Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma.

Autor:	Griesinger AM; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Calzadilla AJ; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Grimaldo E; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Donson AM; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Amani V; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Pierce AM; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Steiner J; Department of Radiology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado., Kargar S; Department of Radiology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado., Serkova NJ; Department of Radiology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, Colorado., Bertrand KC; Department of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, Tennessee., Wright KD; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts., Vibhakar R; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Hankinson T; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Handler M; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Lindsay HB; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Foreman NK; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado., Dorris K; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado.; Department of Pediatrics, University of Colorado Anscutz Medical Campus, Aurora, Colorado.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Apr 15; Vol. 30 (8), pp. 1544-1554.
DOI:	10.1158/1078-0432.CCR-23-3156
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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