A tiny organoid-based test can rapidly predict the effectiveness of lung cancer drugs, speeding up personalised drug testing and decision making in treatments.
Drug testing has long been associated with animal models and human clinical trials, but not anymore. With the rise of 3D bioprinting, miniature organs, or “organoids”, grown from patient cells can now be used to replace both animals and humans to assess the efficacy of medications. Leveraging this technology, scientists from Tsinghua University have grown hundreds of organoids in a nanolitre-scale microwell array system to speed up the testing of lung cancer drugs and decision making in treatments.
One of the greatest advantages of using patient-derived organoids is its ability to allow for more personalised treatments. For cancer patients, this feature is especially useful because cancer models grown from the patients’ own cells can accurately reflect the basic structural and functional characteristics of original cancer tissues. In theory, this means that clinicals can test for and evaluate patient sensitivity to various anti-cancer drugs without even having to administer the medications.
However, despite its promising potential, bringing patient-derived organoids into clinical practice cannot be more challenging. Due to technical limitations and the delicate nature of cell culturing, developing patient-derived organoids can be time-consuming and complicated with low chances of success, thus making them an inefficient technique to test drug sensitivity in clinics.
To improve the practicality of organoids in clinical settings, Peng Liu and his collaborators from Tsinghua University have devised an alternative method of using these models. The team has created a simple system that can quickly produce patient-derived organoids, as well as isolate and perform drug reaction tests. The system works by processing lung cancer tumour tissues in a special integrated superhydrophobic microwell array called the “InSMAR-Chip”.
With conventional methods, it would usually take several weeks or months to culture enough patient-derived organoids to run a test to determine which drugs will be most effective for a patient. Because of this slow developmental process, lung cancer patients have been placed at a huge disadvantage with their chances of recovery being compromised. This is because most cases of lung cancer are often detected during their late stages, and so “patients are reluctant to wait until they receive drug sensitivity test results,” as said by Liu, a professor in Tsinghua’s Department of Biomedical Engineering.
Moreover, “the initial number of [patient-derived organoids] generated from lung cancer tissue ranges from several to thousands, but the number of [patient-derived organoids] required to complete drug screening in a typical well plate is in the order of millions.” As such, there has been a constant shortage of patient-derived organoids even if patients opt to use patient-derived organoids to perform drug tests. Fortunately, with this newly developed system, drug sensitivity tests can now be done within a week.
To create the system, the team first had to devise a way to increase the number of organoids that can be derived from patients. Their solution was to culture the organoids at the nanolitre scale on the InSMAR-Chip, which contains 108 miniaturised wells to measure drug reactions. Compared to conventional techniques of cell culturing that are done at microlitre-scale volumes and require prolonged in vitro expansion to generate just enough organoids and take meaningful drug measures, the nano-litres scale wells on the InSMAR-Chip can evaluate responses to anticancer drugs from just hundreds of organoids. The InSMAR-Chip builds upon a previous innovation by Liu called the SMAR-Chip, but with enhancements like the use of new water-repellent materials that can create uniform droplets in each of the wells.
After developing the chip, Liu and colleagues sought to demonstrate the efficacy of the InSMAR-Chip. According to the test results of the InSMAR-Chip, it was revealed that the tool could not only test drug sensitivity but also flag acquired drug resistance; the researchers were able to verify that lung cancer organoids derived from a patient with resistance to tyrosine kinase inhibitor therapy showed greater resistance to the drug using the InSMAR-Chip test.
Given these results, Liu concluded that “the drug responses reported using our method correlated strongly with genetic mutations and clinical outcomes,” thus validating the potency of the tool to effectively perform drug sensitivity tests on lung cancer. Besides lung cancer, the team has also successfully applied their technology to test drug sensitivity on colorectal, ovarian, liver, and pancreatic cancer samples.
Nevertheless, despite its promising results, the InSMAR-Chip still needs further improvements. The team has reported that they have yet to overcome the challenge of increasing the production of patient-derived organoids from middle- and advanced-stage patients even with their technology.
“Many such samples are obtained through punctures and the number of PDOs generated from these samples is very limited. The success rate of establishing organoids is low,” explained Liu. As such, the team plans to “continue to optimise the sample processing method and organoid culture conditions, with the aim of making this technology more universal.”
Source: Hu et al. (2021). Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week. Nature Communications, 12, 2581.