The landscape of drug sensitivity and resistance in sarcoma
Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information.
Authors
- Jane Yanagawa
- Peyton Tebon (ORCID: https://orcid.org/0000-0002-4673-1760)
- Nicholas Matthew Bernthal (ORCID: https://orcid.org/0000-0003-3338-5878)
- Noah Federman (ORCID: https://orcid.org/0000-0002-2627-6772)
- Ardalan Davarifar (ORCID: https://orcid.org/0000-0002-8779-2893)
- Paul C. Boutros (ORCID: https://orcid.org/0000-0003-0553-7520)
- Jae Hoon Jeong (ORCID: https://orcid.org/0000-0002-4642-5560)
- Jomjit Chantharasamee (ORCID: https://orcid.org/0000-0002-1237-331X)
- Scott D. Nelson (ORCID: https://orcid.org/0000-0001-8852-1967)
- Helena Winata (ORCID: https://orcid.org/0000-0002-1001-5316)
- Alice Soragni (ORCID: https://orcid.org/0000-0002-6634-2885)
- Takafumi N. Yamaguchi (ORCID: https://orcid.org/0000-0003-1082-3871)
- Bartosz Chmielowski (ORCID: https://orcid.org/0000-0002-2374-3320)
- Ahmad Al Shihabi (ORCID: https://orcid.org/0000-0003-4736-6926)
- Arun S. Singh (ORCID: https://orcid.org/0000-0002-1633-7746)
- Sorel Fitz‐Gibbon (ORCID: https://orcid.org/0000-0001-7090-5719)
- Jantzen Sperry
- Sarah Dry (ORCID: https://orcid.org/0000-0002-1858-5225)
- Fritz C. Eilber
- Nasrin Tavanaie
- Francis J. Hornicek (ORCID: https://orcid.org/0000-0002-6916-8042)
- Joseph G. Crompton (ORCID: https://orcid.org/0000-0001-9325-2909)
- Hannah C. Cox (ORCID: https://orcid.org/0000-0002-1798-796X)
- Anusha Kalbasi (ORCID: https://orcid.org/0000-0001-8692-1457)
- Sara Sartini (ORCID: https://orcid.org/0000-0003-3895-4136)
- Alfredo Enrique Gonzalez
- Miranda Diaz-Infante
- Alexandra Y Jensen
- Huyen Thi Lam Nguyen (ORCID: https://orcid.org/0000-0001-6291-6792)
- Jonathan Nakashima
- Summer Norris
Institutions
- University of Miami (US)
- University of California, Los Angeles (US)
- CAE Solutions (United States) (US)
- Broad Center (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1016/j.stem.2024.08.010
- Citations
- 48
- Primary Topic
- Sarcoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 19.69
Funders
- Alan B. Slifka Foundation
- National Institutes of Health
- National Cancer Institute
- Jonsson Comprehensive Cancer Center
- David Geffen School of Medicine, University of California, Los Angeles