Androgen deprivation remains the standard therapy for patients with advanced prostate cancer (CAP) and causes disease remission in most men. However, CaP eventually recurs and thereafter the median survival of patients is less than 1 year. Thus, the transition from androgen-stimulated to recurrent growth represents a critical juncture in the progression of CaP. The Program Project's unifying hypothesis is that activation of the androgen receptor (AR) by low level androgens, mitogen signaling and coactivators mediates recurrent growth of CaP during androgen deprivation therapy. In the first three years of this P01, we demonstrated that AR is wild-type in most recurrent CaP, AR protein is expressed at similar levels in benign prostate and recurrent CaP, AR in recurrent CaP is hypersensitive (transactivated by femtomolar DHT and mitogens), tissue levels of testosterone and DHT within recurrent CaP appear sufficient for AR activation, stem-like cells within the prostate have neuroendocrine characteristics and the neovasculature of CaP xenografts is human not mouse in origin and appear androgen-responsive. The renewal consists of 3 closely-related projects. Project 1 will test the hypothesis that recurrence of CaP during androgen deprivation therapy can be prevented or delayed by attack upon tissue androgens and/or the androgen receptor. The mechanism of generation of tissue levels of androgens in recurrent CaP cells will be elucidated using CaP cell lines, CaP xenografts and clinical specimens. The accumulation of androgens in recurrent CaP tissue will be prevented by inhibiting their formation and augmenting their degradation. The androgen receptor will be inactivated using AR-dominant negatives and siRNA delivered using the lentiviral vector system. Project 2 will test the hypothesis that AR reactivation in the presence of low androgen levels is driven by mitogen signaling. Mechanisms by which EGF and heregulin enhance AR transcriptional activity in recurrent CaP will be determined with a particular emphasis upon AR phosphorylation, p160 coactivators and downstream signaling. The AR domains involved in EGF, heregulin and AR coactivator and corepressor regulation will be defined and the mechanism for loss of inhibition by AR antagonists elucidated. Novel coregulators that may have a role in AR transactivation will be tested for their potential as therapeutic targets. Project 3 will test the hypothesis that CaP recurrence originates from primitive, pluri-potential stem-like cells within the prostate. The role of the basal cell, vascular endothelium and neuroendocrine cells in the emergence of a population of CaP cells capable of growth in relative androgen absence will be examined in short-term human xenografts of benign prostate and CaP, the TRAMP and CWR22 models, and serial prostate biopsies obtained prior to and during androgen deprivation therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077739-09
Application #
7392846
Study Section
Subcommittee G - Education (NCI)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1998-08-01
Project End
2010-03-31
Budget Start
2008-04-21
Budget End
2009-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$1,301,427
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Li, Qiuhui; Deng, Qu; Chao, Hsueh-Ping et al. (2018) Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun 9:3600
Fiandalo, Michael V; Wilton, John H; Mantione, Krystin M et al. (2018) Serum-free complete medium, an alternative medium to mimic androgen deprivation in human prostate cancer cell line models. Prostate 78:213-221
Askew, Emily B; Bai, Suxia; Parris, Amanda B et al. (2017) Androgen receptor regulation by histone methyltransferase Suppressor of variegation 3-9 homolog 2 and Melanoma antigen-A11. Mol Cell Endocrinol 443:42-51
Komisarof, Justin; McCall, Matthew; Newman, Laurel et al. (2017) A four gene signature predictive of recurrent prostate cancer. Oncotarget 8:3430-3440
Su, Shifeng; Chen, Xiaoyu; Geng, Jiang et al. (2017) Melanoma antigen-A11 regulates substrate-specificity of Skp2-mediated protein degradation. Mol Cell Endocrinol 439:1-9
Itkonen, Harri M; Brown, Michael; Urbanucci, Alfonso et al. (2017) Lipid degradation promotes prostate cancer cell survival. Oncotarget 8:38264-38275
Stocking, John J; Fiandalo, Michael V; Pop, Elena A et al. (2016) Characterization of Prostate Cancer in a Functional Eunuch. J Natl Compr Canc Netw 14:1054-60
Frasinyuk, Mykhaylo S; Mrug, Galyna P; Bondarenko, Svitlana P et al. (2016) Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases. ChemMedChem 11:600-11
Minges, John T; Grossman, Gail; Zhang, Ping et al. (2015) Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor. J Biol Chem 290:25174-87
Montecinos, Viviana P; Morales, Claudio H; Fischer, Thomas H et al. (2015) Selective targeting of bioengineered platelets to prostate cancer vasculature: new paradigm for therapeutic modalities. J Cell Mol Med 19:1530-7

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