Precision Medicine In Pediatric Oncology
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Giselle Sholler MD Neuroblastoma & Medulloblastoma Translational Research Consortium Helen DeVos Children’s Hospital/SHMG 10/29/2015
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Precision Medicine In Pediatric Oncology
- 1. Precision Medicine In Pediatric Oncology Giselle Sholler MD Neuroblastoma & Medulloblastoma Translational Research Consortium Helen DeVos Children’s Hospital/SHMG
- 2. Francis Eshun Deanna Mitchell Jessica Foley Andre Bachmann Rick Neubig Don Eslin Nehal Parikh William Ferguson Jeffrey Trent John Carpten David Craig William Roberts Jacqueline Kraveca Giselle Sholler, MD Helen DeVos Children’s Hospital / MSU Joel Kaplan Jeffrey Bond Kathleen A. Neville Timothy Triche Douglas Hawkins Devang Pastakia Sharon Lockhart Mark Fluchel Peter Zage Neuroblastoma and Medulloblastoma Translational Research Consortium Valerie Brown Randy Wada Susan Sencer Michael Kelley Gregory Hale Ted Laetsch Daniel Weiser Lars Wagner Nilay Shah
- 3. Identify Patient- Tailored Drug Therapies Biopsy of Tumor
- 4. Molecular Guided Therapy Trial for Pediatric Cancer Multicenter study to evaluate molecularly guided therapy using DNA exome and RNA sequencing analysis in patients with relapsed or refractory childhood cancers. • Enrollment • Consent • RNA sequencing • DNA Exomes • Report (Sholler) • Safety evaluation • Medical Monitor Review MSU
- 5. Medical History Presented at 4 months old with metastatic Choroid Plexus Carcinoma (CPC) in R ventricle with + CSF, and leptomeningeal disease Initial Treatment Complete tumor resection 11 cycles Chemotherapy
- 6. Treatment of Recurrent CPC Recurrent metastatic tumor after 9 months Tumor in R+L ventricle Dates Rx Response Sept-Nov 2012 (3 cycles) Avastin/Irinotecan/ Temodar Progressive tumor Dec 2012 – Jan 2013 (2 cycles) HD-Methotrexate and Vincristine Stable March 2013 (2 cycles, 6 weeks) Vincristine and HD Carboplatin Stable April 2013 (4 cycles) Ifosfamide Etoposide Stable August – Sept 2013 (2 Cycles) HD-Methotrexate and Vincristine Progressive disease: Stable tumor, but CSF became positive with drop mets to Cauda equina
- 7. MGT Trial Resection of R ventricular tumor Sent for Molecular Testing Well tolerated Results within 10 days Patient started directly onto MGT therapy
- 8. Multidisciplinary Tumor Board Medical Monitor Patient Treatment Tumor Board B Pharmacists PI’s at NMTRC Sites Bioinformatics and Genomics Experts Medical Genetics Expert Pathologist BRadiologist
- 9. MGT Treatment Target/Pathway Medication FGF2 fibroblast growth factor 2 Thalidomide PDGFB platelet derived growth factor Sunitinib HDAC3 HDAC8 Histone deacetylase Vorinostat MTOR pathway genes mammalian target of Rapamycin Sirolimus
- 11. Start of MGT 6 months 20 months Response to MGT Residual tumor left brain <12% of original tumor volume September 2013 March 2014 June 2015
- 12. High Risk Neuroblastoma at Diagnosis MGT : Incorporate targeted agent into chemotherapy 20% are refractory – needs improvement Diagnostic biopsy sent for: Standard pathology testing TGen for DNA exomes, RNA sequencing, ODC SNP Sholler lab for cell line generation and xenografts Tumor Board adds targeted agent to cycles 2- chemo Surgery (re-sequence) Transplant Radiation Antibody Therapy Maintenance with DFMO -50% relapse still Maintenance with DFMO Add to Standard Treatments Genomic Analysis for Tailored Therapy
- 13. Targeted agent choices (rank/z-score -considerations) Vorinostat HDAC pathway Bortezomib NFKB pathway Crizotinib ALK mutation or overexpression Sorafenib FLT3, RET, KIT, KDR, PDGFRA/B, BRAF Dasatinib SRC, PDGFRA/B, KIT, FYN, BTK, CSFR1 Lapatinib EGFR
- 14. Plate Layout and Dilutions Designed in Collaboration with Rick Neubig and Tom Dexheimer Performed by Tom Dexheimer Dilution 2.5-fold dilutions 1 100 uM 2 40 uM 3 16 uM 4 6.4 uM 5 2.56 uM 6 1.024 uM 7 0.4096 uM 8 0.16384 uM 9 0.065536 uM 10 0.0262144 uM 11 0.01048576 uM 12 0.004194304 uM 13 0.001677722 uM 14 0.000671089 uM 15 0.000268435 uM 16 0.000107374 uM 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 A B C D E F G H I J K L M N O P Lapatinib Lapatinib Crizotinib Crizotinib Vorinostat(SAHA) Vorinostat(SAHA) Vorinostat(SAHA) Lapatinib Dasatinib Dasatinib Sorafenib Sorafenib Sorafenib Crizotinib Vehicle Vehicle Bortezomib(Velcade) Bortezomib(Velcade) Bortezomib(Velcade) Dasatinib
- 16. Acknowledgments Sholler Lab: Genevieve Bergendahl, CRN Alyssa Vander Werff, CRA Monica Fleeman, CRA Ping Zhao, PhD Tracey Avequin Elizabeth VanSickle David Hayes HITC: Shannon MacKeigan Julie Steinbrecher Craig Vandellen Josh Havemann Genomics Core: Jeff Bond, PhD Abhinav Beeravally, MSc Research Team: Jeffrey Trent, PhD Andre Bachmann, PhD Melinda Merchant, MD, PhD William Ferguson, MD Bill Roberts, MD Deanna Mitchell, MD Jessica Foley, MD Joel Kaplan, DO, MPH Jackie Kraveka, MD Amy Lee Bredlau, MD Don Eslin, MD Nehal Parikh, MD Melinda Merchant, MD Kathleen Neville, MD Valerie, Brown, MD Francis Eshun, MD Sharon Lockhart, MD Susan Sencer, MD Mark Fluchel, MD Randy Wada, MD Peter Zage, MD Pam Kidd, MD Al Cornelius, MD Rick Neubig, MD, PhD Tom Dexheimer, PhD TransMed –Jeremy Miller
- 17. NMTRC Pediatric Cancer Heroes, Advocates, and Supporters. WE THANK YOU! Swifty Foundatio n