Abstract 7276: Potent anti-proliferative activity of brincidofovir in Diffuse Large B-cell Lymphoma with overexpression of transcriptional repressor TLE1
Authors: Jing Yi Lee, Tun Kiat Ko, Elizabeth Chun Yong Lee, Bavani Kannan, Boon Yee Lim, Zhimei Li, Zexi Guo, Jui Wan Loh, Cedric Chuan-Young Ng, Kelila Xin Ye Chai, Nur Ayuni Binte Muhammad Taib, Kerry Lim, Dachuan Huang, Jing Quan Lim, Masatoshi Hazama, Koji Fukushima, Bin Tean Teh, Soon Thye Lim, Choon Kiat Ong, Jason Yongsheng Chan
Journal: Cancer Research (2024)

Abstract Introduction: Brincidofovir (BCV) is a biologically-active acyclic nucleoside phosphonate and clinically-approved anti-viral agent. Recently, BCV has been demonstrated to display potent anti-proliferative and immunogenic properties in NK/T cell lymphoma (NKTCL). However, its effect on other lymphoma types remain unclear. Methods: We investigated BCV in an expanded cohort of B-cell lymphoma cell-lines (diffuse large B-cell lymphoma [DLBCL], n = 16; Burkitt lymphoma, n = 2; Hodgkin lymphoma, n = 1), in comparison with NKTCL cell lines (n = 11). Mouse xenograft models were deployed to assess in vivo effects. Whole transcriptomic sequencing (RNAseq) was performed to examine Epstein-Barr virus (EBV) status and explore potential mechanisms of action. Results: BCV inhibited viability in all B-cell lymphoma cell-lines in a dose-dependent manner (IC50 0.0798 to 8.414 µg/ml). Marked sensitivity (IC50 &amp;lt; 1 µg/ml) was demonstrated in nine cell-lines, including the MYC/BCL2-rearranged double-hit DLBCL cell-line OCI-LY18 (IC50 0.5 µg/ml). Intraperitoneal BCV (40 mg/kg, 2X per week) inhibited tumor growth in NOD/SCID mice OCI-LY18 xenografts, compared with vehicle alone (p &amp;lt; 0.001, two-tailed t-test). RNAseq showed that most cell-lines (n = 16) were EBV negative. Interestingly, the transcriptional repressor TLE1 was amongst the top upregulated genes in the BCV-sensitive cell-lines (log2foldchange = 8.12, adjusted p = 0.0004). DLBCL patient samples from two independent datasets showed that TLE1-high tumors conferred worse overall survival (GSE11318, n = 200: HR 2.77, 95%CI 1.78 to 4.30, p &amp;lt; 0.0001; GSE10846, n = 414: HR 1.94, 95%CI 1.35 to 2.80, p = 0.0004). Gene set enrichment analysis showed that pathways involved in oxidative phosphorylation and oncogenic signaling were significantly upregulated in the BCV-resistant cell-lines compared to the rest. Notably, these findings are in stark contrast to NKTCL, in which TLE1 loss instead confers BCV sensitivity in vitro and is associated with poor survival outcomes in patients (n = 36; HR 3.44, 95% CI 1.23-10.49, p = 0.0301). Conclusions: Taken together, these results suggest that BCV may be a potential novel therapeutic agent for the treatment of B-cell lymphomas. Further work will be required to investigate the role of TLE1 and other molecular features as potential predictive biomarkers. Citation Format: Jing Yi Lee, Tun Kiat Ko, Elizabeth Chun Yong Lee, Bavani Kannan, Boon Yee Lim, Zhimei Li, Zexi Guo, Jui Wan Loh, Cedric Chuan-Young Ng, Kelila Xin Ye Chai, Nur Ayuni Binte Muhammad Taib, Kerry Lim, Dachuan Huang, Jing Quan Lim, Masatoshi Hazama, Koji Fukushima, Bin Tean Teh, Soon Thye Lim, Choon Kiat Ong, Jason Yongsheng Chan. Potent anti-proliferative activity of brincidofovir in Diffuse Large B-cell Lymphoma with overexpression of transcriptional repressor TLE1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7276.