Researchers utilize the organoid model to find possible novel treatments for pancreatic cancer.

According to a new study by researchers at Weill Cornell Medicine, a drug screening technique that uses lab-grown tissues called organoids to represent tumors has helped identified a promising target for future treatments for pancreatic cancer.

The scientists tested almost 6,000 substances on their pancreatic tumor organoids, which have a common mutation that causes pancreatic cancer, for their study, which was published on December 26 in Cell Stem Cell. One substance that effectively inhibits the formation of the organoids is perhexiline maleate, an already-approved heart medication.

Researchers found that the medicine largely reverses the unusually high production of cholesterol caused by the cancer-causing mutation in the organoids.

According to co-senior author of the study Dr. Todd Evans, vice chair for research in surgery, the Peter I. Pressman MD Professor in Surgery, and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine, “our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers.”

“This study also highlights the value of using genetically well-defined organoids to model cancer and discover new treatment strategies,” stated Dr. Shuibing Chen, a co-senior author and the director of the Center for Genomic Health at Weill Cornell Medicine. Dr. Chen is also the Kilts Family Professor of Surgery and a member of the Hartman Institute for Therapeutic Organ Regeneration.

An organoid-based tumor screening method

Organoids are now commonly used instruments in the study of tissues in both health and illness. They can be genetically modified for precise modeling, they can be fashioned from human or animal tissue, and they can replicate a large portion of the intricate architecture of an organ. Additionally, organoids with their cancer-causing gene alterations can mimic particular tumor forms. In fact, these tumor organoids may be able to simulate human tumors more accurately than any animal model when they are made from human tissue.
For pancreatic ductal adenocarcinoma (PDAC), the most frequent and deadly type of pancreatic cancer, the researchers in the study put up an organoid-based automated drug-screening system. Created using normal mouse pancreatic tissue, the organoids were modified to include several combinations of mutations that are known to cause pancreatic cancers in humans. KrasG12D, the mouse variant of a cancer-causing mutant gene present in the majority of PDAC cases, was present in all the organoids.
The researchers gave the organoids tests on a library of over 6,000 compounds, some of which were FDA-approved medications, and found that several of them might significantly impair the organoids’ ability to grow. The most effective of these was perhexiline maleate, an antiquated medication used to treat angina. All KrasG12D-containing organoids were prevented from growing by a low dosage of the medication, which also killed some of them completely in a matter of days. However, healthy organoids without the mutation were unaffected by the medication.When the medication was applied to human tumor organoids with different types of Kras mutations as well as PDAC-derived tumor organoids from mice, the results were comparable.Researchers discovered that cancer-associated mutnt Kras significantly increases the synthesis of cholesterol in organoid cells by comparing gene activity patterns in treated and untreated organoids