Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations
Open accessAbstract
Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.
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PDX model systems are valuable in basic science and personalized medicine because they have clinical and molecular features representative of human disease.
“These PDX model systems are of particular value in both basic science and potentially personalized medicine research 180,183,222 as they have clinical and molecular features that are quite representative of the human disease 223,224,225,226 .”
From Osteosarcoma (2022) · cites this paper as [183]
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References 53 · Cited by 36
Research works printed but not linked: 1
- [37]Johanna Bendell PL, Kwak Eunice, Pandya Susan, Musib Luna, Jones Cheryl, De Crespigny Alex, Belvin Marcia, McKenzie Meghan, Gates Mary R., Chan Iris and Shapiro Geoffrey. in Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research Vol. 71 (AACR, Orlando, FL, 2011 Apr 2–6;).
- Authors
- Loh, A. H. P., Stewart, E., Bradley, C. L., Chen, X., Daryani, V., Stewart, C. F., Calabrese, C., Funk, A., Miller, G., Karlstrom, A., Krafcik, F., Goshorn, D. R., Vogel, P., Bahrami, A., Shelat, A., & Dyer, M. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Dyer, Michael A.
- ORCID
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 442
- Pages
- 262-270
- ISSN
- 0304-3835 (ISSN-L)
- PMC
- PMC6342199
- OpenAlex
- W2898685440
- Cited by
- 36
- References
- 53
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 3
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Center (CA21765)
- American Lebanese Syrian Associated Charities
- National Medical Research Council Singapore (008-185)
- St. Baldrick’s Foundation and the National Pediatric Cancer Foundation
- National Institutes of Health (EY014867, EY018599, CA168875)
- Howard Hughes Medical Institute
- Alex Lemonade Stand
- Tully Family and Peterson Foundations
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- osteosarcoma, patient-derived xenografts, orthotopic xenograft, combinatorial drug screening, drug repurposing, histone deacetylase inhibitors, PI3K inhibitors, mTOR inhibitors, MEK inhibitors, proteasome inhibitors, PARP inhibitors, gemcitabine, doxorubicin, metastatic cancer, lead compound identification
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Bone Neoplasms, Dose-Response Relationship, Drug, Humans, Mice, Transgenic, Osteosarcoma, Mice, SCID, Mice, Inbred NOD, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Protein Kinase Inhibitors, Cell Proliferation, Histone Deacetylase Inhibitors, High-Throughput Screening Assays, Drug Repositioning, Molecular Targeted Therapy, Proteasome Inhibitors
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