Perhexiline Maleate Might Good Approach for Pancreatic Cancer Management

In a groundbreaking study conducted by researchers at Weill Cornell Medicine, a drug screening system utilizing lab-grown tissues called organoids has unveiled a potential target for future pancreatic cancer treatments. The study, published on December 26 in Cell Stem Cell, employed more than 6,000 compounds to test pancreatic tumor organoids, revealing that an existing heart drug, perhexiline maleate, effectively suppressed the growth of these organoids. 

The pancreatic tumor organoids used in the study contained a common pancreatic cancer-driving mutation. The researchers identified that the mutation led to abnormally high cholesterol production in the organoids, and perhexiline maleate was found to significantly reverse this effect. 

Dr. Todd Evans, study co-senior author and vice chair for research in surgery at Weill Cornell Medicine, emphasized the significance of the findings, stating, “Our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers.” Dr. Shuibing Chen, co-senior author and director of the Center for Genomic Health at Weill Cornell Medicine, highlighted the value of genetically well-defined organoids in modeling cancer and discovering new treatment strategies. 

Organoids have emerged as valuable tools for studying tissues in health and disease. These structures, derived from human or animal tissue, can accurately recreate an organ’s complex architecture and be genetically engineered for precise modeling. The study focused on pancreatic ductal adenocarcinoma (PDAC), the most common and challenging form of pancreatic cancer. 

The researchers established an organoid-based automated drug-screening system using normal mouse pancreatic tissue engineered to contain various mutations known to drive human pancreatic tumours. All organoids contained KrasG12D, a cancer-driving mutant gene found in most PDAC cases. Over 6,000 compounds, including FDA-approved drugs, were tested on these organoids, with perhexiline maleate emerging as the most effective in suppressing growth. 

The researchers discovered that the cancer-driving mutation in the organoids stimulated abnormally high cholesterol production. Perhexiline maleate, an older drug used to treat angina, proved highly effective in blocking growth in organoids containing the KrasG12D mutation. The drug exhibited similar effects in mouse and human PDAC-derived tumor organoids transplanted into mice and in human tumor organoids with other Kras mutations. 

By comparing gene activity patterns in treated and untreated organoids, the team identified that the mutant Kras gene significantly increased cholesterol production, and perhexiline maleate counteracted this effect by inhibiting a key regulatory factor in cholesterol metabolism called SREBP2. 

While the role of cholesterol in promoting cell growth and survival is known, the study suggests that targeting cholesterol may be an effective treatment strategy against PDAC. Perhexiline maleate’s effectiveness across various Kras mutations indicates that cholesterol synthesis could be a general treatment target in KRAS-mutant cancers. 

Dr. Evans expressed optimism about the potential of a cholesterol-targeting strategy, anticipating it to be independent of specific KRAS mutations and making it challenging for treated tumours to develop resistance. 

While perhexiline maleate itself may not be directly used for treating PDAC due to potential side effects, the researchers plan to use it as a starting point for developing a more refined candidate drug. Dr. Chen emphasized the need for a better compound for cancer treatment, considering the side effects associated with perhexiline maleate. The team aims to modify the drug’s chemical structure to improve its potency, safety, bloodstream half-life, and other properties. 

In conclusion, this groundbreaking study not only identifies a promising target for pancreatic cancer treatment but also underscores the value of organoid-based drug screening systems in understanding and combating complex diseases. The findings pave the way for further research and development of refined drugs with enhanced efficacy and safety profiles for treating pancreatic cancer. 

Journal Reference  

Xiaohua Duan et al, A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS, Cell Stem Cell (2023). DOI: 10.1016/j.stem.2023.11.011.