New Hope for Understanding and Treating NETs

In the Form of Laboratory Mini-Organs

Will the ability of a Dutch molecular geneticist to build miniature human organs in a Petri dish solve a decade’s old problem in NET research? How the tiniest laboratory replicas of your small intestine might help scientists run a dress rehearsal to see if your next treatment will work.

The birth of the organoid

A little more than a decade ago, Hans Clevers, MD, PhD, Hubrecht Institute, the Netherlands, made an important discovery. He invented a way to activate the adult stem cell in the small intestine. Using a protein called Lgr5, Dr. Clevers’ laboratory jump-started the stem cell into performing its essential function of repairing and regenerating lost cells. With this finding, Dr. Clevers’ team started growing human organs in a dish to serve as a platform for testing.

They isolate a single stem cell from a tissue sample (healthy or cancerous) and put it in a dish with a gel containing growth factors. The cells replicate and generate new cells. As they expand, they self-organize into the structure of a mini-organ or organoid.

The quest for a NET laboratory model

Researchers use laboratory models to understand cancer cells and to test new treatments. But it has been difficult to produce laboratory models for neuroendocrine tumors. One reason is that the tumors are widely different from one another (called heterogenous). The slow growth of these cells also serves as a major obstacle in conducting efficient and accurate laboratory experiments.  For these reasons, there are only a few preclinical models available to study NET treatments.

NETRF has been involved in the quest to develop a reliable laboratory model for more than a decade. This void is a major obstacle in moving research forward, and it sets NETs apart from other cancer types in being able to achieve progress.

“Being able to create stable and reliable intestinal NET organoids from tumor tissues, that are able to expand indefinitely, will be a major breakthrough in the field of neuroendocrine cancers,” said Effie Tzameli, PhD, NETRF director of research. “For the first time, we will have a precious laboratory tool to use for different types of experimentation.”

The potential of the organoid

NETRF awarded Dr. Hans Clevers a 2017 Accelerator Award, our largest and longest research grant, providing funding for three years to test organoids in NETs. Dr. Clevers will study organoids made from healthy and NET cells to understand how cancer cells develop. He and his team will try to isolate what genomic mutations or cellular communication errors occur. If they identify what goes wrong they will then try to recreate that error using a gene-editing technique called CRISPR/Cas9. Reproducing the formation of NET cancer cells will help confirm the exact path of the disease.

Once the cancer cell development process has been mapped, researchers will look for an opportunity to interrupt this incorrect cellular cycle. They call this an actionable target. Therapies have been developed to act upon specific targets or genomic mutations, for example, by turning cell signaling on or off that is sending the incorrect instruction to create cancer cells.

Organoids can serve as an efficient way to test various therapies in the laboratory (preclinical testing) for large-scale drug testing. The technology could also be used to advance precision therapies. An individual’s tumor tissue, obtained from a biopsy, could be used to grow a person’s own organoid. Researchers could then test a therapy on the person’s organoid first to see if it works. That could help improve the safety, efficiency, and precision of care for individual NET patients.

Be part of a NET revolution

NETRF is working to transform the landscape of NET cancer research with this remarkable study and others of this magnitude. We won’t wait for technology to trickle down to this rare disease type. We are leveraging the most promising advances in science for NET patients today to create a better tomorrow. Put amazing science to work now to cure an uncommon cancer. Give to NETRF.