Patient-Derived Xenografts as a Preclinical Model for Bone Sarcomas

Meohas, Walter; Granato, Regina Alcantara; Guimarães, João Antônio Matheus; Fortuna-Costa, Anneliese; Duarte, Maria Eugênia Leite

doi:10.1590/1413-785220182602186998

Cited by 13 publications

(3 citation statements)

References 18 publications

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“…[261][262][263][264][265] Several studies have reported successful establishment of STS and bone sarcoma PDX models, with an overall engraftment success rate of 32-69% and successful recapitulation of the genetic and phenotypic characteristics of the original tumor. [266][267][268][269][270] Furthermore, a high-throughput drug screen revealed that the most commonly used chemotherapeutics, HDAC and proteasome inhibitors, were active against most sarcoma subtypes. 268 All rhabdomyosarcoma PDX models were particularly sensitive to the WEE1 inhibitor AZD1775 (PubChem CID: 24856436) and AZD1775 combined with current standard of care drugs vincristine (VCR) (PubChem CID: 5978) and irinotecan (IRN) (PubChem CID: 60838) had a better response rate in ERMS and ARMS PDX models compared to AZD1775, VCR and IRN alone.…”

Section: Personalized Precision Medicinementioning

confidence: 99%

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Damerell

Pepper

Prince

2021

Sig Transduct Target Ther

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Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

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Section: Personalized Precision Medicinementioning

confidence: 99%

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Damerell

Pepper

Prince

2021

Sig Transduct Target Ther

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“…Seven articles from Brazil and one from Argentina focused on preclinical platforms (46)(47)(48). In particular, Brazilian researchers developed preclinical models of osteosarcoma and ependymoma to evaluate therapies, given the poor outcomes and unpredictable behavior of bone sarcomas in children (46,47,49). A recent study included a multicenter collaboration among researchers from Argentina, Europe and the United States and reported on the establishment of preclinical models derived from metastatic sites of retinoblastoma patients (48).…”

Section: Discussionmentioning

confidence: 99%

The importance of basic and translational research in caring for children with malignant solid tumors in Latin America

Cancela,

Dinardi,

Aschero

et al. 2024

Revista Panamericana De Salud Pública

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Objective. Basic and translational research in pediatric cancer are essential to improve patient care. To critically assess the developments achieved in these areas in Latin America, we systematically reviewed information published between 2013 and 2023. Methods. Studies of basic and translational research performed by investigators in Latin America evaluating pediatric malignant solid and central nervous system tumors were retrieved from PubMed. Original articles published in English between 2013 and 2023 were included. Collaborations among Latin American authors or among Latin American authors working with researchers from other continents were also included. Studies were excluded if they focused only on adults or on basic research in tumor biology not specifically related to the tumor types analyzed in this review. Results. A total of 550 articles were retrieved, but after removal of duplicates, 514 articles were included in the analysis, the majority of which were authored by researchers affiliated with institutions in Argentina, Brazil and Mexico. These countries also had the highest number of collaborations on original articles published with authors from Europe and North America. Argentina had the highest number of collaborations on original publications, with coauthors from Brazil and Uruguay. The median impact factor of the 244 journals in which articles were published was 3.5. The most commonly studied tumors were osteosarcomas, neuroblastomas and medulloblastomas; the most commonly studied areas were molecular analysis, tumor cell biology and biomarkers. Conclusions. In Latin America, research in pediatric oncology is on the agenda, despite a notable disparity in publication rates and frequency of collaboration between countries. There is a need to strengthen scientific collaboration within Latin America and with countries from other continents to promote research and to develop novel treatment strategies that reflect the local needs of children in Latin America who have solid tumors and brain cancer.

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“…The use of patient-derived xenografts (PDXs) to model cancer enhances the probability of retaining key features of the human disease (11,42,(46)(47)(48)(49). However, only a limited number of osteosarcoma PDX models have been evaluated for metastatic potential in vivo (30,36,40,42,(50)(51)(52).…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities

Schott

Koehne

Sayles

et al. 2023

Preprint

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Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model.

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Patient-Derived Xenografts as a Preclinical Model for Bone Sarcomas

Cited by 13 publications

References 18 publications

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

The importance of basic and translational research in caring for children with malignant solid tumors in Latin America

Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities

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