y 5 m ALL N N MCH 0031, Methodist CH F White/Hispanic 7 m ALL N N MCH 0032, Methodist CH M White/Not Hispanic 8 y ALL N N Cryopreserved 1962 vials at 10 7 cells/vial
5 Solid Tumor PDX Models Established Specimen ID/Source Gender Race/ Ethnicity Age Diagnosis Relapse Y/N Primary/ Metastatic Germline DNA, Y/N/P UY Health/UHS F Hispanic 6 Medulloblastoma N P Y UY Health/UHS F NH White 2 Medulloblastoma N P Y UY Health/UHS M NH White 2 Hepatoblastoma N P Y CPRIT 1739 UTSW-Dallas M NH White 3 Hepatoblastoma N P Y CPRIT 1748 UTSW-Dallas F NH White 11 mo Hepatoblastoma N P Y CPRIT 1763 UTSW-Dallas F AA 2 Wilms N P Y CPRIT 1796 UTSW-Dallas F AA CPRIT 1795 UTSW-Dallas M Hispanic Ovarian N P Y Testicular N P Y COG St. Mary s, FL P Germ Cell P 14 samples < 3months, pending
6 Samples Viably Cryopreserved for Future Distribution Leukemias Specimen ID/Source Diagnosis Current Passage Vials Frozen (passage) , UT Health/UHS Pre B ALL 3 F1-16 F2-42 F , UT Health/UHS Pre BALL 4 F2-254 F , UT Health/UHS B Cell, ALL 2 F1-84 F , UT Health/UHS Pre B ALL 4 F2 537 F , UT Health/UHS B Cell, ALL 2 F1-43 MCH 0026, Methodist CH Pre B ALL 3 F1-220 F2-21 MCH 0027, Methodist CH T- cell ALL 1 F1-5 MCH 0030, Methodist CH ALL 1 F1-6 MCH 0031, Methodist CH ALL 1 F cells/vial
7 Samples Viably Cryopreserved for Future Distribution Solid Tumors Specimen ID Source Gender Race/Ethnicity Age Diagnosis Relapse Primary/ Germline DNA Y/N Metastatic Y/N/P UT Health/UHS F Hispanic 6 Medulloblastoma N P Y 2. CPRIT 1753 UT Southwestern M AA 11 Wilms N P Y UT Health/UHS F NH White 2 Medulloblastoma N P Y 4. CPRIT 1763 UT Southwestern F AA 2 Wilms N P Y UT Health/UHS M Hispanic 14 Osteosarcoma N P N 6. CPRIT 1796 UT Southwestern F AA 16 Ovarian ca, GCT N P Y 7. CPRIT 054 UT Southwestern M Hispanic 10 Refractory ERMS Y P 8. CPRIT 1739 UT Southwestern M NH White 3 Hepatoblastoma N P Y UT Health/UHS M Hispanic 13 Osteosarcoma N M Y UT Health/UHS M NH White 2 Hepatoblastoma N P Y 11. CPRIT 0029 UT Southwestern F AA 4 Wims- Pulmonary Met Y M 12. CPRIT 1795 UT Southwestern M Hispanic 17 Testicular-Mixed GCT N P Y 13. CPRIT 1837 UT Southwestern M NH White 15 Hodgkins Lymphoma 14. CPRIT 1853 UT Southwestern Neuroblastoma 6 pieces/vial
8 Why PDX Models of Childhood Cancer? They maintain the fidelity (pathology, genetics and epigenetics) of childhood cancers. Expanded panels of PDX models will simulate clinical heterogeneity more accurately. PDX models are valuable in elucidating biology and therapy of childhood cancer. Models have been valuable in developing effective therapies with lower toxicity.
