Abstract 6021: Establishment and characterization of cisplatin-resistant nasopharyngeal carcinoma (NPC) patient-derived xenograft

Abstract Background: NPC is particularly common in Southern China and Southeast Asia. The standard treatment for NPC is radiotherapy with or without adjuvant chemotherapy. Despite the high 5-year overall survival rate (85.6%) in early-stage patients, 15% to 20% of the patients still experience recurrence or metastasis. The development of new targeted therapy on NPC is still lagging behind. Considered that phase I clinical trials often recruit late-stage patients who previously received multiple treatments, lack of drug-resistant models may be one of the possible hindrances in targeted therapy development. In-vivo preclinical NPC models are very limited for research. Given the close association with Epstein-Barr virus (EBV) infection in NPC, only four EBV positive (EBV +ve) PDXs and one EBV +ve cell line are available for research. Our lab has been engaging in establishing new NPC models. Previously, we had successfully established four new EBV +ve PDXs: Xeno23, Xeno32, Xeno47 and Xeno76. To establish a more clinically relevant models for preclinical studies and drug resistance research, we continuously treat the PDX transplanted mice with cisplatin. And we successfully established the first cisplatin-resistant Xeno76 (Xeno76-CR) NPC PDX. Method: A 1 mm3 PDX tissues were implanted subcutaneously in Nude mice. Once the tissue started growing into ~100 mm3 in size, 3-5 mg/kg cisplatin was injected intraperitoneally weekly. Once the end point has met, the tumor tissue was repeatedly implanted into another mice, while the rest of the tissues were used for further evaluation. Result: The growth rate of Xeno76-CR has no significant difference with Xeno76 in Nude mice. We confirmed that Xeno76-CR is resistant to cisplatin in-vivo. When treating both Xeno76 and Xeno76-CR with 3 mg/kg cisplatin weekly, there is statistically significant 85.4% tumor growth inhibition in Xeno76, but no significant inhibition effect in cisplatin-treated Xeno76-CR. EBV infection of Xeno76-CR was confirmed with EBER staining. We have also studied whether Xeno76-CR is drug- or specifically cisplatin-resistant. We tested the Xeno76-CR with ixazomib, an oral proteasome inhibitor that can inhibit nuclear factor-kB (NF-kB) signalling pathway, and found significant 57% tumor growth inhibition in-vivo. Conclusion: We have established the first and only EBV +ve cisplatin-resistant NPC PDX, Xeno76-CR, that is a valuable and clinically relevant model for targeted therapies preclinical studies and resistant research. Single-cell RNA sequencing will be performed to examine if stem cell plays any role in cisplatin-resistance. Further genome and transcriptome expression profile and characterization studies are still ongoing. Citation Format: Ka Yee Li, Katie Sze Wai Fung, Chanping You, Yim Ling Yip, Victor Ho Fun Lee, George Sai Wah Tsao. Establishment and characterization of cisplatin-resistant nasopharyngeal carcinoma (NPC) patient-derived xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6021.