Researchers Identify Potential Targeted Therapy for Lung Cancer Using Fly Model
A drug approved by the Food and Drug Administration (FDA) for melanoma in combination with a common cholesterol-lowering drug may show promise in controlling cancer growth in patients with non-small cell lung cancer (NSCLC), according to new research from the Icahn School of Medicine at Mount Sinai. Study findings will appear in the February 16 print issue of the journal Cell Report.
Lung cancer remains the No. 1 cancer killer in both men and women, and causes more deaths than breast, prostate, colon, and pancreatic cancers combined. It is often discovered too late to be treated successfully, and current therapies are highly toxic. Researchers have attempted to identify targeted therapies that are effective and do not harm unaffected tissues.
A team of researchers, led by Ross Cagan, PhD, developed a multi-gene lung cancer model in the fruit fly Drosophila to better understand the mechanisms that promote tumors in NSCLC. Previous studies have highlighted the similarities among key genes in fruit flies and people. Using both fruit fly and human lung cancer cell lines, researchers targeted two of the most common genetic mutations associated with NSCLC— Ras and PTEN (P13K).
“We developed Drosophila lung cancer models by targeting Ras alone and in combination with PTEN knockdown in the tracheal system of the fruit fly,” says Cagan, PhD, Professor in the Department of Developmental & Regenerative Biology, Senior Associate Dean of the Graduate School of Biomedical Sciences, and Director of the Center for Personalized Cancer Therapeutics at Icahn School of Medicine at Mount Sinai. “This led to formation of tumor-like growths.”
Using a robotics-based screening approach, researchers screened a library of 1,192 FDA-approved drugs for any that suppressed tumors in the fly and identified several that improved overall survival. They further explored combining two drugs, the FDA-approved melanoma drug trametinib and fluvastatin, a common cholesterol-lowering drug. Oral administration of these drugs inhibited Ras and PI3K pathway activity, respectively, and combining both drugs led to suppression of tumor formation.
“Our study results suggest a new drug cocktail that is effective in both human lung cancer cell lines and fly models,” says Cagan. “Next steps are to further explore this possibility in human trials in order to assess if it will help patients, but these two drugs make sense from a variety of studies and we find that they act together through multiple mechanisms to control cancer growth in the laboratory.”
Fruit flies can provide an important animal tool in the fight against cancer, says Cagan, providing new molecular and genetic understanding of disease biology and leading to treatments that more specifically kill cancer cells. Use of this knowledge to screen several different drugs, or combinations of drugs, is emerging as an important approach to cancer treatment.
“These simple model systems can be useful for identifying new drug combinations that act in the context of the whole body. Our goal is to leverage them as tools to help identify cocktails that are more effective and less toxic than current standard of care,” added Cagan.
The study was supported by a grant from the National Institutes of Health.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. 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's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.