In the past decade, treatment strategies have shifted from one-size-fits-all to a more patient-matched treatment. The shift toward personalized medicine requires the development of new organoid model systems for preclinical research that can better represent patients' characteristics and eventually translate into better patient outcomes.
Patient-Derived Organoids
Organoids are 3D cultures capable of self-organization, differentiation, and self-renewal. They have emerged as powerful model systems in biomedical research, especially in oncology. The advantages of organoids as 3D cell culture models, compared to 2D culture, include their greater ability to model patient tissue in terms of its structural, functional, and physiological characteristics.
Organoids from the epithelial tissues of several organs, such as the liver, lung, pancreas, and bladder, have been successfully developed in the last decade and used in in vitro and in vivo studies of diseases, drug screening, and treatment responses.
However, creating an in vitro model resembling in vivo conditions does not necessarily guarantee success in a clinical setting. Different patients react differently to the same treatment, and some eventually develop treatment resistance. These differences are influenced by the patient's genetic makeup and environmental and lifestyle differences as well as by genetic mutations that arise within a tumor. Therefore, organoids grown from patient-derived samples are a growing area of interest.
Organoids in Personalized Medicine
Precision medicine, also called personalized or individualized medicine, involves the development or selection of treatments based on individualized genes, proteins, or biomarkers while taking into account the patient's health history and the effects of environment and lifestyle.
The U.S. Food & Drug Administration (FDA) recently recognized precision medicine as a significant game changer in drug research and selection. In addition, the FDA Modernization Act 2.0, passed in 2022, enables drug developers to seek an exemption to animal testing requirements by utilizing alternative technologies. Organoid technology may help replace animal testing in some contexts, and patient-derived organoids, sometimes referred to as tumoroids, can aid researchers in better matching treatments with patients. For example, organoid studies can help predict patients' responses to treatments and could be used to tailor single or combination treatments accordingly.
Patient-derived Organoids in Oncology
Precision oncology is a new perspective in cancer research in which clinicians do not define cancers by the organs they originate in (e.g., breast cancer, lung cancer, liver cancer, etc.) but by subtypes based on a patient's molecular characteristics (e.g., hormone-positive breast cancer and human epidermal growth factor receptor-positive breast cancer).
Patient-derived organoids are well-suited for use in precision oncology. For example, while a 2D culture typically becomes clonal after several passages, organoids are better able to maintain the genetic diversity present in tumors and, therefore, can better capture the drug sensitivity of the original tumor.
Living Biobanks
Living biobanks of patient-derived organoids (or tumoroids) have been generated for brain, breast, lung, liver, and pancreatic cancers, among others. These biobanks reflect the heterogeneity of cancer tissues within and between patients and replicate the known clinical correlations between genetic mutations and patients' responses to targeted treatments.
Panels of patient-derived organoids (or tumoroids) are helping researchers discover drugs, test patients' sensitivity to existing drugs, select drug combinations for cancer patients, and develop personalized cancer immunotherapies.
Advanced Colorectal Cancer
In May 2023, in the Journal of Experimental & Clinical Cancer Research, Lars Henrik Jensen and colleagues published the results of a phase 2, single-center, open-label, non-comparative study that included 90 patients who had metastatic colorectal cancer with poor prognosis and no acceptable treatment options. Biopsies were collected from 90 patients, and 44 patients' biopsies successfully generated organoids that were then used in drug sensitivity screens.
The primary endpoint was progression-free survival at two months. Thirty-four patients representing the precision cohort were treated with nine different regimens, which were selected based on the drug sensitivity results obtained from patients' derived organoids. Half of these patients (17 out of 34) were still alive with no cancer progression at two months, thus meeting the study's primary endpoint.
High-Throughput Sensitivity Testing to Guide Treatment
Another article by Nhan Phan and colleagues describing their high-throughput method for testing the drug sensitivity of patient-derived organoids was published in 2019. They tested organoids derived from four patients — three with ovarian cancer and one with peritoneal cancer — for sensitivity to 240 protein kinase inhibitors. These organoids showed cellular characteristics that correlated well with the patients' cancer cell characteristics, such as the high tumor grade, heterogeneity, and existing drug resistance.
The researchers used the method to predict existing drugs that would be effective treatments for each patient based on the in vitro results. Their method produces results within a week after surgery, which means that, with further development, clinicians could potentially use it to make treatment decisions in real-time.