The goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen dependent prostatic cancer. Our strategy is to identify compounds, which achieve total androgen blockade. We have discovered a number of potent inhibitors of 17alpha-hydroxylase/C17,20-lyase (CYP17). Several of these were found to have multiple activities. Some inhibit 5a- reductase and/or are antiandrogens. VN/85-1, VN/87-1, and L-39 are the three most potent and best characterized compounds to date. The compounds have significant antitumor activity in androgen dependent tumors in mouse xenograft models and cause marked reduction in androgen levels. The following specific aims are proposed in order to develop the most active inhibitors and complete preclinical studies of the lead compounds L-39, VN/85-1, and VN/87-1 and prepare them for Phase I trials.
The Specific Aims of the project are: 1. Metabolic studies of lead compounds: a. Predictive models of metabolism, b. Synthesis of radiolabeled inhibitors, and c. Metabolic studies; 2. To design and synthesize: a. Analogs of current inhibitors to improve metabolic stability and increase efficacy and b. Non-steroidal inhibitors based on a molecular modeling approach; 3. To evaluate analogs and new compounds for inhibition of 17alpha-hydroxylase/ C17,20-lyase and all potent inhibitors for 5alpha -reductase Type I and Type II inhibition; 4. To determine the effects of the CYP17 inhibitors on androgen dependent growth in prostate cancer cells; 5. To determine whether the CYP17 inhibitors are agonists or antagonists of mutant or wild type androgen receptors using binding and transcriptional activation assays; and 6. To optimize the antitumor efficacy of the most potent inhibitors in mouse xenograft models with human prostate cancers (LAPC-4 and LNCaP androgen dependent tumors): a. Determine effective doses, scheduling, and route of administration and b. Compare the effect of lead inhibitors and castration on apoptosis to identify the best compound.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA027440-28
Application #
7266871
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2004-09-23
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
28
Fiscal Year
2007
Total Cost
$316,811
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
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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
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Brodie, Angela; Njar, Vincent; Macedo, Luciana Furtado et al. (2009) The Coffey Lecture: steroidogenic enzyme inhibitors and hormone dependent cancer. Urol Oncol 27:53-63
Vasaitis, Tadas; Belosay, Aashvini; Schayowitz, Adam et al. (2008) Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther 7:2348-57
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
Tang, Yao; Khan, Mohammad A; Goloubeva, Olga et al. (2006) Docetaxel followed by castration improves outcomes in LNCaP prostate cancer-bearing severe combined immunodeficient mice. Clin Cancer Res 12:169-74