Abstract B113: Novel thiosemicarbazones demonstrate pronounced anti-tumor activity in marginal zone lymphoma models, also overcoming resistance to targeted agents

Abstract Background. Despite significant advancements in anti-lymphoma therapies in recent years, treatment failure and disease relapse remain significant clinical challenges in B-cell lymphoma. Therefore, novel therapeutic approaches with distinct mechanisms of action are essential to overcoming drug resistance in lymphoma. Deregulation of iron metabolism is common in cancer cells, particularly lymphomas, and its targeting is an active field of preclinical and clinical research. Thiosemicarbazones are a class of orally bioavailable synthetic compounds that demonstrate economical synthesis, known for their chelating properties, particularly with transition metals such as iron and copper. Due to this ability to disrupt critical metal-dependent cellular processes, novel thiosemicarbazones are being investigated for their anti-tumor activities. Moreover, thiosemicarbazones provide a “double punch mechanism” involving the avid binding of tumor cell iron and copper that are critical for proliferation, followed by the formation of a redox-active iron or copper complex that generates cytotoxic reactive oxygen species. Here, we evaluated five known thiosemicarbazones plus a novel derivative in marginal zone lymphoma (MZL) models, including cells with secondary resistance to BTK, PI3K, and BCL2 inhibitors. Methods. The effect on cell viability was assessed by MTT assay after exposure to increasing concentrations of compounds or DMSO (control) in MZL cell lines (VL51, Karpas1718, and SSK41), and in their derivatives with secondary resistance to BTK, PI3K, and BCL2 inhibitors. Results. We exposed MZL cell lines to increasing concentrations of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), (E)-3-phenyl-1-(2-pyridinyl)-2-propen-1-one 4,4-dimethyl-3-thiosemicarbazone (PPP44mT), 3-phenyl-1-(pyridin-2-yl)prop-2-en-1-one-4-chlorophenyl-3-sele- nosemicarbazone (PPP4ClpSe), phenyl-1-(2-pyridinyl)-2-propen-1-one-4-methoxyphenylthiose-micarbazone (PPP4MeOpT), and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), the latter of which has undergone a phase 1 trial, along with a novel molecule (compound 7). All the compounds showed dose-dependent activity with a median IC50 of 8.55 nM (95%IC, 4.15-12.15). The activity was fully maintained in models with secondary resistance to targeted agents. The most potent compounds were Dp44mT (median IC50 1.1 nM), PPP44mT (4.15 nM), DpC (5.8 nM), followed by PPP4MeOpT (12 nM), compound 7 (15 nM), and PPP4ClPSe (38 nM). No effect was observed using the negative control, 2-benzoylpyridine-2-methyl-3-thiosemicarbazone (Bp2mT), a closely related thiosemicarbazone analogue specially designed not to bind metals. Conclusions. Thiosemicarbazones have very potent single-agent activity in MZL models, which was preserved in models with acquired resistance to targeted agents, appearing consistent with their well-established structure–activity relationships. Novel thiosemicarbazones should be vigorously explored against lymphoma as single agents and tested in combination with established anti-lymphoma agents. Citation Format: Emma Pesenti, Alberto Jesus. Arribas, Mahendiran Dharmasivam, Des Richardson, Francesco Bertoni. Novel thiosemicarbazones demonstrate pronounced anti-tumor activity in marginal zone lymphoma models, also overcoming resistance to targeted agents [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B113.