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 #
3P50CA058236-23S1
Application #
10264513
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Arnold, Julia T
Project Start
1997-09-30
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
23
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Shrestha, Eva; White, James R; Yu, Shu-Han et al. (2018) Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer. J Urol 199:161-171
Lu, Yunqi; Hu, Zhongyi; Mangala, Lingegowda S et al. (2018) MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels. Cancer Res 78:64-74
Das, Swadesh K; Pradhan, Anjan K; Bhoopathi, Praveen et al. (2018) The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion. Cancer Res 78:2852-2863
Karnes, R Jeffrey; Choeurng, Voleak; Ross, Ashley E et al. (2018) Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features. Eur Urol 73:168-175
Menezes, Mitchell E; Bhoopathi, Praveen; Pradhan, Anjan K et al. (2018) Role of MDA-7/IL-24 a Multifunction Protein in Human Diseases. Adv Cancer Res 138:143-182
Jiang, Wen; Ulmert, David; Simons, Brian W et al. (2018) The impact of age on radium-223 distribution and an evaluation of molecular imaging surrogates. Nucl Med Biol 62-63:1-8
Tsang, Sabrina H; Peisch, Samuel F; Rowan, Brendan et al. (2018) Association between Trichomonas vaginalis and prostate cancer mortality. Int J Cancer :
Baena-Del Valle, Javier A; Zheng, Qizhi; Esopi, David M et al. (2018) MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. J Pathol 244:11-24
Martino, Thiago; Kudrolli, Tarana A; Kumar, Binod et al. (2018) The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress. Prostate 78:140-151
Kaur, Harsimar B; Guedes, Liana B; Lu, Jiayun et al. (2018) Association of tumor-infiltrating T-cell density with molecular subtype, racial ancestry and clinical outcomes in prostate cancer. Mod Pathol 31:1539-1552

Showing the most recent 10 out of 750 publications