Researchers at Weill Cornell Medicine have made a significant breakthrough in pancreatic cancer treatment using organoids, lab-grown tissues that model cancers.
Published in Cell Stem Cell on December 26, the study demonstrates the potential of using an existing heart drug, perhexiline maleate, to combat pancreatic cancer.
Led by Dr. Todd Evans and Dr. Shuibing Chen, the research team tested over 6,000 compounds on pancreatic tumor organoids. These organoids contained a common mutation driving pancreatic cancer and exhibited accelerated cholesterol production.
Perhexiline maleate, known for treating heart conditions like angina, emerged as a powerful suppressant of the organoids’ growth. It reverses the abnormal cholesterol production triggered by the cancer-driving mutation.
Dr. Evans, vice chair for research in surgery at Weill Cornell Medicine, emphasized the importance of hyperactive cholesterol synthesis as a targetable vulnerability in most pancreatic cancers.
Dr. Chen, director of the Center for Genomic Health, highlighted the value of using genetically well-defined organoids for modeling cancer and discovering new treatment strategies.
Organoids are increasingly used for studying health and disease because they can replicate much of an organ’s complexity and can be genetically engineered for precision modeling.
In this study, the organoids, made from mouse pancreatic tissue, were engineered with mutations found in human pancreatic tumors.
The researchers identified several compounds that disrupted the growth of these organoids, with perhexiline maleate showing the most promise.
This drug not only inhibited the growth of mouse organoids but also demonstrated effectiveness against human-derived tumor organoids transplanted into mice.
Gene activity analysis revealed that the drug inhibits a key cholesterol metabolic pathway regulatory factor, SREBP2.
Cholesterol is a critical component in cell survival and is known to sustain malignant growth in various tumors.
This study suggests that targeting cholesterol synthesis could be an effective new treatment strategy against pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers.
The discovery that perhexiline maleate is effective against human organoids with different Kras mutations indicates that cholesterol synthesis could be a broad treatment target in KRAS-mutant cancers.
The team hopes this cholesterol-targeting strategy will be effective regardless of specific KRAS mutations and make it difficult for treated tumors to develop resistance.
However, perhexiline maleate, while still used in some countries, has serious side effects, including liver and nerve damage. It was withdrawn from several European markets in the 1980s and never approved in the United States.
The team, therefore, seeks to modify its chemical structure to enhance its potency, safety, and other properties for cancer treatment.
This study marks a promising direction in the fight against pancreatic cancer. The team plans to use perhexiline maleate as a basis for developing a refined PDAC drug and as a tool for studying cholesterol synthesis in PDAC and other cancers.
This approach opens up new avenues for treating one of the most challenging cancers, offering hope for more effective therapies.
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The research findings can be found in Cell Stem Cell.
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