Dataset Information

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 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.

SUBMITTER: Sayles LC

PROVIDER: S-EPMC7134333 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Genome-Informed Targeted Therapy for Osteosarcoma.

Sayles Leanne C LC Breese Marcus R MR Koehne Amanda L AL Leung Stanley G SG Lee Alex G AG Liu Heng-Yi HY Spillinger Aviv A Shah Avanthi T AT Tanasa Bogdan B Straessler Krystal K Hazard Florette K FK Spunt Sheri L SL Marina Neyssa N Kim Grace E GE Cho Soo-Jin SJ Avedian Raffi S RS Mohler David G DG Kim Mi-Ok MO DuBois Steven G SG Hawkins Douglas S DS Sweet-Cordero E Alejandro EA

Cancer discovery 20180928 1

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 ca ...[more]

PMID: 30266815

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Project description:Despite multimodal therapeutic treatments of osteosarcoma (OS), some patients develop resistance to currently available regimens and eventually end up with recurrent or metastatic outcomes. Many attempts have been made to discover effective drugs for improving outcome; however, due to the heterogeneity of the disease, new therapeutic options have not yet been identified. This study aims to explore potential targeted therapy related to protein profiles of OS. In this review of proteomics studies, we extracted data on differentially expressed proteins (DEPs) from archived literature in PubMed and our in-house repository. The data were divided into three experimental groups, DEPs in 1) OS/OB: OS vs osteoblastic (OB) cells, 2) metastasis: metastatic vs non-metastatic sublines plus fresh tissues from primary OS with and without pulmonary metastasis, and 3) chemoresistance: spheroid (higher chemoresistance) vs monolayer cells plus fresh tissues from biopsies from good and poor responders. All up-regulated protein entities in the list of DEPs were sorted and cross-referenced with identifiers of targets of US Food and Drug Administration (FDA)-approved agents and chemical inhibitors. We found that many targets of FDA-approved antineoplastic agents, mainly a group of epigenetic regulators, kinases, and proteasomes, were highly expressed in OS cells. Additionally, some overexpressed proteins were targets of FDA-approved non-cancer drugs, including immunosuppressive and antiarrhythmic drugs. The resulting list of chemical agents showed that some transferase enzyme inhibitors might have anticancer activity. We also explored common targets of OS/OB and metastasis groups, including amidophosphoribosyltransferase (PPAT), l-lactate dehydrogenase B chain (LDHB), and pyruvate kinase M2 (PKM2) as well as the common target of all categories, cathepsin D (CTSD). This study demonstrates the benefits of a text mining approach to exploring therapeutic targets related to protein expression patterns. These results suggest possible repurposing of some FDA-approved medicines for the treatment of OS and using chemical inhibitors in drug screening tests.

Project description:BackgroundDespite international guidelines providing evidence-based recommendations on appropriate management of infants with bronchiolitis, wide variation in practice occurs. This results in infants receiving care of no benefit, with associated cost and is potentially harmful. Theoretical frameworks are increasingly used to develop interventions, utilising behaviour change techniques specifically chosen to target factors contributing to practice variation, with de-implementation often viewed as harder than implementing. This paper describes the stepped process using the Theoretical Domains Framework (TDF) to develop targeted, theory-informed interventions which subsequently successfully improved management of infants with bronchiolitis by de-implementing ineffective therapies. Explicit description of the process and rationale used in developing de-implementation interventions is critical to dissemination of these practices into real world clinical practice.MethodsA stepped approach was used: (1) Identify evidence-based recommendations and practice variation as targets for change, (2) Identify factors influencing practice change (barriers and enablers) to be addressed, and (3) Identification and development of interventions (behaviour change techniques and methods of delivery) addressing influencing factors, considering evidence of effectiveness, feasibility, local relevance and acceptability. The mode of delivery for the intervention components was informed by evidence from implementation science systematic reviews, and setting specific feasibility and practicality.ResultsFive robust evidence-based management recommendations, targeting the main variation in bronchiolitis management were identified: namely, no use of chest x-ray, salbutamol, glucocorticoids, antibiotics, and adrenaline. Interventions developed to target recommendations addressed seven TDF domains (identified following qualitative clinician interviews (n = 20)) with 23 behaviour change techniques chosen to address these domains. Final interventions included: (1) Local stakeholder meetings, (2) Identification of medical and nursing clinical leads, (3) Train-the-trainer workshop for all clinical leads, (4) Local educational materials for delivery by clinical leads, (5) Provision of tools and materials targeting influencing factors, and prompting recommended behaviours, and (6) Audit and feedback.ConclusionA stepped approach based on theory, evidence and issues of feasibility, local relevance and acceptability, was successfully used to develop interventions to improve management of infants with bronchiolitis. The rationale and content of interventions has been explicitly described allowing others to de-implement unnecessary bronchiolitis management, thereby improving care.

Dataset Information

Genome-Informed Targeted Therapy for Osteosarcoma.

Publications

Genome-Informed Targeted Therapy for Osteosarcoma.

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