Researchers at UCLA Health’s Jonsson Comprehensive Cancer Center have developed the largest collection of organoids derived from sarcoma patients to date that may help improve understanding of the disease and better identify therapies that are most likely to work for each individual patient.
The approach, detailed in the journal Cell Stem Cell, uses patients’ own tumor cells that replicate the unique characteristics of the patient’s tumor, allowing scientists to rapidly screen a large number of drugs to identify personalized treatments that can target this rare and diverse group of cancers.
“Sarcoma is a rare and complex disease, making conducting clinical trials to identify effective treatments especially challenging. Some of the rarest subtypes lack a standard treatment entirely. Even when multiple therapy options are available, there is often no reliable, data-driven method for determining the best course of action for an individual patient. Choosing the most effective treatment is like looking for a needle in a haystack,” said Dr. Alice Soragni, senior author of the study and an assistant professor in the Department of Orthopaedic Surgery at the David Geffen School of Medicine at UCLA. “Testing drugs using patient-derived tumor organoids has the potential to help predict how a patient may respond to treatment, with the goal of improving patient outcomes in diseases where treatment options are often limited.”
While sarcomas, which can develop in bone or soft tissue such as muscle and fat, account for only less than 1% of all cancers, they carry a high mortality rate, particularly among young people. The rarity and diversity of sarcoma types (more than 100 distinct subtypes) makes them particularly difficult to study. Responses to conventional therapies can vary widely between patients, making it difficult to determine the most effective course of action for each individual.
To determine whether organoids could improve understanding of how a patient’s tumor might respond to specific drugs or combinations of them, the team assembled a biobank of 294 samples from 126 UCLA patients diagnosed with 25 different subtypes of bone and soft tissue sarcoma. While tumor organoids have been widely used to study carcinomas, this study is the first of its scale to extend organoid development to sarcoma.
The team successfully created tumor organoids from over 110 samples and performed detailed histopathological and molecular analyses to confirm that the organoids retained key features of the original tumors. These organoids were then subjected to high-throughput drug screening using the mini-ring process developed by Soragni and his team, allowing hundreds of drugs to be tested in 3D format in a short period of time.
Using this process, the team was able to identify at least one potentially effective FDA-approved treatment for 59% of the samples tested. They also found that the drug responses observed in the lab matched how patients themselves responded to the treatment in a small number of cases, suggesting that these organoids could be a powerful tool for guiding clinical decisions.
“We have shown that it is possible to generate sarcoma organoids rapidly (within a week after surgery or biopsy) and use them to evaluate a wide range of drugs, including FDA-approved therapies and other treatments currently in clinical trials,” Soragni said.
“This gives us the ability to identify which drugs are most likely to work in a particular patient, which is crucial for a disease as complex as sarcoma, where genomic precision medicine has often failed,” added study author Dr. Noah Federman, the Glaser Family Chair and director of the Pediatric Bone and Soft Tissue Sarcoma Program at UCLA Health’s Jonsson Comprehensive Cancer Center.
Furthermore, the study demonstrated that a large-scale functional precision medicine program could be implemented within a single institution, offering an optimized and scalable model for organoid-based testing.
“Organoids offer a tangible way to match patients with the most promising therapies and this could be a game-changer for sarcoma patients,” said Dr. Nicholas Bernthal, chair and executive medical director of the UCLA Department of Orthopaedic Surgery. “We are optimistic that this approach will lead to better, more personalized care for those who need it most.”
Following the results of this study, the UCLA team will validate the findings in a larger clinical trial that aims to confirm the efficacy of the organoid-based approach in predicting treatment responses in patients with osteosarcoma, the most common type of bone cancer that primarily affects children and young adults.
Soragni, Federman and Bernthal are all members of the Jonsson Comprehensive Cancer Center at UCLA Health. The study’s first authors are Ahmad Shihabi, a project scientist in Soragni’s lab; Peyton Tebon, a visiting project scientist; and Huyen Thi Lam Nguyen, a graduate student. Additional UCLA authors include Sara Sartini, Ardalan Davarifar, Alexandra Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Enrique Gonzalez, Summer Swearingen, Helena Winata, Sorel Fitz-Gibbon, Takafumi Yamaguchi, Jae Jeong, Sarah Dry, Arun Singh, Bartosz Chmielowski, Joseph Crompton, Fritz Eilber, Scott Nelson, Paul Boutros and Jane Yanagawa.
The study was funded by grants from the National Cancer Institute, the Alan B. Slifka Foundation, the David Geffen School of Medicine at UCLA and the Jonsson Comprehensive Cancer Center at UCLA Health.