EPEN-30. 5FU with Radiation Followed by Maintenance of 5FU and ATRA Significantly Improves Survival of 1q+/6q- PFA Ependymoma Xenograft Models. (3rd June 2022)

• Record Type: Journal Article
• Authors: Grimaldo, Enrique; Donson, Andrew; Harris, Faith; Amani, Vladimir; Norris, Gregory; Steiner, Jenna; Serkova, Natalie; Dorris, Kathleen; Foreman, Nicholas; Griesinger, Andrea
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 1
• Page Start: i45
• Page End: i46
• Publication Date: 2022-06-03
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac079.166
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: In a screen of over 100 FDA approved drugs on PFA 1q+ EPN cells, 5-fluorouracil (5FU) and All-Trans-Retinoic Acid (ATRA) were identified as inhibitors of EPN cell line growth. We performed in-vitro cell growth assays combining increasing doses of radiation and 5FU and found a significant synergistic effect on cell growth and apoptosis in 1q+ PFA EPN cell lines. Further growth attenuation was seen when ATRA was added 48 hours following radiation and 5FU treatment. This led us to development of preclinical studies in the 1q+ PFA orthotopic xenograft models MAF-811_XF and MAF-928_XF. In the initial cohort, tumors were allowed to establish prior to treatment start confirmed by MRI. In both MAF-811 and MAF-928, chemotherapy improved survival compared to no treatment. As consistent with standard of care, radiation significantly improved survival (p=0.0016) but there was no added benefit to combining 5FU or 5FU+ATRA with radiation. A second cohort was treated using the same treatment approach, however radiation and 5FU were started with minimal to no visible tumors by MRI. Interestingly, we found a significant increase in survival between vehicle control and combination 5FU+ATRA (HR 5.121, 95% CI: 0.2506, 2.409, p=0.048) in MAF-811 mice. However, again with radiation, there was no significant change in survival with only a single cycle of 5FU+ATRA. This led to continued maintenance of 5FU+ATRA cycles of 6 weeks with 2 weeks off for 4 cycles post radiation in mice with minimal tumor. When 5FU with radiation is followed by 5FU+ATRA and is continued in mice with minimal disease, survival significantly improved when compared to radiation alone (HR 9.020, 95% CI: 1.933 to 42.09, p=0.007). These studies highlight the importance of chemotherapy in minimal disease and is the rationale for a Phase I/II study in relapsed PFA EPN and in upfront 1q+ PFA EPN.