A team of Cleveland Clinic researchers have discovered a key pathway that leads to recurrence and treatment resistance in endometrial cancer, providing the potential for much needed new therapies for women with limited options.
For the past 25 years, standard therapy for endometrial and ovarian cancers has included surgery and the chemotherapy drug cisplatin. While these treatments typically are initially successful, the cancer often recurs and becomes resistant to cisplatin, leaving patients with limited treatment options.
The Cleveland Clinic team studied the unique role of an immune regulatory protein, called CD55, which is abundant on the surface of endometrioid ovarian cancer and uterine cancer cells. Using human cells and patient-derived tissue models, they found CD55 to be the most prevalent on cancer stem cells, a subgroup of aggressive cancer cells that are thought to be responsible for recurrence and spread of many types of cancer.
The researchers discovered that high levels of CD55 caused cancer stem cells to be more aggressive and resistant to cisplatin than non-stem cell cancer cells. The CD55 pathway is unique in that it controls both stem cell self-regulation/growth and therapeutic resistance, while other mechanisms control just one or the other.
In addition, when CD55 was removed from cells, they became sensitive to cisplatin in cell culture models and in pre-clinical mouse models. The researchers hope that blocking the protein will enhance cisplatin treatments and that high expression of CD55 could be used as a biological marker of aggressive gynecologic cancers. The team plans to complete further preclinical testing followed by a clinical trial in patients with CD55-expressing endometrial cancers.
The study was co-led by Justin Lathia, Ph.D., and Ofer Reizes, Ph.D., both of the Department of Cellular & Molecular Medicine in Cleveland Clinic Lerner Research Institute. Dr. Reizes holds the Laura J. Fogarty Endowed Chair for Uterine Cancer Research at Cleveland Clinic.
"We have discovered a unique role for the CD55 complement signaling pathway in cancer as a target which offers an opportunity to prevent recurrence and associated mortality in endometrial cancer patients. Fortunately, there is already an FDA investigational drug that can inhibit the CD55 signaling pathway," Dr. Lathia said. "We hypothesize that using this drug in combination with cisplatin will improve treatment outcomes."
"Endometrial cancer is the most common gynecologic malignancy in the United States, yet research in this area is understudied and underfunded," Dr. Reizes added. "We hope that our study will lead to much needed new therapy options for women with treatment resistant, relapsed disease."
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Research fellow Caner Saygin, M.D., was first author on this study, which was published in the Journal of Experimental Medicine.
This work is funded by National Institutes of Health (NIH) grant CA191263. The work in the Reizes laboratory is also supported by Cleveland Clinic Foundation, Clinical and Translational Science Collaborative of Cleveland (UL1TR000439), Case Comprehensive Cancer Center (P30 CA043703), Cleveland Clinic VeloSano Bike Race, and the Laura J. Fogarty Endowed Chair for Uterine Cancer Research (O.R.). The Lathia laboratory also receives funding from the NIH grants NS089641, NS083629, and CA157948; a Distinguished Scientist Award from the Sontag Foundation, a Research Scholar Award from American Cancer Society, Blast GBM, Cleveland Clinic VeloSano Bike Race, and Case Comprehensive Cancer Center. This work utilized the Leica SP8 confocal microscope that was purchased from NIH SIG grant 1S10OD019972-01.
About Cleveland Clinic
Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. Among Cleveland Clinic's 51,000 employees are more than 3,500 full-time salaried physicians and researchers and 14,000 nurses, representing 140 medical specialties and subspecialties. Cleveland Clinic's health system includes a 165-acre main campus near downtown Cleveland, 10 regional hospitals, more than 150 northern Ohio outpatient locations - including 18 full-service family health centers and three health and wellness centers - and locations in Weston, Fla.; Las Vegas, Nev.; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2016, there were 7.1 million outpatient visits, 161,674 hospital admissions and 207,610 surgical cases throughout Cleveland Clinic's health system. Patients came for treatment from every state and 180 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic.
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About the Lerner Research Institute
The Lerner Research Institute is home to Cleveland Clinic's laboratory, translational and clinical research. Its mission is to promote human health by investigating in the laboratory and the clinic the causes of disease and discovering novel approaches to prevention and treatments; to train the next generation of biomedical researchers; and to foster productive collaborations with those providing clinical care. Lerner researchers publish more than 1,500 articles in peer-reviewed biomedical journals each year. Lerner's total annual research expenditure was $260 million in 2016 (with $140 million in competitive federal funding, placing Lerner in the top five research institutes in the nation in federal grant funding). Approximately 1,500 people (including approximately 200 principal investigators, 240 research fellows, and about 150 graduate students) in 12 departments work in research programs focusing on heart and vascular, cancer, brain, eye, metabolic, musculoskeletal, inflammatory and fibrotic diseases. The Lerner has more than 700,000 square feet of lab, office and scientific core services space. Lerner faculty oversee the curriculum and teach students enrolled in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University - training the next generation of physician-scientists. Institute faculty also participate in multiple doctoral programs, including the Molecular Medicine PhD Program, which integrates traditional graduate training with an emphasis on human diseases. The Lerner is a significant source of commercial property, generating 64 invention disclosures, 15 licenses, 121 patents, and one new spinoff company in 2016. Visit us at http://www.lerner.ccf.org. Follow us on Twitter at http://www.twitter.com/CCLRI.
Journal
Experimental Medicine