Clinical cancer research : an official journal of the American Association for Cancer Research · 2024
Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma.
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Griesinger Andrea M, Calzadilla Annaliese J, Grimaldo Enrique, Donson Andrew M, Amani Vladimir, Pierce Angela M, Steiner Jenna, Kargar Soudabeh, Serkova Natalie J, Bertrand Kelsey C, Wright Karen D, Vibhakar Rajeev, Hankinson Todd, Handler Michael, Lindsay Holly B, Foreman Nicholas K, Dorris Kathleen
Аннотация
PURPOSE: There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population.
EXPERIMENTAL DESIGN: In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting.
RESULTS: 5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA.
CONCLUSIONS: These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.
EXPERIMENTAL DESIGN: In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting.
RESULTS: 5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA.
CONCLUSIONS: These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.