Targeting Replication Stress in Pediatric and AYA Osteosarcoma
Abstract
Osteosarcoma (OS) is extremely challenging to treat for 25-50 percent of the patients already have metastatic disease at the time of diagnosis. The purpose of this proposal is to improve therapy for OS by expanding upon our initial data to target replication stress (RS),a hallmark of OS. We previously used a systems biology approach to select OS patient-derived xenograft models (PDX) that harbor RS signatures such as copy number gains in MYC and RAD21 and demonstrated the feasibility of targeting replication stress via CHK1 and BET inhibitors (Pandya et al., Cancers, 2020). The scope of the work now uses a panel of modeling approaches including metastatic OS to analyze mechanisms-of-action, efficacy, and safety. To address biological variables of race, gender, and age, a diverse panel of pediatric and AYA OS models were developed and characterized by our team. In terms of major findings in year one, we published an integrated bioinformatics and in-vivo validation study showing the fidelity of the molecular signatures between original tumors and PDX as well as promising efficacy in response to BET inhibition as a single agent (Pandya et al., Cancers, 2022). We extended those studies to demonstrate that BET inhibition in combination with salvage therapy further increases efficacy and survival in a model of aggressive OS. The significance of the work to date is that studying clinically relevant in-vivo models will advance OS research and patient care by identifying how these drugs in combination promote OS cell death. These studies will lead to new mechanistic insights and potentially identify new biomarkers of response and additional therapeutic vulnerabilities as well as provide rationale for clinical trial development.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1208006
Entities
People
- Karen Pollok
- Nikan Riyahi
- Pankita Pandya
- Steve Angus
- Wade Clapp