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Under the Microscope: Organoids for Pancreatic Cancer

Despite impressive breakthroughs for treating many types of cancer, pancreatic cancer remains poorly understood and difficult to treat. Only about a third of patients survive for five years after their diagnosis, in part because it is hard to catch pancreatic cancer early and the cancer grows extremely quickly. This means that from the moment a person is diagnosed, every second counts.

“The problem with pancreatic cancer is that we don’t have enough time to find its Achilles’ heel,” explained David Tuveson, PhD, Professor and Director of Cold Spring Harbor Laboratory Cancer Center. “If we can slow it down, we might have time to find the solution to each patient’s tumor.”

Tuveson and his colleagues have spent years trying to understand why pancreatic cancer is so aggressive and what treatments could work better. Now, the team is using an innovative research method to help doctors match patients with treatments that are most likely to work for them.

 

Making a better model

Several years ago, Tuveson and his team became frustrated at how cancer cells grown in a layer on the bottom of petri dishes don’t resemble real tumor cells. To make a model that acts more like an actual tumor, they adopted a method to grow cancer cells in 3D, called organoids, from pancreatic tumors obtained from real patients. Researchers have recently used similar techniques to grow mini brains, intestines, livers and other organs to study other diseases.

Tuveson’s team quickly found that their pancreatic tumor organoids maintained the characteristics of cancer cells much better than traditional cancer cell cultures. With a V Foundation Translational Grant, the researchers tested the organoids’ game-changing potential by exposing them to different treatments, including both experimental drugs and ones that are already in clinical use.

Just like real tumors, some organoids responded well to treatment, while others resisted. To find out why, the researchers examined differences in the gene expression found in various organoids and grouped them according to how they reacted to each treatment.

They discovered that most tumors had one of four gene expression “signatures.” Tumors in the first three groups were affected by various treatments, while those in the fourth group did not respond to any drug. While this fourth group is vexing, Tuveson said that knowing a tumor is not likely to respond to available treatments can help researchers decide where to focus their search for new drugs and help patients and doctors know when it’s worth trying an experimental therapy.

 

Following the signatures to guide treatment strategies

After identifying the four signatures through their organoid studies, the team combed through genetic data collected during previous clinical trials. Sure enough, they found a correlation between the gene expression signatures and patient outcomes. That exciting insight suggests it may be possible for doctors to test a patient’s tumor shortly after diagnosis and use its signature to determine the best treatment option.

“When we got the V Foundation grant, we didn’t know that the organoids would reveal these four signatures,” said Tuveson. “Because they did, we shifted our focus to clinical trials.”

With a new international clinical trial, the team aims to confirm that the signatures can accurately predict a patient’s response to chemotherapy, further refine the signatures, and ultimately use the signatures to guide treatment decisions. If successful, the approach could be a powerful, personalized tool to quickly and reliably find the most effective therapy for each patient.

“If we can identify the right treatment up front, patients will get the best clinical outcome,” said Tuveson, who credits the V Foundation for helping his team move from laboratory studies to clinical trials in just a few years.

“[Our V Foundation grant] was catalytic funding, and the project ballooned very rapidly into something beyond what we hoped for,” said Tuveson. “I’m extremely grateful to the V Foundation for believing in this early on, when we had hope but not evidence. Now, we have evidence.”

While the Achilles’ heel of pancreatic cancer has still not been solved, the signatures discovered in Tuveson’s organoids could help doctors buy more time as they search for effective treatments—and give patients and their families more reason to hope.