Abstract 3: Targeted inhibition of LSD1 in castration-resistant prostate cancer.
Authors: Theisen Emily , Bearss Jared , Sorna Venkataswamy , Bearss David , Sharma Sunil 
Published: August 2014

Epigenetic dysfunction is recognized as a driver in the pathology of various cancers. Promoter DNA hypermethylation, genomic hypomethylation, and aberrant histone acetylation and methylation contribute to epigenetic lesions. Further, genetic mutations in important epigenetic regulators have been identified across various solid and hematological malignancies. These aberrant marks are reversible due to the dynamic nature of epigenetic regulation and present attractive therapeutic targets. While epigenetic therapies, like DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, have shown survival benefit in the clinic there are several potential epigenetic targets whose therapeutic potential remains undefined. The histone lysine specific demethylase 1 (LSD1) is such a target. LSD1 is a FAD-dependent amine oxidase which catalyzes the oxidative demethylation of mono- and dimethyl marks from both lysines 4 and 9 on histone H3 (H3K4 and H3K9). Overexpression of LSD1 correlates with aggressive tumor biology, dedifferentiation, and poor prognosis in various solid malignancies, including prostate, breast, bladder, lung, liver and colorectal tumors. In prostate cancer, upregulation of LSD1 is sufficient to promote ligand-independent androgen-receptor-dependent transcription through demethylation of the repressive histone 3 lysine 9 dimethyl mark (H3K9me2).

Currently reported inhibitors of LSD1 exhibit poor potency and specificity, solubility issues, and irreversibility and preclinical studies using these compounds have offered little in the way of single agent efficacy in solid tumors. Furthermore, inducible LSD1 knockdown experiments in vivo raise significant concerns about the potential for LSD1 inhibitors to block terminal hematopoetic differentiation. More potent and reversible inhibitors are required to discern which solid malignancies present an opportunity for LSD1 enzymatic inhibition as a single-agent and if there is a therapeutic window between single-agent efficacy and hematopoetic toxicity.

HCI-2509 was previously reported as a potent and specific inhibitor for LSD1 with in vitro efficacy in breast cancer and in vivo efficacy in acute myeloid leukemia (AML). Here we report single-agent efficacy of HCI-2509 dosed both orally and intraperitoneally over the course of 21 days using the castration-resistant prostate cancer (CRPC) PC-3 xenografts in vivo. We observed target modulation with increased levels of H3K9me2 in both treatment groups. Additionally, the literature-predicted hematopoetic toxicity was not observed. This suggests that reversible and potent LSD1 inhibition provides a viable therapeutic strategy for CRPC and that dosing strategies can be optimized to avoid serious hematological toxicity. Our efforts are now focused on building a pharmacokinetic/pharmacodynamic model to better understand the clinical potential of LSD1 inhibition in CRPC.

Citation Format: Emily Theisen, Jared Bearss, Venkataswamy Sorna, David Bearss, Sunil Sharma. Targeted inhibition of LSD1 in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1003. doi:10.1158/1538-7445.AM2013-1003