Genome-Informed Targeted Therapy for Osteosarcoma

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 identifi ed, 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-specifi c candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplifi cation (identifi ed by whole-genome sequencing) and changes in gene expression as identifi ed by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specifi c SCNAs leads to signifi cant 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-specifi c dependencies could be identifi ed 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.

LncRNA LINC00588 Suppresses the Progression of Osteosarcoma by Acting as a ceRNA for miRNA-1972

“…Tp53 was first reported to hold intron 1 rearrangement by Masyda et al (Masuda et al, 1987). A series of studies verified the presence of the mutation in TP53 in OS (Chen et al, 2014;Ribi et al, 2015;Sayles et al, 2019). In this study, we found that expression of TP53 was inhibited after overexpression of miRNA-1972, while TP53 expression was enhanced after overexpression of the lncRNA LINC00588 at the protein level.…”

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

“…Several studies, including a large meta-analysis, have associated specific genetic TP53 alterations with survival in patients with OS, 11 suggesting mutation-specific phenotypes. 13 These patterns, however, explain only a small number of events, and the degree of cell-to-cell heterogeneity within a tumor remains unknown, though chromosomal heterogeneity could establish mechanisms for diversity that would facilitate adaptation to cellular stresses, such as chemotherapy. 9 Beyond this small set of mutations, the most common characteristic of OS is structural complexity through chromosomal rearrangements, copy number variation, kataegis, and chromothripsis, which occur broadly throughout the genome.…”

“…Indeed, recent work has shown that a limited set of copy number patterns can group OS tumors into subtypes that may predict response to certain targeted agents. 13 These patterns, however, explain only a small number of events, and the degree of cell-to-cell heterogeneity within a tumor remains unknown, though chromosomal heterogeneity could establish mechanisms for diversity that would facilitate adaptation to cellular stresses, such as chemotherapy. Surprisingly, OS lacks common or recurrent changes in DNA repair pathway genes.…”

Is there a role for chemotherapy after local relapse in high‐grade osteosarcoma?

“…On the other hand, it should be acknowledged that a randomized study focusing on this topic is not feasible. Personalized approaches such as those based on patient‐derived xenografts, immunotherapy, and a genome‐informed strategy might represent an opportunity for these patients in the future . Currently, an individualized treatment should be performed; at the same time, it is important to inform patients with LR from osteosarcoma that, at present, in case of surgical complete remission, no evidence of clinical benefit from second‐line chemotherapy is available.…”