Emond WB, Sawant R, Geitmann M, Winquist J, Brandt P, Bremberg U, Källblad P, Parrow V, Andersson C, Blom K, Najafi N, Bergström T, Swartling FJ, Hellström M, Koehler KF. Potentiation of immunotherapy by LSD1 modulation [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 705.
Abstract
LSD1 has emerged as a potential therapeutic target that increases the effectiveness of immunotherapy. We have developed a series of novel small molecules, exemplified by the lead substance BEA-17, that modulates LSD1 via binding to an allosteric site, without directly inhibiting its enzymatic activity. In cells, BEA-17 induces a reduction of LSD1 and its partner protein CoREST. In addition, BEA-17 upregulates the expression of endogenous retroviral genes and T cell-attractant chemokines and does so in an LSD1-dependent manner. In a co-culture of HeLa and PBMCs, BEA-17 potentiates the cell kill of cancer cells by cytotoxic T cells, also in an LSD1-dependent manner. In a CT26 syngeneic animal model of colon cancer, BEA-17 potentiates the activity of anti-PD1 inhibitors. Finally, in a syngeneic animal GL261 model of glioblastoma, BEA-17 increases the effectiveness of standard-of-care temozolomide + radiation.
Related file
The poster can be downloaded here.
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