9 PPTP Data: Activity of Standard and Novel Cytotoxic Agents Red = Maintained Complete Regressions Orange = Complete Regression Yellow = Partial Regression (>50%)
10 Comparison of Eribulin Pharmacokinetics in Mouse and Adult Patients Mouse Human Eribulin plasma conc. (nm) mg/kg Eribulin plasma conc. (nm) Hours Kolb EA et al Ped Blood Cancer Hours Hours Morgan RJ et al CCP 2015
11 ES-4 Ewing Sarcoma Xenograft: Greater than additive activity for Eribulin + Irinotecan 10.0 Tumor Volume cm Control Time (Weeks) 10.0 Tumor Volume cm Eribulin R x Time (Weeks) 10.0 Tumor Volume cm Irinotecan R x Time (Weeks) 10.0 Tumor Volume cm Vincristine (1 mg/kg) R x Tumor Volume cm Eribulin + Irinotecan R x Tumor Volume cm Vincristine + Irinotecan R x Time (Weeks) Time (Weeks) Time (Weeks)
12 Summary of Median Event-Free Survival for Sarcoma models Treated with Eribulin Or Vincristine Combined with Irinotecan Xenograft Model Tumor Type Eribulin + Irinotecan Vincristine + Irinotecan P EFS (days) Rh10 Alveolar rhabdomyosarcoma > <0.001 Rh30 Alveolar rhabdomyosarcoma 90.8 >160 <0.001 Rh41 Alveolar rhabdomyosarcoma Rh65 Alveolar rhabdomyosarcoma > ES-4 Ewing sarcoma <0.001 CHLA258 Ewing sarcoma <0.001 SKNEP1 Ewing sarcoma >133 > KT-11 Wilms > <0.001 KT-13 Wilms RBD1 Rhabdoid >96.1 > KT-14 Rhabdoid Eribulin 1 mg/kg IP days 1,8 repeated at day 21 Vincristine 1.0 mg/kg IP weekly x 6 (single agent) Vincristine 0.5 mg/kg IP weekly x 6 (combination) Irinotecan 2.5 mg/kg IP days 1-5, repeated at day 21.
13 MEK Inhibitors in Childhood Glioma Low-grade glioma most common brain tumor in children Therapy is limited in those with unresectable disease BRAF aberrations in 70-90% of JPAs, most commonly BRAF-KIAA1549 fusion protein Alternate BRAF aberrations described including BRAFV 600E mutation in 10-15% of JPA
14 Only Mutant BRAF Glioma Respondes to MEK Inhibition CONTROL BT-35 WT BRAF CONTROL BT-40 V600E
15 Phase I Responses to Selumetinib in Pediatric Low-Grade Glioma (PBTC 029 Trial)
16 Inhibition of MEK Suppresses TORC1 in BT-40 BRAF-mutant Tumors BT-35 BT-40 Control 4/0 4/2 Control 4/0 4/2 perk1/2 ERK1/2 ps6 S6 p4e-bp1 4E-BP1 pakt Akt GAPDH
17 Regulation of TORC1 by DNA Damage is Complex Fig5h.' ATM' DNA'damage' Growth' Signals' p53' p63' DNA.PK' Sestrin1/2' REDD1' Akt' AMPK' Raf1'(c.Raf)' TSC1/TSC2' MEK'1/2' p70s6k' 4E.BP1' mtorc1' p70s6k P' ERK'1/2' 4E.BP1 P' rs6' rs6 P' Cam et al JBC, 2015
18 BT40 (Passage 10) Scramble TSC2 shrna Scramble TSC2 shrna Tramatinib (nm) TSC2 p-erk1/2 ERK1/2 p-s6k p-s6 p-4ebp1 4EBP1 GAPDH 12h 24h
19 In BT-40 Cells BRAF Regulates TORC1 via TSC Inhibition 100 Tramatinib (nm) DMSO Scramble shrna TSC2 shrna myrakt1 1 myrakt3 Scramble TSC2-shRNA myrakt1 myrakt
20 BT40 Trametinib+ Rapamycin Study R x R x Regrowth delay R x
21 Goals for Next Year Increase the acquisition of tumor samples, UTSW (brain tumors & leukemias), MD Anderson affiliation for samples. Start molecular characterization (exome sequence, RNAseq). Develop the website to advertise PDX models for Research. Develop the Zebrafish model for primary transplantation.
22 Texas Pediatric PDX Core UTHealth San Antonio Peter Houghton Gail Tomlinson Raushan Kurmasheva Myron Ignatius Alison Grimes Assanasen Chatchawin Abhik Bandyopadhyay Anna Rogojina Luz Perez Prado UTSW Dallas Stephen Skapek James Armatruda Dinesh Rakheja Bo Yao Jiwoon Kim Cristyn Bransteter Erin Butler
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