New drug screening technology finds pancreatic cancer therapeutic target

According to a new study from Weill Cornell Medicine researchers, a drug screening technique that models malignancies using lab-grown tissues called organoids has helped find a promising target for future pancreatic cancer treatments.

The researchers tested over 6,000 substances on their pancreatic tumor organoids, which carry a common pancreatic cancer-causing mutation, in the study, which was published on December 26 in Cell Stem Cell. They discovered one molecule, perhexiline maleate, an existing cardiac medication, that effectively slows the growth of the organoids.

The researchers observed that the cancer-causing mutation in the organoids causes unusually high cholesterol synthesis, which the medication effectively reverses.

“Our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers.” Dr. Todd Evans, study co-senior author, 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

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

Dr. Fong Cheng Pan, a research assistant professor in the department of surgery at Weill Cornell Medicine at the time of the study, was the other co-senior author.

Dr. Xiaohua Duan, a postdoctoral researcher, Dr. Tuo Zhang, an instructor, and Dr. Lingling Feng, a visiting fellow, were all at Weill Cornell Medicine at the time of the study.

A screening technique based on tumor organoids

Organoids have grown in popularity as a technique for investigating tissues in both health and disease. They can be produced from human or animal tissue, can mimic much of the complicated architecture of an organ, and can be genetically altered for precision modeling. With their cancer-causing gene alterations, organoids can also model specific tumor types. Indeed, when produced from human tissue, these tumor organoids have the potential to better simulate human diseases than any animal model.

The researchers created an organoid-based automated drug-screening method for pancreatic ductal adenocarcinoma (PDAC), the most frequent form of pancreatic cancer and one of the most untreatable and fatal malignancies. The organoids were created from normal mouse pancreatic tissue and modified to have a variety of mutations known to cause human pancreatic cancers. KrasG12D, the mouse form of a cancer-causing mutant gene implicated in the majority of instances of PDAC, was discovered in all of the organoids.

The researchers tested a library of over 6,000 substances on the organoids, including FDA-approved medications, and identified many that may significantly disturb their growth. Perhexiline maleate, an older medicine used to treat the heart ailment angina, was the most effective. A low dose of the medicine inhibited growth in all KrasG12D-containing organoids, killing some of them within days, while having no effect on healthy organoids lacking the mutation. The treatment demonstrated similar effects on mouse and human PDAC-derived tumor organoids implanted into mice, as well as on human tumor organoids with additional types of Kras mutations.

By comparing gene activity patterns in treated and untreated organoids, the researchers discovered that cancer-associated mutant Kras significantly increases cholesterol production in organoid cells, and that perhexiline maleate counteracts this effect by inhibiting SREBP2, a key cholesterol metabolic pathway regulatory factor.

Cholesterol as a novel cancer target

The revelation of cholesterol’s participation was not wholly unexpected given that cholesterol is an essential building block utilized in the formation of new cells and a promoter of cell survival; it is also known to be a major sustainer of malignant growth in various other malignancies, particularly lung tumors. The findings suggest that targeting it could be a viable new therapy option for PDAC.

The efficacy of perhexiline maleate in human organoids with various Kras mutations shows that increased cholesterol production could be a broad therapy target in KRAS-mutant malignancies.

“We hope that our cholesterol-targeting strategy will be independent of specific KRAS mutations and will make it difficult for treated tumors to evolve resistance,” Dr. Evans, a member of the Sandra and Edward Meyer Cancer Center, stated.

Perhexiline maleate is unlikely to be employed in its current form to treat PDAC. Although it is currently used to treat angina in Australia and some other countries, it has major adverse effects such as liver damage and peripheral nerve damage, which is why it was withdrawn from numerous European markets in the 1980s and was never approved in the US.

“We want a better compound for cancer treatment,” Dr. Chen explained. She believes that because the drug’s chemical structure is simple, it may be tweaked to improve its potency, safety, bloodstream half-life, and other qualities.

Perhexiline maleate will now be used as a starting point for the creation of a more refined prospective PDAC medication, as well as a laboratory tool for researching cholesterol production in PDAC and other malignancies.

For more information: A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS, Cell Stem Cell, https://doi.org/10.1016/j.stem.2023.11.011