Decoding and Targeting Genomic Instability in Pediatric Osteosarcoma
Abstract
Fiscal Year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: (1) Pediatric, adolescent, and young adult cancers, and (2) Metastatic cancers. Background/Rationale: By addressing the unmet needs of patients with pediatric osteosarcoma (OS), a cancer of bone-forming cells, this proposal addresses three overlapping FY22 PRCRP Topic Areas: Sarcoma, Metastatic Cancers, and Pediatric, adolescent, and young adult cancers. As the most common pediatric bone cancer OS is highly relevant to Service Members and their Families. In the case of metastatic disease, outcomes for children have not improved in decades, with 5-year survival rates varying from 15% to 30%. Unlike many other pediatric cancers, OS is associated with genomic instability, a characteristic that has been studied and successfully exploited therapeutically in adult cancers. Despite these obvious similarities, OS has not received the same level of attention. By applying genome-wide sequencing at the level of individual cells, our group has shown that cell-to-cell variation can lead to genomic instability. Importantly, our work has shown that sequencing of this cell-to-cell variation can reveal information about the cancer s response to therapeutics. Objective/Hypothesis: This proposal seeks to apply the single-cell sequencing methods we have successfully applied in adult cancers to the study of OS patient tumors that have been transplanted and propagated within specialized strains of mice or laboratory-maintained cells. We will not only study the behavior of these patient-derived cancers as they change and evolve over time, but we will also study the behavior of these OS genomes as they respond to drug treatment, drug withdrawal, and interference induced by genetic editing. With these aims, we will address the PRCRP overarching challenges (i) Transform cancer treatment through the identification of new targets, especially for advanced disease and metastasis, and (ii) Identify and elucidate the mechanisms behind cancer epigenetics/genetics and cancer development to improve treatment methods. Benefits to Patients: By studying the impacts of novel drug treatments on patient samples this proposal will seek to directly benefit patients. These experiments may identify novel experimental drugs, drugs that can be repurposed, or drugs that are effective for patients with specific genetic markers. The related studies of patient tumor samples transplanted into mice and maintained in a laboratory environment will reveal genetic markers for the classification of OS tumors, and genetic dependencies associated with OS tumor evolution and metastasis. These genetic markers and relationships will be fundamental to further development of OS diagnostics and therapeutics. Military Health Focus: Service Members are impacted both directly and indirectly by pediatric cancers and metastatic disease. In addition to the physical and emotional costs of these diseases on Service Members and their Families, these disease conditions directly impact mission readiness. The research aims described in this proposal will build a foundation for improved OS diagnostics and directly identify new treatment options. Improving the diagnosis and treatment of OS will reduce time in hospital for military hospitals, maximize Service Members time on duty, and improve mission readiness.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310748
Entities
People
- Samuel Aparicio
Organizations
- Provincial Health Services Authority
- United States Army