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Cited by 75Bone Tumor Diagnosis and TreatmentsSarcoma Diagnosis and TreatmentCholangiocarcinoma and Gallbladder Cancer Studies

Personalized chordoma organoids for drug discovery studies

Open access
Al Shihabi, Ahmad, Davarifar, Ardalan, Nguyen, Huyen Thi Lam, Tavanaie, Nasrin, Nelson, Scott D., Yanagawa, Jane, Federman, Noah, Bernthal, Nicholas +2 more·2022·Science Advances
DOI 10.1126/sciadv.abl3674PMC PMC8849332

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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.

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Crossref · 10.1126/sciadv.abl3674

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66 of 66 references verified0 citation errors · 0 not checkable

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  • Patient-derived organoids can generate xenografts, confirm their tumorigenic capacity, and recapitulate the histology of parental tumors.

    “Patient-derived organoids can also generate xenografts, confirm their tumorigenic capacity and recapitulate the histology of parental tumors15,55.”

    From Organoids (2022) · cites this paper as [15]

    The Results section reports that the chordoma organoids retained the immunohistopathological characteristics of their parental tumors, supporting the histology portion of the claim. The Introduction and Discussion mention chordoma xenograft models, but do not report generating xenografts from these organoids or confirming their tumorigenic capacity in vivo. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Most mutations and CNVs are preserved in late-passage lung cancer organoids, while de novo mutations can be attributed to sub-clonal expansion of small subsets of cells from the original tumor.

    “Most mutations and CNVs are are preserved in the late passage of lung cancer organoids, while de novo mutations can be attributed to the sub-clonal expansion of small subsets of cells present in the tumor of origin15.”

    From Organoids (2022) · cites this paper as [15]

    The Abstract and Discussion describe chordoma organoids that recapitulate features of their parent tumors, but do not address late-passage lung cancer organoids. Searches for mutations, CNVs, and sub-clonal expansion found no passage supporting the claimed genetic preservation or explanation for de novo mutations. Page numbers were not available in our copy. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • Several studies have found concordance between tumor organoids and parent tissue in mutations and copy number variations.

    “Several studies have shown concordance of organoids and parent tissue in terms of mutations and copy number variations (CNV)15,127.”

    From Organoids (2022) · cites this paper as [15]

    The Results section reports that chordoma organoids recapitulated the parent tumors’ immunohistopathological features, and the Discussion describes similar staining and growth profiles. Neither passage establishes concordance in mutations or copy number variations; searches for those genomic measures found no supporting passage in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 3

  1. [34]A. Wellstein, G. Giaccone, M. B. Atkins, E. A. Sausville, in Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e (McGraw-Hill Education, 2017).
  2. [66]K. He, X. Zhang, S. Ren, J. Sun, in 2016 IEEE Conference on Computer Vision and Pattern Recognition (CVPR) (IEEE, 2016), pp. 770–778.
  3. [67]J. Deng, W. Dong, R. Socher, L.-J. Li, Kai Li, Li Fei-Fei, in 2009 IEEE Conference on Computer Vision and Pattern Recognition (IEEE, 2009), pp. 248–255.

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Authors
Al Shihabi, A., Davarifar, A., Nguyen, H. T. L., Tavanaie, N., Nelson, S. D., Yanagawa, J., Federman, N., Bernthal, N., Hornicek, F., & Soragni, A.
Affiliations
  • Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • University of California, Los Angeles (US)
Corresponding author
Soragni, Alice
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-02-18
Volume
8
Issue
7
Pages
eabl3674-eabl3674
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abl3674
PMC
PMC8849332
OpenAlex
W4220764623
Cited by
75
References
66
Citations by year
2026: 13 · 2025: 22 · 2024: 14 · 2023: 18 · 2022: 8
FWCI
11.29
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA244729, P30CA016042, R01CA264248)
  • David Geffen School of Medicine, University of California, Los Angeles
Topics
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
Keywords
chordoma, patient-derived organoids, drug discovery, PI3K/mTOR inhibitors, EGFR inhibitors, NF-κB signaling, intratumoral heterogeneity, high-throughput screening, combination therapy, sacral chordoma, skull base chordoma
MeSH terms
Antineoplastic Agents, Chordoma, Humans, Organoids, Treatment Outcome, Drug Discovery

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