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Cancer Discov. 2019 Jan;9(1):46-63. doi: 10.1158/2159-8290.CD-17-1152. Epub 2018 Sep 28.

Genome-Informed Targeted Therapy for Osteosarcoma.

Author information

1
Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, California.
2
Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, California.
3
Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford University, Stanford, California.
4
Department of Pathology, University of California, San Francisco, California.
5
Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford University, Stanford, California.
6
Biostatistics Core, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
7
Division of Biostatistics, Department of Epidemiology and Biostatistics, University of California, San Francisco, California.
8
Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.
9
Seattle Children's Hospital, University of Washington, Fred Hutchison Cancer Research Center, Seattle, Washington.
10
Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, California. Alejandro.Sweet-Cordero@ucsf.edu.
#
Contributed equally

Abstract

Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.This article is highlighted in the In This Issue feature, p. 1.

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