Abstract 2038: Reactive oxygen species-mediated synergism of fenretinide and romidepsin in preclinical models of T-cell lymphoid malignancies

Abstract

Abstract Introduction: T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. Romidepsin is a histone deacetylase (HDAC) inhibitor that achieved FDA registration as 2nd line therapy for peripheral and cutaneous T-cell lymphomas. The cytotoxic retinoid fenretinide achieved durable complete responses against T-cell lymphomas in early-phase clinical trials and T-cell lymphoma patients who failed prior romidepsin treatment responded to fenretinide. Fenretinide is currently being evaluated in a Phase IIa clinical trial for relapsed/refractory PTCL patients (NCT02495415). We investigated the potential for using these two agents in combination in TCLMs. Methods and Results: Using the DIMSCAN assay, we demonstrated cytotoxic synergy between romidepsin and fenretinide in fifteen TCLM cell lines at clinically-achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous (COG-LL-317m and TX-LY-183x PDX) and disseminated (COG-LL-317m Luc expressing the luciferase gene) TCLM xenograft models than single agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS, measured by DCFDA dye)-dependent increase in pro-apoptotic proteins (Bim, tBid, Bax and Bad), apoptosis (via TUNEL assay), and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin was abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and shRNA knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity and apoptosis. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in fibroblasts and blood mononuclear cells. Conclusion: Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in non-malignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs. Citation Format: Monish Ram Makena, Balakrishna Koneru, Min H. Kang, C. Patrick Reynolds. Reactive oxygen species-mediated synergism of fenretinide and romidepsin in preclinical models of T-cell lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2038. doi:10.1158/1538-7445.AM2017-2038