Weill Cornell Medicine researchers have discovered a promising pancreatic cancer treatment target by utilizing organoids. In the study, the compound perhexiline maleate, a heart drug, showed strong suppression of the organoid's growth.
In the research, published in Cell Stem Cell, the team of researchers tested over 6,000 compounds on tumor organoids containing a common pancreatic cancer-causing mutation. Throughout the testing perhexiline maleate, an existing heart drug, was found to have a suppressing effect on the organoid's growth. Further testing also revealed that the mutation in the organoid causes a high level of cholesterol production, an effect that is largely reversed by the drug.
“Our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers,” said Dr. Todd Evans, study co-senior author.
In the study, researchers utilized an organoid-based automated drug screening system for pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer and the most lethal type of cancer. The organoids used were derived from mouse pancreatic tissue and engineered to contain various human pancreatic cancer mutations, including KrasG12D the mouse version of a mutant gene found in most PDAC.
The library of 6,000 compounds used for testing included FDA-approved drugs and several potential treatments were discovered throughout the analysis. However, perhexiline maleate showed the most promise as a treatment option with a small dose blocking growth in all the KrasG12D organoids and even destroying some within a few days. The drug also showed no adverse impact on healthy organoids that did not contain the mutation.
Despite the findings, Perhexiline maleate is unlikely to be a viable treatment option in its current state. Due to its serious potential side effects including liver damage and peripheral nerve damage the drug has been withdrawn from several markets including the European market and it was never approved for use in the United States.
The drug's simple chemical structure suggests that modifications could be made to improve its potency and safety, providing a better compound for cancer treatment. The team plans to use perhexiline maleate as a starting point to begin the development of a refined PDAC treatment option.