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

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>In this study, we utilize 1q+ PFA <i>in vitro</i> and <i>in vivo</i> models to test the efficacy of combination radiation and chemotherapy in a preclinical setting.</p>Results:<p>5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of <i>UCK2</i> located on chromosome 1q in 1q+ PFA. Experimental downregulation of <i>UCK2</i> resulted in decreased 5FU sensitivity in 1q+ PFA cells. In <i>in vitro</i> 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, <i>in vivo</i> experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA.</p>Conclusions:<p>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.</p></div>