Epigenetic gene silencing ubiquitously accompanies the development of prostate cancer (and other human cancers);reactivation of silenced genes has emerged as a rational treatment strategy. Epigenetic drugs, including small molecule inhibitors of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and 5-meCpG-binding domain proteins (MBDs), trigger the reactivation of ~400 genes or more in cancer cells, and change the chromatin structure of many other genes in such a way as to facilitate expression in response to signaling and/or stress pathways. The new phenotypes induced in prostate cancer cells by epigenetic drugs expose unforeseen vulnerabilities to drugs targeting the products of genes that are now critical for survival in the reprogrammed state induced by the epigenetic drug. For this reason, the efficacy of epigenetic drugs in cancer may not be limited to reactivation of silenced tumor suppressor genes;rather, epigenetic drugs may also augment the activity of selected targeted drugs for cancer treatment by inducing synthetic lethality with epigenetic therapy (ISLET). An ongoing discovery research program has identified several promising combinations of DNMT inhibitors and targeted drugs that appear to exhibit properties of synthetic lethality;i.e., at concentrations where neither drug alone appears toxic to prostate cancer cells propagated in vitro, combined treatment exerts profound effects on prostate cancer cell survival. The goals of this Project are to undertake a structured preclinical assessment of these candidate combinations to prioritize the most promising for translation to clinical development for advanced prostate cancer.

Public Health Relevance

Progression to metastasis is the major cause of prostate cancer mortality, and is nearly universally associated with DNA methylation alterations. Since the DNA methylation alterations are reversible, we propose that it may be possible to re-program the epigenome in cancer cells by use of a DNA methyltransferase inhibitor, and then cripple new vulnerabilities in these re-programmed cancer cells to allow systemic treatment of prostate cancer. Here we propose pre-clinical testing to facilitate future clinical testing.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Regter, Sietze; Hedayati, Mohammad; Zhang, Yonggang et al. (2014) Androgen withdrawal fails to induce detectable tissue hypoxia in the rat prostate. Prostate 74:805-10
Ku, ShengYu; Lasorsa, Elena; Adelaiye, Remi et al. (2014) Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer. PLoS One 9:e103680
Chalfin, Heather J; Frank, Steven M; Feng, Zhaoyong et al. (2014) Allogeneic versus autologous blood transfusion and survival after radical prostatectomy. Transfusion 54:2168-74
Bhatnagar, Akrita; Wang, Yuchuan; Mease, Ronnie C et al. (2014) AEG-1 promoter-mediated imaging of prostate cancer. Cancer Res 74:5772-81
Brennen, W Nathaniel; Rosen, D Marc; Chaux, Alcides et al. (2014) Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer. Prostate 74:1308-19
Paller, C J; Olatoye, D; Xie, S et al. (2014) The effect of the frequency and duration of PSA measurement on PSA doubling time calculations in men with biochemically recurrent prostate cancer. Prostate Cancer Prostatic Dis 17:28-33
Durham, Nicholas M; Nirschl, Christopher J; Jackson, Christopher M et al. (2014) Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One 9:e109080
Gurel, Bora; Lucia, M Scott; Thompson Jr, Ian M et al. (2014) Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev 23:847-56
Lutz, Eric R; Wu, Annie A; Bigelow, Elaine et al. (2014) Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res 2:616-31
Zheng, Qizhi; Peskoe, Sarah B; Ribas, Judit et al. (2014) Investigation of miR-21, miR-141, and miR-221 expression levels in prostate adenocarcinoma for associated risk of recurrence after radical prostatectomy. Prostate 74:1655-62

Showing the most recent 10 out of 579 publications