The landscape of drug sensitivity and resistance in sarcoma

Ahmad Al Shihabi; Peyton J Tebon; Huyen Thi Lam Nguyen; Jomjit Chantharasamee; Sara Sartini; Ardalan Davarifar; Alexandra Y Jensen; Miranda Diaz-Infante; Hannah Cox; Alfredo Enrique Gonzalez; Summer Norris; Jantzen Sperry; Jonathan Nakashima; Nasrin Tavanaie; Helena Winata; Sorel T Fitz-Gibbon; Takafumi N Yamaguchi; Jae H Jeong; Sarah Dry; Arun S Singh; Bartosz Chmielowski; Joseph G Crompton; Anusha K Kalbasi; Fritz C Eilber; Francis Hornicek; Nicholas M Bernthal; Scott D Nelson; Paul C Boutros; Noah C Federman; Jane Yanagawa; Alice Soragni

doi:10.1016/j.stem.2024.08.010

The landscape of drug sensitivity and resistance in sarcoma

Cell Stem Cell. 2024 Oct 3;31(10):1524-1542.e4. doi: 10.1016/j.stem.2024.08.010. Epub 2024 Sep 20.

Authors

Ahmad Al Shihabi¹, Peyton J Tebon², Huyen Thi Lam Nguyen³, Jomjit Chantharasamee⁴, Sara Sartini³, Ardalan Davarifar⁵, Alexandra Y Jensen³, Miranda Diaz-Infante³, Hannah Cox³, Alfredo Enrique Gonzalez⁶, Summer Norris³, Jantzen Sperry⁷, Jonathan Nakashima⁷, Nasrin Tavanaie³, Helena Winata⁶, Sorel T Fitz-Gibbon⁶, Takafumi N Yamaguchi⁶, Jae H Jeong⁶, Sarah Dry⁸, Arun S Singh⁴, Bartosz Chmielowski⁴, Joseph G Crompton⁹, Anusha K Kalbasi¹⁰, Fritz C Eilber¹¹, Francis Hornicek¹², Nicholas M Bernthal³, Scott D Nelson⁸, Paul C Boutros¹³, Noah C Federman¹⁴, Jane Yanagawa¹⁵, Alice Soragni¹⁶

Affiliations

¹ Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Certis Oncology Solutions, Inc., San Diego, CA, USA.
⁸ Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Division of Surgical Oncology David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Division of Surgical Oncology David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹² Department of Orthopedic Surgery, University of Miami, Miami, FL, USA.
¹³ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁵ Department of Surgery, Division of Thoracic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁶ Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected].

PMID: 39305899
DOI: 10.1016/j.stem.2024.08.010

Abstract

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.

Keywords: high-throughput drug screening; organoids; patient-derived models; precision medicine; sarcoma; tumor organoids.

MeSH terms

Adult
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Drug Resistance, Neoplasm* / drug effects
Female
Humans
Male
Middle Aged
Organoids / drug effects
Organoids / pathology
Sarcoma* / drug therapy
Sarcoma* / pathology

Substances

Antineoplastic Agents