Researchers at Weill Cornell Medicine utilized a drug screening system employing lab-grown tissues known as organoids to unearth a promising target for future pancreatic cancer treatments. The study, published in Cell Stem Cell on Dec. 26, involved testing over 6,000 compounds on pancreatic tumor organoids containing a prevalent cancer-driving mutation. Among the compounds, an existing heart drug named perhexiline maleate emerged as a potent suppressor of organoid growth.
The researchers uncovered a crucial link—the cancer-driving mutation triggers an excessive production of cholesterol in the organoids, a process effectively reversed by the identified drug. Dr. Todd Evans, co-senior author and vice chair for research in surgery at Weill Cornell Medicine, emphasized the significance of targeting hyperactive cholesterol synthesis as a potential vulnerability in most pancreatic cancers.
Co-senior author Dr. Shuibing Chen, director of the Center for Genomic Health at Weill Cornell Medicine, highlighted the value of employing genetically well-defined organoids to model cancer and discover novel treatment strategies. This groundbreaking approach not only identifies a promising therapeutic target but also underscores the importance of precision and innovation in cancer research.
A tumor organoid-based screening system
Organoids have emerged as indispensable tools for studying tissues in health and disease, offering the ability to replicate complex organ architectures. Whether derived from human or animal tissue, organoids can be genetically engineered for precise modeling and have proven particularly valuable in mimicking tumor types with cancer-driving gene mutations.
In a groundbreaking study, researchers established an organoid-based automated drug-screening system tailored for pancreatic ductal adenocarcinoma (PDAC), the most common and challenging form of pancreatic cancer. These organoids, originating from normal mouse pancreatic tissue, were genetically modified to harbor various sets of mutations driving human pancreatic tumors, notably including the KrasG12D mutation.
Screening over 6,000 compounds, including FDA-approved drugs, identified perhexiline maleate as the most potent inhibitor of organoid growth. Originally used to treat angina, this drug exhibited a remarkable capacity to impede the growth of all KrasG12D-containing organoids, even causing the outright destruction of some within days. Crucially, it had no adverse effects on healthy organoids lacking the mutation. The drug's efficacy extended to both mouse and human PDAC-derived tumor organoids transplanted into mice, as well as human tumor organoids with other Kras mutations.
Analysis of treated and untreated organoids revealed that the cancer-associated mutant Kras significantly elevates cholesterol production in organoid cells. Perhexiline maleate counteracts this effect by inhibiting SREBP2, a key regulatory factor in the cholesterol metabolic pathway. This innovative approach not only identifies a promising candidate for PDAC treatment but unveils critical insights into the underlying mechanisms of cancer progression, potentially paving the way for more effective therapeutic strategies.
Cholesterol as an emerging cancer target
The revelation of cholesterol's pivotal role in pancreatic ductal adenocarcinoma (PDAC) was not entirely unexpected, given its fundamental role as a building block for new cells and a supporter of cell survival. This aligns with existing knowledge of cholesterol's significance in sustaining malignant growth in various tumors, including lung tumors. The study's findings propose that targeting cholesterol could emerge as a potent strategy in the fight against PDAC.
Perhexiline maleate's efficacy in human organoids carrying diverse Kras mutations suggests that disrupting turbo-charged cholesterol synthesis could be a universal treatment approach for KRAS-mutant cancers.
“We anticipate that our strategy targeting cholesterol will be broadly applicable across various KRAS mutations, potentially hindering the development of resistance in treated tumors,” stated Dr. Evans, a member of the Sandra and Edward Meyer Cancer Center.
While perhexiline maleate may not be directly used for PDAC treatment due to its associated side effects, the researchers aim to refine it into a more suitable candidate. Despite its withdrawal from certain markets in the 1980s, the drug's chemical simplicity offers promise for modification to enhance potency, safety, bloodstream half-life, and other crucial properties.
Dr. Chen expressed the team's intention to leverage perhexiline maleate as a foundation for developing an improved PDAC drug, as well as a valuable tool for investigating cholesterol synthesis in PDAC and other cancers. This marks a significant step toward translating research insights into potential clinical applications for more effective cancer treatments.
Source: Weill Cornell Medical College