Organoids May Point to Best Therapy

Organoids—miniature, three-dimensional tumors grown from a patient's cancer cells—accurately predict response to treatment in patients with gastrointestinal cancer, according to a recent study (Science 2018;359:920–6).

Technology for creating patient-derived organoids was pioneered by Hans Clevers, MD, PhD, a scientist at the Hubrecht Institute and research director of the Princess Máxima Center in the Netherlands, who showed that organoids have biologic properties similar to the original tumors.

Nicola Valeri, MD, PhD, of the Institute of Cancer Research in London, UK, the new study's senior author, and his team wanted to investigate whether organoids created from gastrointestinal cancers would respond to treatment like the original tumors did.

“Very little was available when we started, and even now, on whether ex vivo responses in organoids could inform us as to what's going to happen in the patient,” he says. “But these are cancers where there are options, and you want to find the right option for the right patient.”

Valeri and his team grew organoids from 110 metastatic tumor samples from 71 patients with chemorefractory colorectal or gastroesophageal cancer who were enrolled in phase I/II clinical trials. In 21 cases, researchers exposed organoids to the same treatments that patients received, finding that drugs that were ineffective in organoids were ineffective in patients 100% of the time, whereas drugs that yielded a response in organoids yielded a response in 88% to 90% of the patients.

The team also profiled 151 cancer-related genes, establishing a 96% match between the mutational spectrum of the organoids and the original tumors, and tested a library of 55 drugs on the organoids.

“This is one of the first studies where we managed to compare what happens in the clinical model, in this case organoids, and the clinical response,” Valeri explains, addingthat he expects organoids to be used with sequencing to determine whether a patient is likely to respond to a treatment. In addition, organoids will be valuable for studying tumors that don't respond to treatment, he says.

Valeri and his team now plan to grow organoids from circulating tumor cells rather than tumor tissue to better capture the heterogeneity of a patient's cancer. They are also attempting to grow organoids in a microenvironment like the tumor's.

“This is the first formal demonstration for cancer that tumor organoids predict patient responses,” Clevers says, “so I think it's a big breakthrough.”

For Clevers, who was not involved in the study, the next advance would be a prospective trial that compares patients who receive treatment based on their organoid response with patients who receive treatment based on tumor pathology or DNA analysis, “and shows that decision-making based on organoids is better.”

Clevers points out, however, that until organoids become less expensive and less complicated to produce, they will likely be used only in specific contexts, such as for improving the utility of DNA sequencing and for drug development.

“Using organoids, you can gather information on drug resistance and drug sensitivity with much higher throughput than in clinical trials, and you can match that information to DNA profiles and learn what exactly the DNA sequence can tell you about whether a patient will or will not respond,” he says. “So, organoids would help to break the resistance/sensitivity code.” –Catherine Caruso

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