Stem Cell Models Point to New Treatment Avenues for Pancreatic CancerNews
The Context: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the US, and is one of the most untreatable and lethal of cancers. Scientists are in desperate need of new ways to find drugs that can stop or slow progression of this disease.
The Study: By testing thousands of drugs on 3D stem cell models of the pancreas called organoids containing common pancreatic cancer-causing mutations, a team co-led by NYSCF – Robertson Stem Cell Investigator Alumna Shuibing Chen, PhD, of Weill Cornell Medicine, identified a new heart disease drug that inhibits pancreatic cancer growth. The research appears in Cell Stem Cell.
The Importance: This study demonstrates the power of organoids for testing new drugs and highlights the importance of cholesterol as a target for precision therapies in pancreatic cancer.
You likely recognize pancreatic cancer as one of the most severe and deadly forms of the disease. Current drugs aren’t quite cutting it, but thanks to stem cells and advances in drug testing, new therapies could be closer than you think.
Organoids Open the Door for Drug Testing
Organoids are 3D models of human tissue made from stem cells, and they can provide an unprecedented glimpse into what is happening inside the human body, as well as serve as testing material for new drugs.
“This study highlights the value of using genetically well-defined organoids to model cancer and discover new treatment strategies,” Dr. Chen said in an article from Weill Cornell.
In their experiment, the team created pancreatic organoids that carried certain genetic mutations in a gene called Kras known to be associated with pancreatic cancer. Then, they tested more than 6,000 drugs (many of which were already FDA-approved) on these organoids to see which could disrupt organoid growth (and thus might be able to disrupt tumor growth).
Interestingly, a drug called perhexiline maleate, used to treat angina – a condition that reduces blood flow to the heart, blocked growth in the cancer mutation-carrying organoids, causing them to wither away within days. In healthy organoids, the drug showed no adverse effects. The team then transplanted pancreatic organoids into mice and treated them with the drug, finding similar results.
Why a Heart Drug?
You might be wondering how a heart drug could be impacting pancreatic tumors. The answer, it seems, lies with cholesterol.
The cancer-associated mutations, the team found, were boosting production of cholesterol in the organoids. Cholesterol is also a big player in heart conditions, and perhexiline maleate can slow its production.
“Our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers,” noted study co-senior author Todd Evans, PhD. “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.”
Perhexiline maleate is, in its current form, likely not a suitable candidate for widespread use as a cancer treatment. It can carry some serious side effects such as liver and peripheral nerve damage, and is not approved in the United States. However, Dr. Chen notes that the drug can likely be tweaked to make it more appropriate for clinical use.
“We want a better compound for cancer treatment,” said Dr. Chen. “The simplicity of the drug’s chemical structure suggests that it probably can be modified to improve its potency, safety, bloodstream half-life and other properties.”
A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS
Xiaohua Duan, Tuo Zhang, Lingling Feng, Neranjan de Silva, Benjamin Greenspun, Xing Wang, Jenna Moyer, M. Laura Martin, Rohit Chandwani, Olivier Elemento, Steven D. Leach, Todd Evans, Shuibing Chen, Fong Cheng Pan. Cell Stem Cell. 2023. DOI: https://doi.org/10.1016/j.stem.2023.11.011
Cover image: Perhexiline maleate induces cell death of human pancreatic cancer organoids. (Red: Cell death marker; Blue: DAPI) Credit: Xiaohua Duan