Androgen is required to regulate (i.e. balance) both the rate of proliferation and death of androgen dependent and sensitive normal prostatic epithelial cells. This regulation is via transcriptional control involving the ligand occupied androgen receptor (AR) complex. In prostate cancer cells, regulation by the ligand/AR axis is modified such that excess malignant cell growth continuously occur. During the last 4 years, a series of unique xenografts and molecular biology methods were used to document that the androgen regulation of proliferation and death of normal prostatic epithelial cells involves a paracrine dependence on prostate stromal cells. During the progression of prostate cancer, there are changes within the AR axis which result in the conversion from a paracrine dependence upon stromal cells o a direct autocrine mechanism for the regulation of proliferation and death of metastatic prostate cancer cells. This autocrine-dependent AR axis in malignant cells involves either ligand-dependent or ligand-independent pathways. presently, LHRH analogs effectively lower the serum testosterone level (i.e. androgen ablation) to activate the apoptotic elimination of the ligand (i.e. androgen) dependent prostate cancer cells within a metastatic patient. Such androgen ablation does not eliminate either the androgen sensitive or independent prostate cancer cells also present. While these cells are not dependent upon androgen for survival, their survival is dependent upon the continued expression of unoccupied AR. Geldanamycin binds to the Heat Shock 90 protein (HSP-90) when it is bound to unoccupied AR. Such binding enhances the degradation of the AR protein and thus the apoptotic death of these AR dependent prostatic cancer cells. Since geldanamycin is too toxic for systemic delivery, we purpose to chemically modify geldanamycin to produce a primary amine containing analog (Specific Aim 1). This analog will be covalently coupled via peptide bond to specific peptides to produce prodrugs. These peptide prodrugs will be designed so that they are substrates for the enzymatic activity of either Prostate Specific Antigen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052645-06
Application #
6669093
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Mullins, Christopher V
Project Start
1997-07-07
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
6
Fiscal Year
2003
Total Cost
$286,125
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Antony, Lizamma; van der Schoor, Freek; Dalrymple, Susan L et al. (2014) Androgen receptor (AR) suppresses normal human prostate epithelial cell proliferation via AR/?-catenin/TCF-4 complex inhibition of c-MYC transcription. Prostate 74:1118-31
Vander Griend, Donald J; Litvinov, Ivan V; Isaacs, John T (2014) Conversion of androgen receptor signaling from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells involves a gain of function in c-Myc regulation. Int J Biol Sci 10:627-42
Isaacs, John T; D'Antonio, Jason M; Chen, Shuangling et al. (2012) Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. Prostate 72:1491-505
Williams, Simon A; Jelinek, Christine A; Litvinov, Ivan et al. (2011) Enzymatically active prostate-specific antigen promotes growth of human prostate cancers. Prostate 71:1595-607
D'Antonio, Jason M; Vander Griend, Donald J; Antony, Lizamma et al. (2010) Loss of androgen receptor-dependent growth suppression by prostate cancer cells can occur independently from acquiring oncogenic addiction to androgen receptor signaling. PLoS One 5:e11475
Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora et al. (2010) Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells. Prostate 70:90-9
Sedelaar, J P Michiel; Isaacs, John T (2009) Tissue culture media supplemented with 10% fetal calf serum contains a castrate level of testosterone. Prostate 69:1724-9
Vander Griend, Donald J; Konishi, Yuko; De Marzo, Angelo M et al. (2009) Dual-label centromere and telomere FISH identifies human, rat, and mouse cell contribution to Multispecies recombinant urogenital sinus xenografts. Prostate 69:1557-64
Vander Griend, Donald J; Karthaus, Wouter L; Dalrymple, Susan et al. (2008) The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res 68:9703-11
Collins, Connie; Carducci, Michael A; Eisenberger, Mario A et al. (2007) Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint. Cancer Biol Ther 6:1360-7

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