SREBP-2

A groundbreaking study presents crucial insights into the ocular effects of Zika virus infection during pregnancy and offers promising avenues for therapeutic intervention. A groundbreaking study published in the journal iScience presents crucial insights into the ocular effects of Zika virus infection during pregnancy and offers promising avenues for therapeutic intervention. Produced by a team of researchers in the Department of Ophthalmology, Visual and Anatomical Sciences at the Wayne State University School of Medicine, the paper, "Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology," provides compelling evidence of the involvement of cholesterol metabolism in ZIKV-related eye abnormalities. Zika virus, or ZIKV, has emerged as a public health threat and poses significant challenges to reproductive health worldwide. While congenital ZIKV infection has been shown to cause neurological disorders, primarily microcephaly -- abnormal shrinking of the head circumference -- several clinical studies have linked ZIKV to ocular deformities in infants. These include retinal lesions, microphthalmia, hemorrhagic retinopathy, retinal pigmented epithelium mottling, optic neuritis and hypoplasia of the optic nerve. Despite the ZIKV infection causing severe neurological and ocular abnormalities in infants, no specific vaccines or antiviral treatments are available. In their research, the team conducted a transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells, revealing significant alterations in the cholesterol pathway. "Our study aimed to uncover the molecular mechanisms underlying ZIKV-related eye abnormalities, with a focus on cellular metabolism," said Ashok Kumar, Ph.D., professor of ophthalmology, visual and anatomical sciences, and senior author of the study. "By elucidating the roles of key players in cholesterol metabolism, we sought to identify potential targets for therapeutic intervention." The researchers investigated the functional roles of ATP-binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREBP-2), two critical regulators of cholesterol metabolism, during ocular ZIKV infection. Their cell culture experiments demonstrated that increased ABCG1 activity, mediated via liver X receptors (LXRs), led to reduced ZIKV replication, while inhibition of SREBP-2 reduced viral replication by lowering cholesterol levels. In vivo studies using mouse models of ZIKV-induced chorioretinal lesions revealed that treatment with an LXR agonist or SREBP-2 inhibitor mitigated ocular abnormalities associated with ZIKV infection. These treatments were accompanied by decreased expression of inflammatory mediators and increased activation of antiviral response genes. "This study highlights the intricate interplay between cholesterol metabolism and ZIKV infection in the eye," explained Sneha Singh, Ph.D., a postdoctoral fellow in Kumar's lab. "Our findings suggest that targeting cholesterol pathway components, such as ABCG1 and SREBP-2, could offer promising therapeutic strategies for mitigating ZIKV-induced ocular complications." "The implications of our study extend beyond Zika virus, as the mechanisms uncovered can potentially apply to other enveloped viruses such as West Nile virus, Japanese encephalitis virus and Dengue virus," Kumar said. Kumar's team is utilizing a lipidomics approach to pinpoint lipid molecules possessing both proviral and antiviral properties, with the overarching goal of unearthing novel antiviral therapeutics. The publication of this paper underscores Wayne State's commitment to advancing scientific knowledge and addressing pressing global health challenges. The interdisciplinary collaboration and innovative methodologies employed in this research exemplify the institution's dedication to excellence in scientific inquiry. "Through the innovative research team that Dr. Kumar has established, they are at the forefront of developing breakthroughs that will play a vital role in therapeutic interventions in eye abnormalities caused by the Zika virus," said Ezemenari M. Obasi, Ph.D., vice president for research at Wayne State. "This study is an excellent example of how Wayne State's research is making discoveries that can impact lives in Detroit and around the world." This research was made possible through funding from the National Institutes of Health's National Eye Institute (Grants: R21AI135583, R01EY026964, 1R01EY032149-01 and R01 EY027381).

An image of cancer organoid cells treated with perhexiline maleate. The red in the image is a marker of cell death, indicating where the cells were destroyed by the drug. Scientists have shown that an old heart drug can inhibit growth of one of the most common and lethal forms of pancreatic cancer, at least in preclinical models.  In a study published Dec. 26 in Cell Stem Cell, researchers from Weill Cornell Medicine showed that perhexiline maleate—a calcium channel blocker used to treat angina—could stifle the growth of KRAS-G12D-mutated pancreatic ductal adenocarcinoma in human organoid models that had been transplanted into mice. Its mechanism of action could form the basis of future drugs.  Perhexiline maleate, prescribed as Pexid or Pexsig, was used as an anti-angina treatment until the 1980s, when it was sidelined in most countries due to its side effect profile, a review article by researchers at the University of Adelaide explains. While the drug was never approved for use in the U.S., it is still used by clinicians in New Zealand and Australia. It works by shifting the metabolism of fatty acids and carbohydrates in a way that helps the heart process oxygen more efficiently, thus reducing the symptoms of angina.   Scientists first demonstrated perhexiline’s anti-cancer potential in 1984, when they showed that it could sensitize leukemia cells to chemotherapy. Since then, it has shown to not only boost chemo but also to inhibit growth on its own in cell lines and mouse models of breast, lung, brain, liver and other cancers with a variety of different gene mutations.  In the new study, the researchers didn’t set out to test perhexiline maleate specifically. They started by setting up an automated drug screening system that looked at the efficacy of different drugs on organoids made from mouse pancreatic cells that had been engineered with the many different types of mutations associated with pancreatic ductal adenocarcinoma, including a mouse version of KRAS-G12D. Organoids are three-dimensional cell cultures grown from stem cells that function like the tissue of the organ they represent.  Of the 6,000 compounds tested, perhexiline maleate emerged the winner. The drug was able to not only stop all of the cancerous organoids from growing, but even destroyed some of them altogether. It also appeared to have no effect on healthy, non-mutated organoid cells.  The researchers then tested perhexiline maleate on mice transplanted with the same type of organoids, along with another group that received human-derived cancerous organoids. The drug inhibited the growth of the cells in both of those models, along with a separate set of human-derived pancreatic cancer organoids with different types of KRAS mutations.  When the researchers compared gene patterns between treated and untreated organoids, they noticed that the KRAS-G12D mutation was boosting the production of cholesterol in the mutated cells. Perhexiline maleate was counteracting that effect, thereby stopping the cancerous organoids from growing, by inhibiting a protein involved in cholesterol synthesis called SREBP2.  While this wasn’t news to the researchers, as cholesterol is well known to play a role in cancer progression and synthesis, it did mark the first time that scientists had shown that targeting it could be effective against pancreatic ductal adenocarcinoma with KRAS-G12D mutations. The fact that it worked in human organoids with other types of KRAS mutations could mean that the treatment mechanism is less vulnerable to being overcome by cancer resistance, the researchers noted in a press release.  In the same release, the scientists added perhexiline maleate itself will not be used as an anti-cancer agent, as the risk of side effects—namely liver and nerve damage—is too high. Instead, researchers will likely tinker with its chemical structure to come up with a candidate that has the same anti-cancer effects without the drawbacks.

