All-trans retinoic acid (ATRA), a derivative of vitamin A (retinol), is required for the appropriate cellular proliferation and differentiation of normal human prostate epithelial cells. Human prostate cancer cells contain much lower levels of ATRA than normal cells. We hypothesize that aberrant metabolism of ATRA and dysregulation of gene expression in prostate tumor cells are related to the abnormal growth properties of the tumor cells. A rationale for using retinoic acid in prostate cancer therapy is further supported by the effectiveness of ATRA in the treatment of acute promyelocytic leukemia (APL). We hypothesize that the efficacy of ATRA can be enhanced if it is administered in combination with retinoic acid metabolism blocking agents (RAMBAs) plus low doses of selective histone deacetylase inhibitors (HDACIs) such as trichostatin A(TSA) or suberoylanilide hydroxamic acid (SAHA). HDACIs will act by sensitizing prostate cancer cells towards ATRA differentiation activity. The discovery of the retinoic acid receptor (RAR)/ADAC complex provides a rationale for combining RAs and HADCIs. The goals of this proposal are to use in vitro cell culture and also mouse xenograft models to ascertain the effectiveness of ATRA, various RAMBAs plus HDACIs in inhibiting the growth and inducing the differentiation of the human prostate cell lines, LNCaP, LAPC-4, PC-3 and DU-145. A second goal of the project is to understand at the molecular level the mechanisms by which the combination treatments result in human prostate tumor cell growth inhibition. These studies may provide a much clearer rationale for new clinical treatments for prostate cancer in humans. If this approach appears successful, we will consider the need for developing novel HDAC inhibitors in the subsequent RO1 proposal on the strengths of our expertise in drug design, discovery and development. The long-term goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen-dependent and androgen independent prostatic cancer. The following specific aims that are proposed should enable us obtain substantial data that may support our hypothesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA117991-02
Application #
7140176
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Forry, Suzanne L
Project Start
2005-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$155,886
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Njar, Vincent C O; Brodie, Angela M H (2015) Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J Med Chem 58:2077-87
Purushottamachar, Puranik; Godbole, Abhijit M; Gediya, Lalji K et al. (2013) Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer. J Med Chem 56:4880-98
Purushottamachar, Puranik; Patel, Jyoti B; Gediya, Lalji K et al. (2012) First chemical feature-based pharmacophore modeling of potent retinoidal retinoic acid metabolism blocking agents (RAMBAs): identification of novel RAMBA scaffolds. Eur J Med Chem 47:412-23
Bruno, Robert D; Vasaitis, Tadas S; Gediya, Lalji K et al. (2011) Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model. Steroids 76:1268-79
Vasaitis, Tadas S; Bruno, Robert D; Njar, Vincent C O (2011) CYP17 inhibitors for prostate cancer therapy. J Steroid Biochem Mol Biol 125:23-31
Purushottamachar, Puranik; Khandelwal, Aakanksha; Vasaitis, Tadas S et al. (2008) Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent. Bioorg Med Chem 16:3519-29
Bruno, Robert D; Gover, Tony D; Burger, Angelika M et al. (2008) 17alpha-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Mol Cancer Ther 7:2828-36
Gediya, Lalji K; Khandelwal, Aakanksha; Patel, Jyoti et al. (2008) Design, synthesis, and evaluation of novel mutual prodrugs (hybrid drugs) of all-trans-retinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro. J Med Chem 51:3895-904
Moreira, Vania M A; Vasaitis, Tadas S; Guo, Zhiyong et al. (2008) Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth. Steroids 73:1217-27
Gediya, Lalji K; Belosay, Aashvini; Khandelwal, Aakanksha et al. (2008) Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts. Bioorg Med Chem 16:3352-60

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