Related Experiment Video
Updated: Oct 3, 2025
Author Spotlight: Enhanced Generation of Patient-Derived 3D Organoids for Glioblastoma and Glioma
Published on: January 19, 2024
Personalized chordoma organoids for drug discovery studies
Ahmad Al Shihabi1,2, Ardalan Davarifar1,3,4, Huyen Thi Lam Nguyen1
1Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Abstract:
Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective treatments. Therefore, there is a need for discovery of novel therapeutic approaches. Patient-derived organoids can accelerate drug discovery and development studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter- as well as intrapatient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-κB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.
Insights
Patient-derived organoids offer a new way to study rare chordoma tumors. High-throughput screening identified targeted agents and pathways, like PI3K/mTOR and NF-κB, as promising for novel chordoma therapies.
Area of Science:
- Oncology
- Translational Medicine
- Drug Discovery
Background:
- Chordomas are rare, aggressive tumors originating from notochordal remnants, typically in the sacrum or skull base.
- Conventional chemotherapy is often ineffective against chordomas, and their rarity hinders clinical trial development.
- Novel therapeutic strategies are urgently needed for chordoma treatment.
Purpose of the Study:
- To establish and characterize patient-derived chordoma organoids as a preclinical model.
- To utilize organoids for high-throughput drug screening to identify effective therapeutic agents.
- To explore potential molecular targets and pathways for combination therapy in chordoma.
Main Methods:
- Successful establishment of seven chordoma organoid models from five patients with diverse tumor sites and disease stages.
- Characterization of organoids to confirm recapitulation of parent tumor features and inter-/intra-patient heterogeneity.
- High-throughput screening of targeted agents on organoids to assess efficacy.
Main Results:
- Organoids accurately reflected the heterogeneity of the original chordoma tumors.
- Screening identified PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors as highly effective molecules.
- Pathway analysis revealed sensitivity of NF-κB and IGF-1R pathways to perturbations.
Conclusions:
- Patient-derived chordoma organoids are viable preclinical models for drug discovery.
- Targeted agents like PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors show promise for chordoma treatment.
- The NF-κB and IGF-1R pathways represent potential targets for future combination therapies.
