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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by
Courtney R Schott1,2, Amanda L Koehne1, Leanne C Sayles1
1Department of Pediatrics, University of California San Francisco, San Francisco, California.
Purpose:
Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. 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, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes.
Experimental Design:
Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model.
Results:
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 in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden.
Conclusions:
The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.
Insights
New osteosarcoma cell models accurately reflect patient metastatic disease, aiding research into rare cancers. These models show promise for testing new therapies against osteosarcoma metastasis.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Osteosarcoma is a rare cancer with poor outcomes for metastatic disease.
- Its complex and heterogeneous genomic landscape necessitates diverse preclinical models.
- Understanding osteosarcoma metastasis is crucial for developing effective treatments.
Purpose of the Study:
- To develop and characterize novel osteosarcoma patient-derived xenograft (PDX)-derived cell lines.
- To evaluate these models for their ability to recapitulate the metastatic spectrum of osteosarcoma.
- To assess the preclinical efficacy of a targeted therapy in these models.
Main Methods:
- Whole-genome and RNA sequencing of patient samples, PDXs, and PDX-derived cell lines.
- In vivo characterization of metastatic phenotype in intravenous and orthotopic murine models.
- Preclinical testing of a cyclin-dependent kinase inhibitor (dinaciclib) in an orthotopic amputation model.
Main Results:
- PDX-derived cell lines largely maintained patient expression profiles, with some developing whole-genome duplication.
- Cell lines exhibited heterogeneous metastatic capacity and tissue tropism in vivo.
- The cyclin-dependent kinase inhibitor dinaciclib significantly reduced metastatic tumor burden.
Conclusions:
- Osteosarcoma PDX-derived cell lines effectively model the variation in metastasis predilection sites seen in patients.
- This panel of new cell lines offers a valuable resource for the osteosarcoma research community.
- These models will advance the study of osteosarcoma biology and preclinical therapeutic development.
