netrin-1

NEW YORK, June 17, 2024 /PRNewswire/ -- Kathryn J. Moore, PhD, the Jean and David Blechman Professor of Cardiology in the Department of Medicine at NYU Grossman School of Medicine, has been awarded the Lefoulon Delalande Institut de France Grand Prize in Science (the Grand Prix Scientifique) for 2024. Moore, also director of the Cardiovascular Research Center at NYU Langone Health, was honored for her answers to central questions in the field of cardiovascular physiology, including, for instance, how persistent activation of the immune system (chronic inflammation) by excess cholesterol drives the development of plaques in the arteries of patients with atherosclerosis. The award is conferred annually by the Lefoulon-Delalande Foundation at the Institut de France in various areas of medical science. With a different theme each year (but often focused on cardiology), the prize comes with a $650,000 award, making it the largest of its kind in cardiovascular research. Moore's research team discovered that the immune system recognizes certain (oxidized) forms of cholesterol using signaling proteins (receptors) designed to detect foreign invaders (e.g. bacteria). This immune response sets off chronic inflammation of the arteries that results in the formation of plaques, which compromise arterial blood flow and can lead to heart attacks. Moore and colleagues also showed that when immune system cells known as macrophages engulf oxidized cholesterol, it can lead to the formation of cholesterol crystals that sound an inflammatory alarm. These intracellular cholesterol crystals trigger a protein group called the NLRP3-inflammasome complex. This complex is responsible for generating the potent pro-inflammatory cytokine interleukin-1b, whose inhibition has been shown in clinical trials to reduce risk of cardiovascular events. "I am thrilled to receive this prize that honors the work carried out by my research team over the last two decades," said Moore. "It has been an honor to work with such talented trainees and world-class colleagues in pursuit of answers to why chronic inflammation develops in response to hyper-cholesterolemia and drives cardiovascular diseases that place such a burden on millions of patients globally." In other work, Moore and colleagues revealed the role of a molecule called netrin-1 in causing macrophages to accumulate in atherosclerotic plaques and fat (adipose) tissue of obese individuals to drive a vicious cycle of chronic inflammation, insulin resistance, and cardiometabolic disease. Moore also made discoveries on the role of tiny RNA molecules in regulating the pathways that control cholesterol levels in cells and the blood. She showed that these "microRNAs" can repress the pathways that help cells rid themselves of excess cholesterol, resulting in the accumulation of cholesterol-laden immune cells in plaques and the development of atherosclerotic disease. Importantly, she found that microRNAs, in particular miR-33, could be targeted therapeutically to promote the normal balance of cholesterol in the body. "The impact of Dr. Moore's work on both the current and near-future of treatment for cardiovascular diseases is nothing short of profound," said Glenn I. Fishman, MD, director of the Leon H. Charney Division of Cardiology at NYU Grossman School of Medicine. "It is great to see such an innovative and dedicated scientist be recognized in this way," added Fishman, also vice chair for research for the Department of Medicine. "There is no better example than Dr. Moore of the kind of exemplary scientist we seek to support at our institution," said Dafna Bar-Sagi, PhD, senior vice president, vice dean for science, and chief scientific officer at NYU Langone Health. "Congratulations to her and the entire cardiology team." Dr. Moore shares the award this year with Christopher Glass, MD, PhD, professor of Cellular and Molecular Medicine at the University of California at San Diego. Previous awards recognizing Dr. Moore's research include in 2022 a Gill Heart and Vascular Institute Award, given each year to honor individuals who have made outstanding contributions to the field of cardiovascular medicine. In 2021, she was elected to the National Academy of Sciences, among the highest honors in the scientific field. Members of the academy serve pro bono as "advisers to the nation" on science, engineering, and medicine. Lastly, in 2017, Dr. Moore received a $6.7 million "Outstanding Investigator Award" from the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. The award funded her work seeking to determine the role of an unusual form of genetic material called long noncoding RNA, or lncRNA. She found that this class of molecules regulates the body's immune response to plaques, which are made of cholesterol, fatty substances, and cellular waste that blocks arteries. Understanding IncRNAs may lead to new treatment approaches for cardiovascular diseases that remain the leading cause of death worldwide, she says. Contact: Gregory Williams, [email protected] SOURCE NYU Langone Health System

