New methods for identifying novel drug targets to treat pancreatic cancer are critical. Now, a drug screening system using organoids, that models pancreatic cancer, has helped uncover a promising target for potential pancreatic cancer treatments.

In the study, scientists at Weill Cornell Medicine tested more than 6,000 compounds on the pancreatic tumor organoids, which contain a common pancreatic cancer-driving mutation. They identified one compound—an existing heart drug called perhexiline maleate—that powerfully suppressed the organoids’ growth.

The work was published recently in Cell Stem Cell, in a paper titled, “A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS.

The study highlights “the value of using genetically well-defined organoids to model cancer and discover new treatment strategies,” said Shuibing Chen, MD, director of the Center for Genomic Health and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine.

In the study, the researchers set up an organoid-based automated drug-screening system for the most common form—but a highly untreatable and lethal form of pancreatic cancer— pancreatic ductal adenocarcinoma (PDAC). The organoids were engineered to contain various sets of mutations known to drive human pancreatic tumors. All the organoids contained KrasG12D, the mouse version of a cancer-driving mutant gene found in most cases of PDAC.

The researchers tested a library of more than 6,000 compounds, including FDA-approved drugs, on the organoids, identifying several that could substantially disrupt their growth. They found that a modest dose of perhexiline maleate—an older drug used to treat the heart condition known as angina—blocked growth in all the KrasG12D-containing organoids. In addition, it destroyed some of them within days while having no adverse impact on healthy organoids lacking the mutation. The drug had similar effects against mouse and human PDAC-derived tumor organoids transplanted into mice, and in human tumor organoids carrying other types of Kras mutation.

By comparing gene activity patterns in treated and untreated organoids, the researchers found that cancer-associated mutant Kras greatly boosts the production of cholesterol in organoid cells, and that perhexiline maleate opposes this effect by inhibiting a key cholesterol metabolic pathway regulatory factor called SREBP2.

“Our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers,” said Todd Evans, MD, vice chair for research in surgery and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine.

The discovery of cholesterol’s role was not entirely surprising, since cholesterol is already known to be an important sustainer of malignant growth for some other tumors, including lung tumors. Now, the results suggest that targeting it may be an effective new treatment strategy against PDAC.

Perhexiline maleate’s effectiveness in human organoids harboring several different Kras mutations also suggests that turbo-charged cholesterol synthesis can be a general treatment target in KRAS-mutant cancers.

“We hope that our cholesterol-targeting strategy will be independent of particular KRAS mutations and will make it hard for treated tumors to evolve resistance,” said Evans.

Perhexiline maleate is unlikely to be used as-is for treating PDAC. Although it is still prescribed as an angina drug in Australia and some other countries, it can have serious side effects, including liver damage and peripheral nerve damage—which is why it was withdrawn from several European markets in the 1980s, and was never approved in the United States.

The team now plans to use perhexiline maleate as a starting point for the development of a more refined candidate PDAC drug, and as a laboratory tool for studying cholesterol synthesis in PDAC and other cancers.

Previous articleCell That Helps Prevent Cellular Senescence Uncovered
Next articleNovartis, Voyager Ink Up-to-$1.3B Expansion of Neuro Gene Therapy Collaboration