Significant advances as well productive failures have resulted from evaluation of chromatin remodeling as a target in advanced prostate cancer (PCA). Our group has recently proposed the role of histone deacetylase (HDAC) inhibitors as antiangiogenesis agents for PCA by demonstrating their effect on the modulation the transcriptional factor HIF-1 alpha (hypoxia inducible factor 1 alpha). The principal objective of the proposed research is to further determine the therapeutic potential of targeting HIF-1 alpha and angiogenesis with novel combination strategies involving HDAC inhibitors for the treatment of PCA. Our central hypotheses are that 1) targeting HDAC has shown preclinical and clinical activity in PCA;2) HIF-1 alpha and angiogenesis are affected by HDAC inhibitors and other targeted therapies in PCA;and 3) there is a need to assess the selectivity of HDAC inhibitors and to determine optimal combination strategies in PCA. To this end we will pursue the following goals: 1) to further define the role of specific HDACs in the modulation of HIF-1 alpha and angiogenesis in PCA;2) to evaluate novel combination strategies using xenograft models with targeted agents such as mTOR and microtubule inhibitors with antiangiogenesis activity likely to be enhanced by use of HDAC inhibitor;and 3) to conduct clinical studies with a rational combination strategy of HDAC and mTOR inhibitors in PCA. To achieve our goals we will pursue the following Specific Aims:
Specific Aim #1 To assess the modulation of HIF-1 alpha and angiogenesis by specific HDAC isozymes in an in vitro PCA bone microenvironment model;
Specific Aim #2 To determine the antitumor and antiangiogenesis activity of novel strategies targeting HIF-1 alpha with combination of HDAC, microtubule and mTOR inhibitors in in vivo PCA models;
Specific Aim #3 To assess the biological and clinical activity of an antiangiogenesis combination strategy with HDAC and mTOR inhibitors in PCA patients. These studies are significant because they represent the development of rational combinations with HDAC inhibitors by exploiting both their transcriptional and non-transcriptional regulation of prostate tumor growth and angiogenesis. We expect that these studies will provide 1) new insights on the role of HDACs in prostate tumor microenvironment, 2) early clinical evidence that combining HDAC inhibitors and molecular targeted inhibitors increases the antitumor effects, and 3) the foundation for future clinical trials in PCA patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA058236-18S1
Application #
8719552
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
2013-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
18
Fiscal Year
2013
Total Cost
$137,622
Indirect Cost
$15,324
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Pradhan, Anjan K; Talukdar, Sarmistha; Bhoopathi, Praveen et al. (2017) mda-7/IL-24 Mediates Cancer Cell-Specific Death via Regulation of miR-221 and the Beclin-1 Axis. Cancer Res 77:949-959
Zamboni, Camila G; Kozielski, Kristen L; Vaughan, Hannah J et al. (2017) Polymeric nanoparticles as cancer-specific DNA delivery vectors to human hepatocellular carcinoma. J Control Release 263:18-28
Sharma, Anup; Mendonca, Janet; Ying, James et al. (2017) The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion. Mol Oncol 11:655-669
Winchester, Danyelle A; Till, Cathee; Goodman, Phyllis J et al. (2017) Association between variants in genes involved in the immune response and prostate cancer risk in men randomized to the finasteride arm in the Prostate Cancer Prevention Trial. Prostate 77:908-919
Guedes, Liana B; Almutairi, Fawaz; Haffner, Michael C et al. (2017) Analytic, Preanalytic, and Clinical Validation of p53 IHC for Detection of TP53 Missense Mutation in Prostate Cancer. Clin Cancer Res 23:4693-4703
Markowski, Mark C; Silberstein, John L; Eshleman, James R et al. (2017) Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer. JCO Precis Oncol 2017:
Graham, Mindy Kim; Principessa, Lorenzo; Antony, Lizamma et al. (2017) Low p16(INK4a) Expression in Early Passage Human Prostate Basal Epithelial Cells Enables Immortalization by Telomerase Expression Alone. Prostate 77:374-384
Torres, Alba; Alshalalfa, Mohammed; Tomlins, Scott A et al. (2017) Comprehensive Determination of Prostate Tumor ETS Gene Status in Clinical Samples Using the CLIA Decipher Assay. J Mol Diagn 19:475-484
Lotan, Tamara L; Torres, Alba; Zhang, Miao et al. (2017) Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers. Oncotarget 8:22772-22782
Platz, Elizabeth A; Kulac, Ibrahim; Barber, John R et al. (2017) A Prospective Study of Chronic Inflammation in Benign Prostate Tissue and Risk of Prostate Cancer: Linked PCPT and SELECT Cohorts. Cancer Epidemiol Biomarkers Prev 26:1549-1557

Showing the most recent 10 out of 725 publications