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FDA-approved drug shuts down Ewing sarcoma cells
Researchers at Georgetown Lombardi Comprehensive Cancer Center have identified a drug, already approved to treat a type of leukemia, might also help young people with a much rarer and aggressive form of cancer, Ewing sarcoma.
Their findings, reported in Oncogene, mean that the drug, clofarabine (Clolar) soon could be tested in a clinical trial for Ewing sarcoma, a cancer found in bone or soft tissue. It predominately affects young people between the ages of 10 and 20, and while survival can be as high as 70 percent, treatment-related side effects can produce other cancers, heart problems and infertility.
"Our goal is to improve both survival and quality of life for Ewing sarcoma patients, and this drug, when used in combination with other therapies, may do the trick. Our work provides knowledge on how to make safer derivatives with fewer side effects for Ewing sarcoma patients."
Üren worked with a team of investigators from Georgetown Lombardi and from Italy and Turkey.
The researchers targeted the CD99 protein, which is highly expressed in Ewing sarcoma cells. CD99 is a transmembrane protein - one end projects out of the cancer cell surface while the other exists inside the cell. In fact, making a diagnosis of Ewing sarcoma depends on both (1) the appearance of the cell under the microscope and (2) the fact these cells express CD99 protein. Investigators still don't know exactly what CD99 does, but earlier research using experimental monoclonal antibodies that bind to and inhibit CD99, stopped tumor growth in laboratory models of the disease.
The team took an unconventional approach and searched a National Cancer Institute database of 2,607 compounds to find one that could potentially help Ewing sarcoma patients. They didn't tailor the search based on finding the right molecule that perfectly fits into a pre-selected groove in the structure of CD99, but looked to see if anything would bind anywhere on the protein. They then examined what happened when these molecules stuck together.
They found 150 compounds that could attach/link to CD99. Only two had a beneficial function. One was clofarabine, the other cladribine (Leustatin) used to treat hairy cell leukemia, B-cell chronic lymphocytic leukemia and multiple sclerosis. Both FDA approved drugs
According to Üren, while both drugs "drastically" inhibited the growth of Ewing sarcoma cells in lab and animal studies, clofarabine "decimated" the cancer.
When the two FDA approved drugs bind to CD99, they work both on the outside and inside of the cell. Üren: "It is the inside action of the drugs - their ability to alter DNA metabolism - that produces the known toxicity associated with them. We believe it is sufficient to act only on the outside of the protein to kill Ewing sarcoma cells. Therefore, a derivative of clofarabine - just the part that latches onto CD99 without activating it - would likely work very well in the treatment of Ewing sarcoma."
Aykut Üren MD, believes that clofarabine in its existing form should, and could, soon be tested as a treatment. He adds that the study offers tantalizing clues that inhibiting CD99 may work as a treatment for other cancers or for a number of immune disorders that display these same proteins.
Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy that predominantly affects children and adolescents. CD99 is a cell surface protein that is highly expressed on ES cells and is required to maintain their malignancy. We screened small molecule libraries for binding to extracellular domain of recombinant CD99 and subsequent inhibition of ES cell growth. We identified two structurally similar FDA-approved compounds, clofarabine and cladribine that selectively inhibited the growth of ES cells in a panel of 14 ES vs. 28 non-ES cell lines. Both drugs inhibited CD99 dimerization and its interaction with downstream signaling components. A membrane-impermeable analog of clofarabine showed similar cytotoxicity in culture, suggesting that it can function through inhibiting CD99 independent of DNA metabolism. Both drugs drastically inhibited anchorage-independent growth of ES cells, but clofarabine was more effective in inhibiting growth of three different ES xenografts. Our findings provide a novel molecular mechanism for clofarabine that involves direct binding to a cell surface receptor CD99 and inhibiting its biological activities.
Authors: Haydar Çelik, Marika Sciandra, Bess Flashner, Elif Gelmez, Neslihan Kayrakl?o?lu, David V. Allegakoen, Jeff R. Petro, Erin J. Conn, Sarah Hour, Jenny Han, Lalehan Oktay, Purushottam B. Tiwari, Mutlu Hayran, Brent T. Harris, Maria Cristina Manara, Jeffrey A. Toretsky, Katia Scotlandi & Aykut Üren
This work was supported by grants from the Children's Cancer Foundation, Hyundai Hope on Wheels, the Alan B. Slifka Foundation, the Italian Association for Cancer Research and the National Cancer Institute (P30CA51008).
About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute as a comprehensive cancer center -- the only cancer center of its kind in the Washington, DC area. A part of Georgetown University Medical Center and MedStar Georgetown University Hospital, Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Connect with Georgetown Lombardi on Facebook(Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer).
About Georgetown University Medical Center
Georgetown University Medical Center (GUMC is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health. Connect with GUMC onFacebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@gumedcenter).
Georgetown University has filed a patent application for the use of CD99 inhibitors in the treatment of Ewing sarcoma, in which Üren, Çelik and Toretsky were listed as inventors.
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Irregular shaped cells characteristic of Ewing sarcoma. A brown stain is used to identify when CD99 is present as it is on all the cells seen here. This study offers tantalizing clues that inhibiting CD99 may work as treatment for Ewing sarcoma and other cancers, and for a number of immune disorders that display these proteins. Image credit: Aykut Üren