Timothy E. G. Krueger
Targeting LSD1 for Direct Effects and Induction of Anti-Tumor Immunity Against Lethal Prostate Cancer
Lysine-Specific Demethylase 1 (LSD1) was the first protein discovered to be able to remove methyl marks from histone proteins, thus repressing transcription of associated genes. LSD1 has been found to be overexpressed in numerous cancers, causing pro-tumorigenic disruptions in numerous processes including cell cycle control, glycolytic metabolism, metastasis, and differentiation. Inhibition of LSD1 has been shown to be able to reverse these abnormal gene expression patterns and have direct efficacy against cancer cells. These efforts have resulted in numerous ongoing clinical trials to test LSD1 inhibitors against a variety of blood malignancies. Additionally, inhibition of LSD1 directly induces the expression of inflammatory chemokines and endogenous retroviruses (ERVs) in cancer cells. This triggers a viral response that leads to production of inflammatory stimuli and recruits CD8+ T cells to tumors that are normally immunologically unresponsive. While small cell lung cancer is the only solid malignancy to have been tested with LSD1 inhibitors in clinical trials to date, prostate cancer (PCa) is an enticing candidate due to the additional pivotal role of LSD1 in mediating the androgen receptor signaling that is the key driver of PCa progression. This study will test both the direct anti-proliferative effects and indirect immunological effects of LSD1 inhibition against lethal castration resistant PCa. CRISPR-Cas9 has been employed to obtain LSD1 knock-out PCa cell lines, and IMG-7289 will be used as a novel, specific, and readily translatable small molecule LSD1 inhibitor. RNA-Seq, ChIP-Seq, and NanoString analysis will inform of broad transcriptional changes following pharmacologic or genetic inhibition of LSD1 and will help identify critical pathways controlled by LSD1 in PCa. Additionally, flow cytometry analysis of syngeneic MycCaP tumors in FVB mice treated with IMG-7289 will identify any changes in immune populations and surface markers that either trigger immune reactivity on their own or that could be targeted/ enhanced with potential combinatorial immunotherapies.
Earning a Predoctoral Fellowship in Pharmacology/Toxicology from the PhRMA Foundation is an honor that is incredibly gratifying on a personal level, and it is a crucial step in my development and pursuit of a career in industry. More than that, however, fellowships such as this drive innovative research that can have a real impact on patient care.