Abstract 1665: Imipramine enhances the efficacy of lomustine by regulating WNT-β-catenin signaling in glioblastoma

Abstract

Abstract Background: Glioblastoma (GBM) is one of the most aggressive and difficult-to-treat brain cancers. Surgical excision followed by concurrent temozolomide (TMZ), and radiation therapy are the current standard of care for GBM. Lomustine, another alkylating regimen, has also been approved for the treatment of patients with recurrent GBM in addition to TMZ. However, the primary GBM frequently recur as therapy-resistant relapses resulting in shorter survival of patients. To date, no systemic therapies have shown proven survival benefit in recurrent GBM. In this study, we examined whether FDA approved anti-depressant drug Imipramine serve as the potent option for treating patients with recurrent GBM and to improve efficacy of approved chemotherapy. Methods: We investigated the anticancer effects of Imipramine using both established and patient-derived GBM cell lines. We tested the effect of Imipramine and Lomustine combination therapy using cell viability, colony formation, migration and apoptosis assays. Mechanistic studies were conducted using RNA-seq, western blotting, RT-PCR and reporter assays. In vivo efficacy of combination therapy was evaluated using orthotopic mouse models. Results: Our results showed that antidepressant Imipramine blocked the growth of recurrent GBM. Furthermore, Imipramine enhanced the response of Lomustine in therapy resistant GBM cells as a combination therapy and significantly reduced the cell survival and migration, and increased the apoptosis in both established and patient derived GBM cells. Further, our results demonstrated that Imipramine inhibits growth of self-renewing cancer stem cells, which contribute to drug resistance and relapse of GBM. Mechanistic studies revealed that the Imipramine treatment abrogated the WNT-β-catenin signaling, which was confirmed by TOPFLASH reporter assay. Conclusion: Collectively, the results from our study suggest that Imipramine alone and in combination with Lomustine can be used for treating recurrent GBM. Based on these results, a clinical trial is currently ongoing, where we are testing the efficacy of Imipramine for treating patients with recurrent GBM. Citation Format: Prabhakar Pitta Venkata, Arhan Rao, Santosh Timilsina, Panneerdoss Subbarayalu, Andrew Brenner, Gangadhara Reddy Sareddy, Manjeet Rao, William Kelly, Ratna Vadlamudi. Imipramine enhances the efficacy of lomustine by regulating WNT-β-catenin signaling in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1665.