My long term goal is a career in translational research, focused on the molecular investigation and clinical treatment of prostate cancer. My immediate career goal is to develop the expertise in prostate cancer biology and clinical research that will allow me to pursue an independent career as a physician-investigator. Through a combination of didactics and mentored research experiences I will lay a groundwork in statistics, ethics, prostate tumor biology and clinical trial development that will position me to apply for and obtain funding in clinical research areas that will grow out of my current interests in the molecular effects of androgens on prostatic epithelial tissue. The research infrastructure of the Hutchinson Center and the University of Washington, the collaborative environment created by the Prostate SPORE and Program in Prostate Cancer Research, and the dual scientific and clinical mentorship provided by my mentors encompass all the resources I will need to successfully transition to an independent career. Establishing whether intraprostatic androgen levels can be suppressed to below a threshold at which essentially all prostate cancer cells undergo apoptosis has never been quantitatively addressed. In this proposal we will quantitative the pharmacologic and treatment efficacy of androgen lowering treatment strategies by measuring intraprostatic androgen levels in context of tissue and molecular correlates of tumor regression. Men with localized prostate cancer will be randomized to receive three months of neoadjuvant hormonal therapy with one of four treatments designed to progressively inhibit the androgen axis. Prostate samples obtained at diagnosis and prostatectomy will be assayed for treatment efficacy based on androgen levels, histological measures of tissue response, and assessment of androgen-regulated gene expression. Relevance: Prostate cancer is the most common cancer in American men, and the second leading cause of cancer-related death. Prostate cancer cells rely on the hormone testosterone for survival. Current methods of hormonal treatment only inhibit testicular hormone production, and ultimately fail to control the growth of prostate cancer cells. Our study will determine whether treatments inhibiting multiple sources of testosterone production (testicular, adrenal and prostatic) will be more effective than current methods in decreasing hormone levels inside the prostate, and therefore, more effective in killing prostate cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23CA122820-01
Application #
7136931
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2006-08-15
Project End
2011-06-30
Budget Start
2006-08-15
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$134,460
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Mostaghel, Elahe A; Morgan, Andrew; Zhang, Xiaotun et al. (2014) Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis. PLoS One 9:e111545
Mostaghel, Elahe A; Lin, Daniel W; Amory, John K et al. (2012) Impact of male hormonal contraception on prostate androgens and androgen action in healthy men: a randomized, controlled trial. J Clin Endocrinol Metab 97:2809-17
Mostaghel, Elahe A; Plymate, Stephen (2011) New hormonal therapies for castration-resistant prostate cancer. Endocrinol Metab Clin North Am 40:625-42, x
Mostaghel, Elahe A; Marck, Brett T; Plymate, Stephen R et al. (2011) Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 17:5913-25
Wright, Jonathan L; Kwon, Erika M; Ostrander, Elaine A et al. (2011) Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev 20:619-27
Mostaghel, Elahe A; Geng, Linda; Holcomb, Ilona et al. (2010) Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention. Cancer Res 70:1286-95
Mostaghel, Elahe A; Montgomery, Bruce; Nelson, Peter S (2009) Castration-resistant prostate cancer: targeting androgen metabolic pathways in recurrent disease. Urol Oncol 27:251-7
Mostaghel, Elahe A; Nelson, Peter S (2008) Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab 22:243-58
Montgomery, R Bruce; Mostaghel, Elahe A; Vessella, Robert et al. (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68:4447-54
Marks, Leonard S; Mostaghel, Elahe A; Nelson, Peter S (2008) Prostate tissue androgens: history and current clinical relevance. Urology 72:247-54

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