Despite the introduction of new AR pathway inhibitors such as abiraterone and MDV3100, clinical responses are transitory and many patients do not respond, demonstrating the importance of ligand and AR-independent mechanisms of PCa progression. This proposal evaluates the novel hypothesis that the chromatin modifying enzyme LSD1 mediates survival of ligand and AR-independent CRPC (extending its previously identified function as a driver of ligand-mediated AR activity). Specifically, we find that i. LSD1 overexpression is ubiquitous in metastatic CRPCs, including AR+ and AR- tumors;ii. the predominant category of ligand-independent LSD1 target genes involves control of the cell cycle and proliferation;and iii. LSD1 acts in an AR-axis independent manner by promoting cMyc driven tumor growth. Our data re-shape the accepted paradigm of LSD1 as a driver of ligand-mediated PCa growth, and additionally place it as a central driver in the progression of both ligand-independent AR+ CRPC and AR null CRPC. These data strongly suggest that suppression of LSD1 in the clinical setting will not only inhibit AR-pathway dependent PCa, but will inhibit the growth and potentially prevent progression to fully-androgen independent CRPC, thereby establishing the rationale for LSD1 inhibition as an important, mechanism-based therapeutic target. To fully elucidate the activity of LSD1 in driving CRPC, this project will: 1. Determine the role of c-Myc in LSD1-mediated induction of ligand-independent proliferation pathways in castration sensitive and castration resistant PCa models;2. Determine the anti-tumor efficacy of LSD1 suppression using the new LSD1 inhibitor SP-2509, alone or in combination with MDV3100, in ligand-independent AR+ and AR- preclinical CRPC models;and 3. Determine the biological effects, safety, and anti-tumor activity of the new LSD1 inhibitor SP-2509 in a phase I trial in men with metastatic CRPC. The need to target and translate key mechanisms such as the activity of LSD1, which is capable of simultaneously interdicting development of both AR-dependent and AR-independent mechanisms of progression and resistance, is an innovative approach of paramount importance and will yield novel data of immediate clinical translational relevance.

Public Health Relevance

This proposal will apply novel insights regarding the role of LSD1 in promoting ligand and AR-independent CRPC survival and lethal progression. Using in vitro cell lines, in vivo xenograft models, and tumor biopsies from men with CRPC enrolled in a phase 1 study of a novel LSD1 inhibitor, we will establish the specific mechanisms by which LSD1 acts, and lay the groundwork for phase II evaluation of LSD1 inhibitor therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-M (M1))
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Hruszkewycz, Andrew M
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Fred Hutchinson Cancer Research Center
United States
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Kuo, Kevin F; Hunter-Merrill, Rachel; Gulati, Roman et al. (2015) Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer. Clin Genitourin Cancer 13:6-Oct
Lam, Hung-Ming; Vessella, Robert L; Morrissey, Colm (2014) The role of the microenvironment-dormant prostate disseminated tumor cells in the bone marrow. Drug Discov Today Technol 11:41-7
True, Lawrence D (2014) Methodological requirements for valid tissue-based biomarker studies that can be used in clinical practice. Virchows Arch 464:257-63
Sprenger, Cynthia C T; Plymate, Stephen R (2014) The link between androgen receptor splice variants and castration-resistant prostate cancer. Horm Cancer 5:207-17
Montgomery, Bruce; Cheng, Heather H; Drechsler, James et al. (2014) Glucocorticoids and prostate cancer treatment: friend or foe? Asian J Androl 16:354-8
O'Hurley, Gillian; Prencipe, Maria; Lundon, Dara et al. (2014) The analysis of serum response factor expression in bone and soft tissue prostate cancer metastases. Prostate 74:306-13
Tarnow, Carolin; Engels, Géraldine; Arendt, Annika et al. (2014) TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol 88:4744-51
Barnett, Christine M; Heinrich, Michael C; Lim, Jeong et al. (2014) Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer. Clin Cancer Res 20:1306-12
Mostaghel, Elahe A; Plymate, Stephen R; Montgomery, Bruce (2014) Molecular pathways: targeting resistance in the androgen receptor for therapeutic benefit. Clin Cancer Res 20:791-8
Chéry, Lisly; Lam, Hung-Ming; Coleman, Ilsa et al. (2014) Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget 5:9939-51

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