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Targeting the DNA Repair Pathway in Ewing Sarcoma

Ewing’s Sarcoma is a bone and soft tissue tumor that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive but survival for metastatic and recurrent disease is poor. Whole genome sequencing of 19 Ewing’s Sarcoma tumors showed that STAG2 was mutated in 10% (2/19) of the tumors and STAG2 protein was absent in 14% (13/106) tumors by immunohistochemical staining. Previous studies have shown that glioblastoma cells lacking STAG2 are more sensitive to poly-ADP ribose polymerase (PARP) inhibitors. We found that Ewing’s Sarcoma cell lines are sensitive to PARP inhibitors irrespective of STAG2 protein expression. Ewing Sarcoma cell lines are defective in double strand DNA break repair. PARP inhibitor cytotoxicity in Ewing’s Sarcoma cells was potentiated 10-1,000 fold by DNA damaging agents (irinotecan and temozolomide). To extend these studies in vivo, we developed an orthotopic Ewing’s Sarcoma mouse model and performed pharmacokinetic and pharmacodynamic studies with three different PARP inhibitors (BMN-673, olaparib and veliparib) in clinical development for pediatric cancer. Those data were used to design preclinical phase I studies to identify tolerable drug combinations for pilot efficacy testing (preclinical phase II). Based on the results of the preclinical phase I/II data, we performed a double blind, randomized, placebo controlled preclinical phase III trial with 274 mice in 15 treatment groups. Irinotecan administered in a low-dose protracted schedule optimized for pediatric patients was an effective DNA damaging agent to combine with olaparib and BMN-673 and was better tolerated than combinations with temozolomide. Combining olaparib or BMN-673 with irinotecan and temozolomide gave complete and durable responses in over 80% of the mice.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001001020 Illumina HiSeq 2000 38
EGAD00001001432 Illumina HiSeq 2000 1337
EGAD00001001433 Illumina HiSeq 2000 906
Publications Citations
Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.
Cancer Discov 4: 2014 1342-1353
The Childhood Solid Tumor Network: A new resource for the developmental biology and oncology research communities.
Dev Biol 411: 2016 287-293
Sequencing Overview of Ewing Sarcoma: A Journey across Genomic, Epigenomic and Transcriptomic Landscapes.
Int J Mol Sci 16: 2015 16176-16215
Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.
Elife 5: 2016 e13446
Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors.
Science 361: 2018 eaam8419