Unlocking the potential of patient-derived organoids for personalized sarcoma treatment

Researchers at UCLA Health Jonsson Comprehensive Cancer Center have developed the largest collection to date of organoids derived from sarcoma patients, which may help improve understanding of the disease and better identify therapies most likely to work for each patient.

The approach, detailed in the review Stem celluses patients’ own tumor cells that mimic the unique characteristics of a patient’s tumor, allowing scientists to rapidly screen large numbers of drugs to identify personalized treatments that can target this rare and diverse group of cancers.

“Sarcoma is a rare and complex disease, which makes it particularly difficult to conduct clinical trials to identify effective treatments. Some of the rarer subtypes do not benefit from standard treatment at all.

“Even when multiple treatment options are available, there is often no reliable, data-driven way to determine the best course of action for a given patient. Choosing the most effective treatment is like looking for a needle in a haystack,” said Alice Soragni, MD, senior author of the study and assistant professor in the department of orthopedic surgery at the David Geffen School of Medicine at UCLA.

“Drug testing with patient-derived tumor organoids can potentially help predict how a patient may respond to treatment, with the aim of improving patient outcomes for diseases where treatment options are often limited.”

Sarcomas, which can develop in bone or soft tissues such as muscle and fat, account for less than 1% of all cancers but carry a high mortality rate, particularly among young people. The rarity and diversity of sarcoma types (more than 100 distinct subtypes) make them particularly difficult to study. Responses to conventional therapies can vary widely among 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, the team built 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 this scale to extend organoid development to sarcoma.

The team successfully created tumor organoids from more than 110 samples and performed detailed histopathological and molecular analyses to confirm that the organoids retained key characteristics of the original tumors. These organoids were then subjected to high-throughput drug screening using the mini-ring pipeline developed by Soragni and his team, allowing hundreds of drugs to be tested in 3D format in a short period of time.

Through this process, the team was able to identify at least one potentially effective treatment approved by the U.S. Food and Drug Administration (FDA) for 59% of the samples tested. In addition, they found that the drug responses observed in the lab matched how patients themselves responded to treatment in a small number of cases, suggesting that these organoids could be a powerful tool to guide clinical decisions.

“We have shown that it is possible to rapidly generate sarcoma organoids (within a week of surgery or biopsy) and use them to test a large number 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 for a particular patient, which is crucial for a disease as complex as sarcoma, where precision genomic medicine has often failed,” added study author Noah Federman, MD, Glaser Family Endowed Chair and director of the Pediatric Bone and Soft Tissue Sarcoma Program at UCLA Health Jonsson Comprehensive Cancer Center.

Additionally, the study demonstrated that a functional, large-scale precision medicine program could be implemented within a single institution, providing a simplified and scalable model for organoid-based testing.

“Organoids offer a practical way to bring the most promising therapies to patients, and this could be a game changer for sarcoma patients,” said Nicholas Bernthal, MD, 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 to confirm the effectiveness 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.