Prostate cancer is a complex disease characterized by recurrent gene deletions and amplifications. Human genetic data demonstrate correlation between dual loss of CHD1 and MAP3K7 with lethal prostate cancer. We recently showed in both published and unpublished data that MAP3K7 and CHD1 loss leads to aggressive castrate-resistant prostate cancer. We did this with two independent model systems providing strong support for the overall conclusions of the studies that provide a functional link between these two novel tumor suppressors and prostate cancer aggressiveness. Because MAP3K7 and CHD1 are both tumor suppressors, and by definition lost or inactivated in prostate cancer, neither are directly targetable with therapeutic strategies. We hypothesize that cells with loss of MAP3K7 and CHD1 have dependence on novel survival pathways and we propose to exploit these pathways to kill tumors that have lost MAP3K7 and/or CHD1. We will use two complementary approaches to identify therapeutic vulnerabilities.
In Aim 1 we will screen human prostate cells with knockdown of CHD1 and/or MAP3K7 for the ability of common prostate cancer drugs to inhibit growth and tumorigenesis in vitro and in vivo.
In aim 2 we will use a genome-wide shRNA screen to identify synthetic lethal targets in cells with loss of MAP3K7 and/or CHD1. This is a high-risk, high-gain project appropriate for an R21 type funding mechanism.
Each aim i s independent and each needs to be done. Together the two aims will define potential therapeutic approaches to an extremely aggressive variant of prostate cancer.

Public Health Relevance

Prostate cancer is a significant health problem in the US. This project will identify potential synthetic lethality incurred by specific loss of a common prostate tumor suppressor. If this project is successful it could lead to personalized medicine for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA187354-01A1
Application #
8873686
Study Section
Special Emphasis Panel (ZCA1-SRB-2 (J1))
Program Officer
Alley, Michael C
Project Start
2015-04-06
Project End
2017-03-31
Budget Start
2015-04-06
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$168,970
Indirect Cost
$60,220
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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