Genome-informed targeted therapy for osteosarcoma

Leanne C. Sayles, Marcus R. Breese, Amanda L. Koehne, Stanley G. Leung, Alex G. Lee, Heng Yi Liu, Aviv Spillinger, Avanthi T. Shah, Bogdan Tanasa, Krystal Straessler, Florette K. Hazard, Sheri L. Spunt, Neyssa Marina, Grace E. Kim, Soo Jin Cho, Raffi S. Avedian, David G. Mohler, Mi Ok Kim, Steven G. Dubois, Douglas S. HawkinsE. Alejandro Sweet-Cordero

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)46-63
Number of pages18
JournalCancer discovery
Volume9
Issue number1
DOIs
StatePublished - Jan 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Genome-informed targeted therapy for osteosarcoma'. Together they form a unique fingerprint.

Cite this