A new scientific finding is the foundation for the first clinical trial in the U.S. to study an experimental drug's ability to fight pancreatic cancer with metastasis to the liver.   Pancreatic cancer is tricky to manage because it spreads easily and early, and the tumors have a unique biological makeup. But, researchers made a breakthrough by learning about the genetic changes that occur during tumor migration -- and also found a drug that can obstruct the process. The next step is a groundbreaking clinical trial at the University of Rochester's Wilmot Cancer Institute, planned for early in 2024, to test the drug from their laboratory discovery, said senior investigator Darren Carpizo, MD, PhD, co-leader of Wilmot's Genetics, Epigenetics and Metabolism research program, and chief of Surgical Oncology at the University of Rochester Medical Center. "We will be the first institution in the U.S. to study the safety and effectiveness of the experimental drug, known as NP137, on pancreatic cancer that has spread to the liver," Carpizo said. Carpizo and several collaborators recently published the results of their bench science investigation in the journal Cell Reports, and Carpizo will lead the Wilmot clinical trial with Aram Hezel, MD, chief of Hematology/Oncology at Wilmot, and Nabeel Badri, MBChB, a medical oncologist at Wilmot. The five-year survival rate for pancreatic cancer is only 12 percent, which is a slight increase in 2023 compared to previous years. The number of cases is rising worldwide, however, and by 2030, pancreatic cancer is predicted to be the second leading cause of cancer deaths. Why is pancreatic cancer deadly? First, because it spreads (metastasizes) very early during its development. In 85 percent of patients, the cancer has already spread outside of the pancreas at diagnosis. Even when the cancer is localized to the pancreas and surgical removal is possible, the majority of patients face a recurrence of their cancer. The metastasis causes these patients to eventually succumb to the disease, which is why researchers are focused on understanding the biology of metastatic pancreatic cancer. Second, although pancreatic cancer cells do not have to travel far to reach the liver, along the way they genetically reprogram themselves and become stronger. The result: newly seeded cancer cells in the liver have a distinctly different biology from the primary tumor in the pancreas, and are able to resist standard treatment, Carpizo said. In their latest work, Wilmot researchers built on what was already known about a key gene, Netrin-1, involved in pancreas, breast and colon cancers. They discovered, for the first time, the complex mechanisms that allow Netrin-1 to drive the lethal, genetic changes as pancreatic cancer cells migrate to the liver. They also showed how Netrin-1 activates hepatic stellate cells, which are involved in liver fibrosis, a serious chronic disease, priming the liver as a host for cancer. In mice and in tissue studies, when researchers suppressed Netrin-1 with the anti-cancer drug (NP137), cancer was less likely to spread and cancer cell death occurred. The team includes scientists from Rutgers University, where Carpizo worked as a surgeon-scientist before joining Wilmot in 2020, Fox Chase Cancer Center in Philadelphia, and a laboratory in France. The Wilmot clinical trial will likely require eligible patients to take two cycles of NP137 before surgery, undergo surgery to remove the cancer, and then take more of the experimental medication along with chemotherapy after surgery for up to six months, Carpizo said. He noted that NP137 is made by Netris Pharma, of Lyon, France, and is currently being tested in clinical trials in that country. The Pancreatic Cancer Action Network (PanCAN) funded much of the work through a grant to Carpizo; Wilmot also provided pilot funding. PanCAN has emphasized that the recent, small uptick in survivorship rates for pancreatic cancer is due to transformative research and clinical trials, and strongly recommends that patients talk to their oncologists about clinical trials at every stage of their disease. Carpizo's study is part of a larger collaborative effort at Wilmot aimed at pancreatic cancer. Others, including URMC Surgery Chair David Linehan, MD., and Wilmot investigator Scott Gerber, PhD., and members of the Cancer Microenvironment research program, are also conducting studies on new, targeted treatments. The goal is to use newly discovered drugs in combination with immunotherapy, radiation therapy, and chemotherapy to attack pancreatic cancer.

