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ANDROGEN AND GROWTH FACTOR SIGNALING IN PROSTATE CANCER

Award Number: R01CA105402
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/11/2004
PERIOD OF PERFORMANCE END DATE: 01/31/2009

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ANDROGEN AND GROWTH FACTOR SIGNALING IN PROSTATE CANCER - DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2008 ( Subtotal = $148,210 )
2008	2008	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	5	1/24/2008	NON-COMPETING CONTINUATION	$148,210
														Subtotal = $148,210

Issue Date FY: 2007 ( Subtotal = $148,210 )
2007	2007	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	4	1/24/2007	NON-COMPETING CONTINUATION	$148,210
														Subtotal = $148,210

Issue Date FY: 2006 ( Subtotal = $152,637 )
2006	2006	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	3	2/1/2006	NON-COMPETING CONTINUATION	$152,637
														Subtotal = $152,637

Issue Date FY: 2005 ( Subtotal = $234,148 )
2005	2005	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	2	1/31/2005	NON-COMPETING CONTINUATION	$234,148
														Subtotal = $234,148

Issue Date FY: 2004 ( Subtotal = $307,336 )
2004	2004	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	1	2/11/2004	NEW	$307,336
														Subtotal = $307,336

Grand Total All Awards = $990,541

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ANDROGEN AND GROWTH FACTOR SIGNALING IN PROSTATE CANCER

Award Number: R01CA105402

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/11/2004

PERIOD OF PERFORMANCE END DATE: 01/31/2009

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