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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA058236-19A1
Application #
8739713
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
1997-09-30
Project End
2019-08-31
Budget Start
2014-09-25
Budget End
2015-08-31
Support Year
19
Fiscal Year
2014
Total Cost
$240,607
Indirect Cost
$92,084
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Guedes, Liana B; Morais, Carlos L; Almutairi, Fawaz et al. (2016) Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer. Clin Cancer Res 22:4651-63
Haffner, Michael C; Weier, Christopher; Xu, Meng Meng et al. (2016) Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol 238:31-41
Barakat, David J; Mendonca, Janet; Barberi, Theresa et al. (2016) C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion. Cancer Lett 375:152-61
Murtola, Teemu J; Gurel, Bora; Umbehr, Martin et al. (2016) Inflammation in Benign Prostate Tissue and Prostate Cancer in the Finasteride Arm of the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 25:463-9
Jackson, Christopher M; Kochel, Christina M; Nirschl, Christopher J et al. (2016) Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination. Clin Cancer Res 22:1161-72
Hedayati, Mohammad; Haffner, Michael C; Coulter, Jonathan B et al. (2016) Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation. Clin Cancer Res 22:3310-9
Trock, Bruce J; Fedor, Helen; Gurel, Bora et al. (2016) PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer cores predicts the presence of un-sampled grade 4 tumor: implications for active surveillance. Mod Pathol 29:764-71
Wu, Jianguo; Ivanov, Andrei I; Fisher, Paul B et al. (2016) Polo-like kinase 1 induces epithelial-to-mesenchymal transition and promotes epithelial cell motility by activating CRAF/ERK signaling. Elife 5:
Levy, Oren; Brennen, W Nathaniel; Han, Edward et al. (2016) A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials 91:140-50
Lotan, Tamara L; Wei, Wei; Morais, Carlos L et al. (2016) PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer. Eur Urol Focus 2:180-188

Showing the most recent 10 out of 691 publications