In a new study published in the journal Nature, researchers have unveiled a promising therapeutic strategy for combating endometrial cancer (EC) by blocking the protein Netrin-1. The study, titled "Netrin-1 blockade inhibits tumor growth and EMT features in endometrial cancer," presents compelling evidence of the efficacy of a novel anti-Netrin-1 antibody in reducing tumor progression and inhibiting epithelial-to-mesenchymal transition (EMT). Blockade of Netrin-1Netrin-1, known for its critical role in neuronal navigation, angiogenesis, and cell survival during embryonic development, has been found to be upregulated in various types of cancers, including endometrial carcinomas. Leveraging this knowledge, the research team sought to investigate the potential of Netrin-1 blockade as a therapeutic approach for EC. The study commenced with an examination of Netrin-1 upregulation in human endometrial carcinomas, confirming its presence in the majority of cases. To test the effectiveness of Netrin-1 blockade, an anti-Netrin-1 antibody called NP137 was employed in an EC mouse model. The results demonstrated that NP137 effectively reduced tumor progression.  Building on these promising preclinical findings, the researchers conducted a Phase I trial involving 14 patients with advanced EC. Administering NP137 as a single agent, the trial yielded encouraging outcomes, with eight patients experiencing stable disease and one patient exhibiting an objective response as RECIST v.1.1 (Response Evaluation Criteria in Solid Tumours version 1.1, partial response, 1 out of 14, 51.16% reduction in target lesions at 6 weeks) as the best response to NP137 treatment, demonstrating a reduction in target lesions of up to 54.65% over six months.  To gain insights into the mechanism of action of NP137, the researchers performed gene profiling on mouse tumors. The analysis revealed that, in addition to inducing cell death, NP137 inhibited the process of epithelial-to-mesenchymal transition (EMT). To validate these findings in human patients, paired pre- and on-treatment biopsies from EC patients in the NP137 trial were subjected to various RNA sequencing techniques.  The researchers performed bulk RNA sequencing (RNA-seq) on matched pre-treatment and on-treatment biopsies from patients with endometrial cancer (EC) in the NP137 trial to evaluate the mechanism of action of NP137. Bulk RNA-seq is a technique that involves sequencing the total RNA pool from a tissue sample, as opposed to isolating individual cells. The researchers used this technique to identify changes in gene expression patterns in tumor cells before and after NP137 treatment. They found that NP137 treatment led to an overall decrease in tumor epithelial-to-mesenchymal transition (EMT), which was associated with changes in immune cell infiltration and increased interactions between cancer cells and the tumor microenvironment. This suggests that netrin-1 blockade using NP137 could be a promising clinical strategy for inhibiting tumor progression and EMT features in endometrial cancer by reducing netrin-1 signaling. Netrin-1 blockade inhibits endometrial adenocarcinoma progression in preclinical models.Combine with carboplatin-paclitaxelGiven the critical role of EMT in conferring resistance to current standard treatments, the researchers further explored the potential of combining NP137 with carboplatin-paclitaxel.  To evaluate the efficacy of combining NP137 with carboplatin-paclitaxel, experiments were conducted in an endometrial cancer (EC) mouse model. They found that the combination treatment resulted in both tumour shrinkage and inhibition of epithelial-to-mesenchymal transition (EMT), which could mitigate resistance to standard therapies. The researchers also performed bulk RNA sequencing, spatial transcriptomics, and single-cell RNA sequencing on matched pre- and on-treatment biopsies from NP137 trial patients with EC, and observed an overall reduction in tumour EMT that was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. The combination therapy outperformed carboplatin-paclitaxel alone in the EC mouse model, suggesting that NP137 can enhance the effectiveness of standard treatments. These experiments imply that blocking netrin-1 using NP137 in combination with carboplatin-paclitaxel could be a promising therapeutic strategy for treating endometrial cancer. These findings highlight the clinical significance of Netrin-1 blockade as a dual strategy, addressing both tumor debulking and EMT inhibition. By targeting Netrin-1, researchers believe they have the potential to overcome resistance to standard treatments, offering new hope to patients with endometrial cancer. This breakthrough study, led by Philippe A. Cassier and a team of international researchers, represents a major advancement in the field of cancer therapeutics. The identification of Netrin-1 blockade as a viable clinical strategy could pave the way for the development of targeted therapies for endometrial cancer and potentially other cancer types characterized by Netrin-1 upregulation. Clinical response in patients with EC following NP137 treatment.The research team plans to continue their investigations, conducting further clinical trials to validate the efficacy and safety of NP137 in a larger cohort of endometrial cancer patients. If successful, this approach could revolutionize the treatment landscape for endometrial cancer and potentially impact the broader field of cancer therapy. As the fight against cancer continues, the discovery of Netrin-1 blockade as a potential therapeutic breakthrough brings renewed hope for patients and clinicians alike, heralding a future where improved treatment options may become a reality. Reference Cassier, P.A., Navaridas, R., Bellina, M. et al. Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer. Nature (2023).