ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
Systematic Screening Identifies Dual PI3K and mTOR Inhibition as a Conserved Therapeutic Vulnerability in Osteosarcoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 70 citations in OpenAlex.
- Phosphatidylinositol 3-kinase and mechanistic target of rapamycin dualinhibitor, VDC597, as a therapeutic agent for canine osteosarcoma.The Journal of pharmacology and experimental therapeutics · 2025Article
- Advancements in Osteosarcoma Therapy: Overcoming Chemotherapy Resistance and Exploring Novel Pharmacological Strategies.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Injectable hyaluronate-L- cysteine gel potentiates photothermal therapy in osteosarcoma via vorinostat-copper cell death.Materials today. Bio · 2024Article
- Cyclin L1 participates in Adriamycin resistance and progression of osteosarcoma via PI3K/AKT-mTOR pathway.Aging · 2024Article
- Review
- Article
- HOXC13-driven TIMM13 overexpression promotes osteosarcoma cell growth.Cell death & disease · 2023Article
- Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway.Cell death & disease · 2023Article
- Repurposing Drugs in Small Animal Oncology.Animals : an open access journal from MDPI · 2022Review
- The anti-osteosarcoma cell activity by the sphingosine kinase 1 inhibitor SKI-V.Cell death discovery · 2022Article
- Multifunctional microcapsules: A theranostic agent for US/MR/PAT multi-modality imaging and synergistic chemo-photothermal osteosarcoma therapy.Bioactive materials · 2022Article
- Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Discovery of novel candidates for anti-liposarcoma therapies by medium-scale high-throughput drug screening.PloS one · 2021Article
- Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies.International journal of molecular sciences · 2020Review
- Role of PI3K/AKT pathway in cancer: the framework of malignant behavior.Molecular biology reports · 2020Review
- Novel agent DMAMCL suppresses osteosarcoma growth and decreases the stemness of osteosarcoma stem cell.Cell cycle (Georgetown, Tex.) · 2020Article
- In vivo and in vitro inhibition of osteosarcoma growth by the pan Bcl-2 inhibitor AT-101.Investigational new drugs · 2020Article
- Recent and current clinical trials in canine appendicular osteosarcoma.The Canadian veterinary journal = La revue veterinaire canadienne · 2020Review
- TBRG4 Knockdown Suppresses Proliferation and Growth of Human Osteosarcoma Cell Lines MG63 Through PI3K/Akt Pathway.OncoTargets and therapy · 2020Article
- Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression.Frontiers in oncology · 2020Review
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
purposeOsteosarcoma is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of osteosarcoma, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for osteosarcoma patients. EXPERIMENTAL
designWe have used genetically engineered murine models of human osteosarcoma in a systematic, genome-wide screen to identify new candidate therapeutic targets. We performed a genome-wide siRNA screen, with or without doxorubicin. In parallel, a screen of therapeutically relevant small molecules was conducted on primary murine- and primary human osteosarcoma-derived cell cultures. All results were validated across independent cell cultures and across human and mouse osteosarcoma.
resultsThe results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary osteosarcoma cell cultures in vitro in both human and mouse osteosarcoma, whereas specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on osteosarcoma cell cultures.
conclusionsThe approaches described here have identified dual inhibition of the PI3K-mTOR pathway as a sensitive, druggable target in osteosarcoma, and provide rationale for translational studies with these agents.
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