Abstract 6681: Inhibition of LSD1 using the reversible inhibitor SP2577 promotes Interferon dependent anti-tumor response in adrenocortical carcinoma

Abstract

Purpose: Adrenocortical carcinoma (ACC) is a rare and aggressive disease with poor prognosis. The first line of treatment is surgery followed by chemotherapy (Mitotane), though these therapies still result in a dismal 15-44% survival rate after 5 years. Currently, there is no effective second line of treatment. Efforts have been made to treat ACC with immune therapy agents such as Avelumab, a PD-L1 antibody, but a recent study showed that there was only an overall response rate of 6% in a phase 1 clinical trial, further exhibiting a need for the development of novel therapeutics. Further research suggests that the current first line ACC treatments may benefit from the addition of immune therapies that induce an Interferon Beta (IFN-β) response in the tumor microenvironment. Previous studies have shown that treatment with IFN-β induces cell death and sensitizes human ACC lines to Mitotane, implying that combination of therapies that induce an IFN-β response may improve the anti-tumor response to Mitotane.

Recently, inhibition of Lysine-Specific histone Demethylase 1 (LSD-1) was shown to stimulate an IFN-dependent anti-tumor response driven by the expression of Endogenous Retroviral Elements (ERVs) in a variety of cancer types. In addition, PD-L1 expression has also been shown to increase after LSD-1 inhibition. Yang, et al. reported that SP-2509, a preclinical analog of SP-2577 (Seclidemstat, currently in clinical phase I trials, Salarius Pharmaceuticals, Houston, TX) was able to induce the expression and release of interferons and cytokines in triple negative breast cancer models. In this study we investigate the ability of SP-2577 to promote the expression of IFN-β in human ACC cell lines, resulting in an anti-tumor immune response.

Experimental Design: qRT-PCR was performed on ACC cell lines H295R and SW-13 at 48 and 72 hours post treatment to verify the ability of SP-2577 to promote IFN-β expression. ACC cells were co-cultured with peripheral blood mononuclear cells (PBMCs) in a 3D platform to evaluate lymphocyte infiltration following SP-2577 treatment. Interferons, chemokines, and cytokines were quantified in the culture supernatant after treatment with SP-2577 using the Meso Scale Discovery platform.

Results: qRT-PCR showed that SP-2577 promotes ERV-mediated immune response in ACC cell lines via the expression and release of interferons, chemokines, and cytokines. Additionally, SP-2577 stimulates lymphocyte infiltration in an ACC derived 3D-spheroid platform further resulting in a cytotoxic effect.

Conclusion: Our data suggests that the LSD-1 inhibitor SP-2577 can be used as a single agent in ACC patients to promote immune response and can potentially sensitize the tumor to first line of therapy, Mitotane.

This study was supported by funding from the TGen Foundation.

Citation Format: Sunil Sharma, Raffaella Soldi, Alexis Weston, Samuel Sampson, Sherin Daniel Ampanattu, Scott Celinski, Haiyong Han, Mohan Kaadige, Michael Berens, Jeffrey Trent. Inhibition of LSD1 using the reversible inhibitor SP2577 promotes Interferon dependent anti-tumor response in adrenocortical carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6681.