Abstract Ependymoma (EPN) is the third most common malignant pediatric brain tumor. The most frequent and aggressive EPN subgroup, posterior fossa ependymoma group A (PFA-EPN), occurs predominantly in younger children with a 5-year progression-free survival of 33%. In the absence of recurrent mutations, PFA EPN tumors are driven by EZHIP overexpression resulting in global loss of the gene repressive chromatin mark H3K27me3. Despite progress in EPN molecular characterization, the standard treatment remains surgery with adjuvant radiation therapy. As such, identifying novel therapies for PFA-EPN is an important unmet medical need. To define therapeutic sensitivities for PFA-EPN, we performed a drug screen using multiple drug libraries: (i) a 120 drug FDA-Approved Oncology collection (ODL3), (ii) a CTD2 Informer Set of 320 tool compounds, and (iii) a 336 drug Epigenetics Drug Collection on three patient-derived PFA-EPN cell lines. We found that these PFA-EPN cell lines were sensitive to several clinically relevant drugs, including those targeting epigenetic regulators. Multiple histone methyltransferase, proteasome, BCL2, and BET domain inhibitors were also identified as high-value drug candidates. These results warrant further PFA-EPN functional evaluation in vivo, but dose-limiting toxicity and limited blood-brain barrier (BBB) penetration are known limitations for many of the identified compounds. To overcome these limitations, we are applying a novel P-selectin-targeted fucoidan-based nanoparticle (FiNP) technology recently shown as a viable approach for effective BBB drug penetration specifically at brain tumor sites in vivo. As proof of principle, we have successfully fucoidan-encapsulated BET domain inhibitor drugs including a BRD2/3/4 PROTAC degrader (dBET6) providing improved pharmacological properties. Our preliminary results show P-selectin expression on treatment-naive human PFA-EPN tumor vasculature with current studies underway to assess effects of low dose ionizing radiation on P-selectin tumor vasculature expression enhancement, FiNP tumor localization throughout the tumor space, as well as therapeutic assessment in PFA-EPN PDX mouse models. Collectively, these findings provide new putative therapeutic approaches in these rare yet aggressive tumors. Citation Format: Jon D. Larson, Darren Finlay, Yan Yuen Lo, Rabi Murad, Ming Zhao, Antony MichaelRaj, Sachin A. Kumar, Kristen Vogt, Ian Pass, Charles Handley, Bryan K. Li, Robert J. Wechsler-Reya, Michael D. Taylor, Kristiina Vuori, Michael Jackson, Daniel A. Heller, G. Praveen Raju, Lukas Chavez. Targeted posterior fossa A ependymoma therapy using a tumor-selective nanoparticle drug delivery approach abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6177.
Larson et al. (Fri,) studied this question.