A drug screening system that models cancers using lab-grown tissues called organoids has helped uncover a promising target for future pancreatic cancer treatments. A drug screening system that models cancers using lab-grown tissues called organoids has helped uncover a promising target for future pancreatic cancer treatments, according to a new study from researchers at Weill Cornell Medicine. In the study, published Dec. 26 in Cell Stem Cell, the scientists tested more than 6,000 compounds on their pancreatic tumor organoids, which contain a common pancreatic cancer-driving mutation. They identified one compound -- an existing heart drug called perhexiline maleate -- that powerfully suppresses the organoids' growth. The researchers discovered that the cancer-driving mutation in the organoids forces the abnormally high production of cholesterol, which the drug largely reverses. "Our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers," said study co-senior author Dr. Todd Evans, vice chair for research in surgery, the Peter I. Pressman MD Professor in Surgery, and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine. "This study also highlights the value of using genetically well-defined organoids to model cancer and discover new treatment strategies," said co-senior author Dr. Shuibing Chen, director of the Center for Genomic Health, the Kilts Family Professor Surgery and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine. The other co-senior author was Dr. Fong Cheng Pan, a research assistant professor in the department of surgery at Weill Cornell Medicine during the study. The study's co-first authors were postdoctoral researcher Dr. Xiaohua Duan, instructor Dr. Tuo Zhang, and a visiting fellow, Dr. Lingling Feng, all at Weill Cornell Medicine during the study. A Tumor Organoid-Based Screening System Organoids have become popular tools for studying tissues in health and disease. They can be made from human or animal tissue, they can recreate much of an organ's complex architecture, and they can be genetically engineered for precision modeling. Organoids can also model specific tumor types with their cancer-driving gene mutations. Indeed, when these tumor organoids are derived from human tissue, they have the potential to model human cancers better than any animal model. In the study, the researchers set up an organoid-based automated drug-screening system for the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) -- one of the most untreatable and lethal of cancers. The organoids, made from normal mouse pancreatic tissue, were engineered to contain various sets of mutations known to drive human pancreatic tumors. All the organoids contained KrasG12D, the mouse version of a cancer-driving mutant gene found in most cases of PDAC. The researchers tested a library of more than 6,000 compounds, including FDA-approved drugs, on the organoids, identifying several that could substantially disrupt their growth. The best of these was perhexiline maleate, an older drug used to treat the heart condition called angina. A modest dose of the drug blocked growth in all the KrasG12D-containing organoids, destroying some of them outright within days, while having no adverse impact on healthy organoids lacking the mutation. The drug had similar effects against mouse and human PDAC-derived tumor organoids transplanted into mice, and in human tumor organoids carrying other types of Kras mutation. By comparing gene activity patterns in treated and untreated organoids, the researchers found that cancer-associated mutant Kras greatly boosts the production of cholesterol in organoid cells, and that perhexiline maleate opposes this effect by inhibiting a key cholesterol metabolic pathway regulatory factor called SREBP2. Cholesterol as an Emerging Cancer Target The discovery of cholesterol's role was not entirely surprising, since cholesterol is an essential building-block used in making new cells, and a promoter of cell survival; it is already known to be an important sustainer of malignant growth for some other tumors, including lung tumors. Now, the results suggest that targeting it may be an effective new treatment strategy against PDAC. Perhexiline maleate's effectiveness in human organoids harboring several different Kras mutations also suggests that turbo-charged cholesterol synthesis can be a general treatment target in KRAS-mutant cancers. "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," said Dr. Evans, who is also a member of the Sandra and Edward Meyer Cancer Center . Perhexiline maleate is unlikely to be used as-is for treating PDAC. Although it is still prescribed as an angina drug in Australia and some other countries, it can have serious side effects, including liver damage and peripheral nerve damage -- which is why it was withdrawn from several European markets in the 1980s, and was never approved in the United States. "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, she said. The team now plans to use perhexiline maleate as a starting point for the development of a more refined candidate PDAC drug, and as a laboratory tool for studying cholesterol synthesis in PDAC and other cancers.