bioRxiv. 2023 May 26. pii: 2023.05.25.542375. [Epub ahead of print]
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 Swearingen,
Nasrin Tavanaie,
Sarah Dry,
Arun Singh,
Bartosz Chmielowski,
Joseph G Crompton,
Anusha Kalbasi,
Fritz C Eilber,
Francis Hornicek,
Nicholas Bernthal,
Scott D Nelson,
Paul C Boutros,
Noah Federman,
Jane Yanagawa,
Alice Soragni.
Sarcomas are a family of rare malignancies composed of over 100 distinct histological subtypes. The rarity of sarcoma poses significant challenges in conducting clinical trials to identify effective therapies, to the point that many rarer subtypes of sarcoma do not have standard-of-care treatment. Even for established regimens, there can be substantial heterogeneity in responses. Overall, novel, personalized approaches for identifying effective treatments are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) are clinically relevant models representative of the physiological behavior of tumors across an array of malignancies. Here, we use PDTOs as a tool to better understand the biology of individual tumors and characterize the landscape of drug resistance and sensitivity in sarcoma. We collected n=194 specimens from n=126 sarcoma patients, spanning 24 distinct subtypes. We characterized PDTOs established from over 120 biopsy, resection, and metastasectomy samples. We leveraged our organoid high-throughput drug screening pipeline to test the efficacy of chemotherapeutics, targeted agents, and combination therapies, with results available within a week from surgery. Sarcoma PDTOs showed patient-specific growth characteristics and subtype-specific histopathology. Organoid sensitivity correlated with diagnostic subtype, patient age at diagnosis, lesion type, prior treatment history, and disease trajectory for a subset of the compounds screened. We found 90 biological pathways that were implicated in response to treatment of bone and soft tissue sarcoma organoids. By comparing functional responses of organoids and genetic features of the tumors, we show how screenings can provide an orthogonal set of information to facilitate optimal drug selection, avoid ineffective therapies, and mirror patient outcomes in sarcoma. In aggregate, we could identify at least one effective FDA-approved or NCCN-recommended regimen for 59% of the specimens tested, providing an estimate of the proportion of immediately actionable information identified through our pipeline.