Organoids are miniature versions of human organs that are advancing the study of biology and medicine. These three dimensional, simplified structures can provide an excellent research model, and in some cases, can be tailored to individuals. Now scientists from Columbia University Irving Medical Center (CUIMC) and NewYork-Presbyterian have generated bladder cancer organoids using cells from patient tumors. Bladder cancer is the fifth most common type in the US, and this work, which was published in Cell, shows how organoids can guide the use of therapeutics in patients.
While genetic information about a patient can be a powerful tool and may help show what treatment is best for some kinds of cancer, it does not necessarily indicate how a patient will respond to specific therapeutics.
"The great advantage of organoids is that they are essentially avatars of a patient's tumor," explained study leader Michael M. Shen, Ph.D., professor of medicine, genetics & development, urology, and systems biology at Columbia University Vagelos College of Physicians and Surgeons. "Having these personalized laboratory models, which we can make in a matter of weeks, will let us test multiple different drugs on the tumor and help us bring precision medicine to individuals with bladder cancer."
Shen is a member of NewYork-Presbyterian/CUIMC's Herbert Irving Comprehensive Cancer Center who started developing organoids for bladder cancer around four years ago. That meant figuring out the specifications for growing them, including the environmental conditions, the nutrients, and culture techniques that keep them alive. These conditions can vary widely between different kinds of organoids.
In the current study, organoids were made from the tumor cells of 22 patients with invasive bladder cancer. They had many of the same genetic and molecular features as the patient tumors they were derived from; growing to about one millimeter in diameter, they also had a similar appearance. Genetic changes also happened to the tumors over time; a phenomenon called clonal evolution.
"Clonal evolution is a major driver of tumor progression and drug resistance. It's remarkably difficult to model for a solid tumor," said Shen. "With these organoids, we will be able to study how bladder tumors evolve and perhaps learn how to prevent tumors from becoming resistant to treatment."
Organoids were generated from samples taken from three patients before as well as after treatment. "This offers a new way to study the molecular mechanisms associated with drug response and drug resistance," noted Shen.
There is a lack of decent research models for bladder cancer. "The creation of bladder cancer organoids is an important advance in the field," noted study co-author James M. McKiernan, MD, the John K. Lattimer Professor of Urology and chair of urology at Columbia University Vagelos College of Physicians and Surgeons, and urologist-in-chief at NewYork-Presbyterian/Columbia. "This should greatly improve our understanding of the genomics of bladder cancer, how these tumors respond to drugs, and how they develop drug resistance. Ultimately, this may allow us to develop new therapies for the disease and predict an individual patient's response to treatment."
Now, tests are planned to evaluate how well the organoids predict outcomes. These "co-clinical" trials have patients and their organoids exposed to the same drug. "This would establish whether organoids can be used to predict how an individual patient will respond to a specific therapy," explained Shen. "At present, it's very difficult to know beforehand exactly which drugs may be most effective for a given patient."
Tumor removal and chemotherapy or immunotherapy is currently the mode of treatment when bladder cancer has not yet reached muscle tissue. These types of tumors tend to come back and need repeat treatments. They can progress to a harder to treat and deadlier form when a muscle is affected; such patients often have to have surgery for bladder removal.
"Since bladder removal has such a profound effect on quality of life, most patients seek to avoid it," said Shen. "We desperately need better, more targeted therapies for both types of bladder cancer."