2. Academic Validation
  3. Genomic profiling of a collection of patient-derived xenografts and cell lines identified ixabepilone as an active drug against chemo-resistant osteosarcoma

Genomic profiling of a collection of patient-derived xenografts and cell lines identified ixabepilone as an active drug against chemo-resistant osteosarcoma

  • J Exp Clin Cancer Res. 2025 Jul 8;44(1):195. doi: 10.1186/s13046-025-03440-5.
Maria Cristina Manara # 1,  Francesca Bruzzese # 2,  Laura Formentini 3 4,  Lorena Landuzzi 3,  Laura Pazzaglia 3,  Maria Antonella Laginestra 3,  Marianna Carrabotta 3,  Maria Serena Roca 5,  Federica Iannelli 5,  Laura Grumetti 5,  Laura Addi 5,  Alessandro Parra 3,  Camilla Cristalli 3,  Michela Pasello 3,  Alberto Bavelloni 3,  Francesca Carreras 3,  Francesca Ruzzi 4,  Giuseppe Bianchi 6,  Marco Gambarotti 7,  Alberto Righi 7,  Alfredo Budillon 8,  Pier-Luigi Lollini 4 9,  Katia Scotlandi 10
Affiliations

Affiliations

  • 1 Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, via di Barbiano 1/10, Bologna, 40136, Italy. mariacristina.manara@ior.it.
  • 2 Experimental Animal Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.
  • 3 Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, via di Barbiano 1/10, Bologna, 40136, Italy.
  • 4 Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
  • 5 Experimental Pharmacology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.
  • 6 Clinica Ortopedica e Traumatologica III a Prevalente Indirizzo Oncologico, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • 7 Department of Anatomy and Pathological Histology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • 8 Scientific Directorate, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.
  • 9 IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, 40138, Italy.
  • 10 Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, via di Barbiano 1/10, Bologna, 40136, Italy. katia.scotlandi@ior.it.
  • # Contributed equally.
PMID: 40624718 DOI: 10.1186/s13046-025-03440-5
Abstract

Background: Osteosarcoma (OS) shows a multitude of genetic and chromosomal abnormalities together with large biological heterogeneity. These features limited the identification of novel drugs to treat patients with metastases and/or chemo-resistant tumors. The purpose of this study was to create additional resources for drug screening by generating patient-derived xenograft (PDXs) and PDX-derived cell lines that reflect the spectrum of OS heterogeneity.

Methods: PDXs were derived from OS collected at diagnosis, surgical resections, or metastases. PDX-derived cell lines were also established. Targeted DNA Sequencing and digital PCR were applied to identify major genetic alterations. High-throughput drug screening by using a library of 2880-FDA approved compounds and conventional MTT assays were performed to identify the most effective drugs against in vitro and in vivo growth of chemo-resistant OS.

Results: Targeted DNA Sequencing demonstrated alterations in the most commonly amplified oncogenes, such as MYC, CCNE1, DDR2, CDK4, MDM2, and AURKA. Recurrent deletions and SNVs were found in TP53, CDKN2A, RB1, PTEN, and VHL. Copy number variant (CNV) alterations in PDXs, PDX-derived cell lines and xenografts developed from cell lines (CDX) correlated very well with those observed in the matched original human tumors. Drug screenings identified and repurposed five compounds with efficacy against chemoresistant OS. In this context, we prioritized ixabepilone as a drug capable of inducing tumor regression in mice.

Conclusions: We enriched the scientific community with additional, molecularly characterized OS models to be used for testing novel therapies and supported the inclusion of ixabepilone into treatment plans for chemoresistant OS.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13046-025-03440-5.

Keywords

Drug resistance; High-throughput drug screening; Ixabepilone; Osteosarcoma; Patient-Derived-Xenografts.

Figures
Products