Tumor Organoids For High-Throughput Drug Screening
By Deborah Borfitz
November 13, 2019 | Interest is growing among oncology researchers in using tumor organoids to mimic cancer characteristics and drug responses in humans. Papers are being published almost daily on new approaches to engineering these tiny, three-dimensional (3D) models, leaving researchers optimistic that they will one day soon be used to personalize treatment decisions—fulfilling a priority goal of precision medicine.
So says Alice Soragni, a cancer biologist at the University of California, Los Angeles David Geffen School of Medicine, as well as an officer at the Society for Functional Precision Medicine (SFPM) promoting the use of lab-based assays to aid treatment selection for cancer patients. Relative to healthy-tissue organoids and organs-on-a-chip, growing tumor organoids is a straightforward exercise because the cells comes directly from the operating room (OR), she adds.
Earlier this year, in a paper published in Communications Biology, Soragni and her colleagues described their simple, high-throughput approach using tumor organoids to screen hundreds to potentially thousands of drugs—with results available within a week of surgery. “My lab focuses on leveraging this platform for many different applications, including to answer biological questions about how tumors originate and evolve as well as for functional medicine application, with the goal of using such a system for therapy selection in future clinical trials,” she says.
The platform developed by the lab is a modified version of high-throughput screenings to make the format more compatible with automation. They generate little rings of tumor organoids in a gel-like substance around the rim of each well in a 96-well plate. Cancer cells obtained during surgical resections develop into organoids barely visible to the human eye within these rings, Soragni explains.
Directly seeding the organoids with patient tumor cells instead of using established cell lines or patient cells implanted in mice first saves time and avoids cells undergoing changes and selection during subculturing, says Soragni.
Many cancer drugs fail during clinical trials because of their effectiveness in a very small number of patients, she continues. By extending organoid technology to cancer research, scientists could be able to identify responsive patients ahead of time. This functional screening data would also be of enormous value (DOI: 10.1038/s41568-019-0172-2) to oncologists treating rare tumors for which there is currently no standard of care.
“As long as we can get cells [from patients’ tumor], grow them, and develop these models, we can potentially test any drug of interest,” says Soragni, adding that her lab routinely works with biopsy material. The process developed by Soragni’s lab requires only a minute amount of patient tissue.
Researchers have been developing tumor organoids from a variety of cancers, and efforts have been increasing over the last few years, says Soragni. Her recently published study used tumor organoids derived from ovarian or peritoneal cancers.
While her work focuses on solid tumors, other researchers perform functional assays for blood cancers. “We all share the same idea of trying to extend functional assays into the clinical arena,” Soragni says.
Tumor cells isolated from solid tumors tend to prefer to grow in 3D as they do in the body than in two-dimensional sheets on plastic, says Soragni. Cancer cells readily grow and thrive in Matrigel, a gelatinous substance derived from mouse sarcoma cells. For the approach used in her lab, screening of tumor organoids is generally done in less than a week, so there is no need to immortalize them—with less risk of them changing or selecting fast-growing clones.
“We’re trying to stay as close to the tumor of origin as possible,” she says, working with surgeons and pathologists to get samples from the OR. “We prefer to perform short-term cultures. The longer you grow them, the more you select for cells and subclones which may not be recapitulative of the tumor of origin.”
After receiving tumors from the OR, tissue disassociation yields a single-cell suspension that gets mixed with cold liquid Matrigel, which solidifies when it hits body temperatures (37 degrees Celsius), Soragni continues. Since the mini-rings form around the edge of the wells, they’re empty in the center. Robots can therefore be used to feed the cells or add drugs to all 96 wells within about 90 seconds.
The miniaturized, high-throughput approach allows tumor organoids to be developed using a core needle biopsy, routinely providing enough tissue to screen for hundreds of conditions, says Soragni.
Researchers can of course also get cells from metastases elsewhere in the body, Soragni adds. One major focus of her lab currently is sarcoma (rare tumors of the bone, muscle and connective tissues), one of the most common in pediatrics being osteosarcoma. Tumor organoids can be created from metastases to perform high-throughput drug screening.
Next Big Step
It is easy to envision techniques such as this being translated in clinical settings to help match patients to therapies and facilitate patient selection for clinical trials, Soragni says. Tumor organoid screenings have the potential to be personalized to each patient, with the oncologist specifying the drugs to be tested.
Dual models that pair tumor organoids with immune cells from the patient are now under development, adds Soragni, which could have a significant impact on the development and testing of immuno-oncology drugs.
The big unknown is how well tumor organoids reflect drug response in patients, she says. “To go from mirroring what you know has happened to accurately foreseeing what will happen in a patient is a big jump. This is why we want to formally prove clinical utility of these models, which is the next big step.”