Prostate cancer first presents as an androgen dependent disease, and can thus be treated with androgen reduction therapies, such as castration. The beneficial effects, however, are transitory, and the cancer invariably progresses to become refractory to hormone ablation. Most of these advanced prostate cancers, continue to express and apparently require the Androgen Receptor, but are now capable of growing at very low, castrate, levels of androgen. What are the mechanisms by which the Androgen Receptor becomes responsive to low androgen concentrations? A significant portion of these recurrent cancers display upregulation of autocrine and paracrine growth factor loops that utilize Ras signaling, and we hypothesize that this Ras-mediated growth factor signaling is a major contributor to prostate cancer progression. We have shown that Ras signaling correlates with prostate cancer progression in patient samples, that expression of activated Ras is sufficient to drive progression, and that expression of dominant negative Ras restores androgen dependence to a cell line that had progressed to apparent androgen """"""""independence."""""""" Importantly, both prostate cancers and prostate cancer cells stimulated with Ras continue to require a functional Androgen Receptor but become responsive to very low levels of hormone. The goal of this research proposal is to understand the biochemical and molecular pathways by which Ras signaling sensitizes the Androgen Receptor to low levels of androgen. We propose the following three Aims:
Aim 1. Determine the roles of Ras family members and effectors in progression to decreased androgen dependence. Ras is a multi-effector protein and a member of a complex protein family. We will determine which components of this signaling network are responsible for driving prostate cancer to reduced hormone dependence.
Aim 2. Identify the intersection point between Ras signaling and the Androgen Receptor lifecycle. We will determine the targets of Ras signaling that allow the Androgen Receptor to respond to low concentrations of androgen, focusing on assembly of transcriptional complexes.
Aim 3. Identify the MAP Kinase substrates that regulate AR sensitivity to androgen. The Ras ? MAP Kinase pathway is an essential component of the mechanisms by which Ras alters androgen dependence of growth and gene expression. Once we have identified the intersection point(s) between Ras ? MAP Kinase signaling and the AR lifecycle, we will use an engineered """"""""pocket mutant"""""""" MAP Kinase and ATP analogs to identify direct MAP Kinase substrates. This research will be informative with respect to understanding the integration of steroid and growth factor signaling, as well as in identifying the optimal therapeutic targets for advanced prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105402-05
Application #
7344878
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Jhappan, Chamelli
Project Start
2004-02-11
Project End
2009-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2008
Total Cost
$148,210
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Gioeli, Daniel; Wunderlich, Winfried; Sebolt-Leopold, Judith et al. (2011) Compensatory pathways induced by MEK inhibition are effective drug targets for combination therapy against castration-resistant prostate cancer. Mol Cancer Ther 10:1581-90
DaSilva, John; Gioeli, Daniel; Weber, Michael J et al. (2009) The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor. Cancer Res 69:7402-11
Pienta, Kenneth J; Abate-Shen, Cory; Agus, David B et al. (2008) The current state of preclinical prostate cancer animal models. Prostate 68:629-39
Vomastek, Tomas; Iwanicki, Marcin P; Burack, W Richard et al. (2008) Extracellular signal-regulated kinase 2 (ERK2) phosphorylation sites and docking domain on the nuclear pore complex protein Tpr cooperatively regulate ERK2-Tpr interaction. Mol Cell Biol 28:6954-66
Bigler, Dora; Gioeli, Daniel; Conaway, Mark R et al. (2007) Rap2 regulates androgen sensitivity in human prostate cancer cells. Prostate 67:1590-9
Gioeli, Daniel; Black, Ben E; Gordon, Vicki et al. (2006) Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol Endocrinol 20:503-15
Kraus, Sarah; Gioeli, Daniel; Vomastek, Tomas et al. (2006) Receptor for activated C kinase 1 (RACK1) and Src regulate the tyrosine phosphorylation and function of the androgen receptor. Cancer Res 66:11047-54
Sharma, Charu; Vomastek, Tomas; Tarcsafalvi, Adel et al. (2005) MEK partner 1 (MP1): regulation of oligomerization in MAP kinase signaling. J Cell Biochem 94:708-19
Gioeli, Daniel (2005) Signal transduction in prostate cancer progression. Clin Sci (Lond) 108:293-308