Investigators identified several dozen new and existing drugs as possible ependymoma treatment candidates. The drugs were found by screening 5,303 existing medicines, natural products and other compounds for activity against the tumor, which develops in the brain and spine of children and adults. The work is published in the current edition of the scientific journal Cancer Cell.
The list of candidate drugs included 5-fluorouracil (5-FU). 5-FU has been widely used to treat a variety of adult cancers but has not been formally tested against ependymoma. Based on study results, St. Jude is planning a clinical trial of 5-FU in young ependymoma patients, said senior author Richard Gilbertson, M.D., Ph.D., director of the St. Jude Comprehensive Cancer Center. Gilbertson credited the method used in this study with highlighting 5-FU’s potential.
Researchers hope to use the same system to expand chemotherapy options for patients with other cancers. “This approach should significantly advance the efficiency and speed with which we discover and develop new treatments for rare cancers and cancer subtypes,” the investigators noted. Jennifer Atkinson, Ph.D., a former St. Jude postdoctoral fellow, is the first author. R. Kiplin Guy, Ph.D., chair of the St. Jude Department of Chemical Biology and Therapeutics, and Gilbertson are corresponding authors.
Rather than waiting years for clinical trial results, this system promises to take just months to provide key information about a drug’s effectiveness and optimal administration, Gilbertson said.
The results are good news for patients with ependymoma and other cancers where treatment options are limited and the outlook remains bleak. While overall childhood cancer survival rates are now almost 80 percent, ependymoma remains incurable in up to 40 percent of patients. The tumor is found in 150 to 200 U.S. children annually, making it the third most common pediatric brain tumor. Treatment has changed little in the past 40 years and is limited to surgery and radiation.
Along with identifying and prioritizing drug development candidates against ependymoma, the research provided insight into the tumor’s biology. The screening identified several messenger proteins, known as kinases, as possible new regulators of the tumor cell proliferation that makes cancer deadly. The abnormal tumor kinase activity occurred in certain pathways in tumor cells, including the insulin-signaling pathway and the centrosome cycle.
This study builds on earlier research led by Gilbertson that showed ependymoma includes nine different tumor subtypes. Each begins when particular mutations occur in stem cells from different regions of the brain or spine. Stem cells are the specialized cells that can divide and take on more specific functions.
For this project, investigators focused on a subtype D ependymoma. In earlier research, Gilbertson and his colleagues showed that extra copies of the EPHB2 gene caused this tumor subtype. The investigators used this information to develop an accurate model of subtype D ependymomas in mice. The mouse model includes the same mutation in the same neural stem cell responsible for the human disease and was crucial for speeding drug development.
Researchers used an automated system to check 5,303 existing drugs, natural products and other compounds for activity against four different types of mouse brain cells, including normal neural stem cells, subtype D ependymoma tumor cells and cells from a different brain tumor.
Of the 634 compounds that showed activity against subtype D ependymoma cells, four demonstrated a two-fold greater ability to block the growth of the tumor cells, but not normal cells. The drugs included 5-FU and two closely related compounds. The fourth was beta-escin, which belongs to a family of drugs that are generating interest as potential chemotherapy agents.
5-FU also proved more effective than four other chemotherapy drugs in slowing tumor growth and extending the lives of mice with subtype D ependymoma. 5-FU also appeared less toxic to normal mouse brain cells than another drug, bortezomib, included in the study. The findings provided preliminary evidence that the screening system might provide an early indication of drug toxicity. The information could help guide treatment and prioritize drugs for development, researchers said.
The screening also highlighted a possible role for kinase inhibitors. Those are drugs that block activity of proteins that help drive cell division and sustain tumors. More than 18 inhibitors are in clinical trials that target the kinases this study tied to proliferation of both normal and ependymoma tumor cells.
The study’s other authors are Anang Shelat, Tanya Kranenburg, Nidal Boulos, Karen Wright, Helen Poppleton, Kumarasamypet Mohankumar, Timothy Phoenix, Paul Gibson, Liqin Zhu, Yiai Tong, Chris Eden, David Ellison, Amar Gajjar and Clinton Stewart, all of St. Jude; Angel Montero Carcaboso, Alexander Arnold, Robert Johnson Clementine Feau, all formerly of St. Jude; and Waldemar Priebe, Dimpy Koul and W.K. Alfred Yung, of University of Texas MD Anderson Cancer Center.
The study was funded in part by the National Institutes of Health, the Collaborative Ependymoma Research Network and ALSAC.St. Jude Children’s Research Hospital
Summer Freeman | Newswise Science News
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Life Sciences
23.03.2018 | Materials Sciences
23.03.2018 | Process Engineering