Mount Sinai researchers have developed a novel method to identify aggressive early-stage lung cancers and target drugs known as aurora kinase inhibitors to tumors that are especially likely to respond to them. The findings, published in Nature Communications on March 24, could lead to great advances in treatment for lung adenocarcinoma, the most common type of lung cancer.
The Mount Sinai team used a genomics network model to measure tumor invasiveness—distinguishing aggressive tumors from so-called “indolent” ones, which often cannot be told apart via chest CT scan—and identify those that will respond to aurora kinase inhibitors, molecules that can inhibit gene signature regulators.
“The approaches to diagnosing and treating early-stage lung adenocarcinoma are evolving and are based upon advances in understanding the biology and clinical activities of these tumors,” said senior author Charles Powell, MD, MBA, Janice and Coleman Rabin Professor of Medicine and Chief of Pulmonary, Critical Care and Sleep Medicine at the Icahn School of Medicine at Mount Sinai. “Our work using novel network approaches, in collaboration with Sema4, to identify signatures of invasiveness and to identify drugs that can intercept progression of these cancers should contribute to advancing the understanding and outcomes for this cancer.”
The research team used a genetically engineered mouse model to define the role of aurora kinases in early progression of the disease. They performed molecular profiling of early-stage lung cancer samples with RNA sequencing and identified signature genes associated with invasiveness of tumors. Researchers from Sema4 used novel genomic networking approaches to identify key network regulators and therapeutic drugs to demonstrate that targeting the signaling pathway reduces lung cancer spread and improves survival. They identified and tested aurora kinase inhibitors, including AMG900, as an effective treatment to intercept lung cancer progression in the models.
The researchers encourage further validation and clinical testing in human tumors. Future studies should examine opportunities to similarly intervene in signaling by immune cells or other cells in the surrounding tumor stroma, researchers said, since cancer progression relies on the interaction between tumor cells and surrounding cells.
Researchers from Weill Cornell Medicine-NewYork-Presbyterian Hospital and Sema4, a patient-centered health intelligence company, contributed to this study. This work was supported by grants from the National Institutes of Health (R01CA163772, R01HL130826, and R01CA240342), the New York State Stem Cell Science Program (C34052GG), the American Thoracic Society Foundation-Unrestricted Grant (ATS-2017-24), the American Lung Association of the Northeast Lung Cancer Discovery Award (LCD-504985), and the Department of Defense (W81XWH-19-1-0613).
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The Mount Sinai Health System is New York City’s largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai advances medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture ambulatory surgery centers; more than 415 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked on U.S. News & World Report’s “Honor Roll” of the top 20 U.S. hospitals and is top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. Mount Sinai Kravis Children’s Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report’s “Best Medical Schools,” aligned with a U.S. News & World Report “Honor Roll” Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.
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