The diagnosis and treatment of prostate cancer (PrCa) is a complex clinical problem that affects millions of men each year in the US, producing >200,000 new diagnoses and >27,000 deaths. Most PrCa is localized and slow growing;a smaller fraction metastasizes and causes death. Since prostate cancer derives from androgen dependent epithelium, some cases of localized PrCa and most cases of metastatic PrCa are treated via androgen deprivation therapy (ADT). ADT is a more specific therapy than surgery or radiation, inducing apoptosis in both localized and dispersed prostate epithelial tumor cells, rather than ablating the entire gland and causing damage to surrounding structures. However, androgens have systemic effects beyond regulating the growth and differentiation of prostate epithelium and ADT therefore produces considerable side-effects. Moreover, ADT frequently fails. The development of novel, targeted therapies that trigger PrCa apoptosis in a selective manner offers the possibility of reduced side-effects and improved control of disease progression. Our overall goal is to elucidate the mechanism of prostate apoptosis in response to androgen withdrawal, to eventually design therapies that selectively mimic the apoptotic effects of ADT. To achieve this goal, we have investigated androgen withdrawal induced apoptosis (AWIA) in normal rodents and model prostate cell lines. Recently, we developed a novel magnetic resonance imaging (CHESS-MRI) protocol to quantitate prostate regression and found that tumor necrosis factor (TNF) signaling is required, but not sufficient, for AWIA. Previously, we showed that FLIP, an inactive homologue of caspase-8 that inhibits TNF signaling, decreases following androgen withdrawal. The expression of both FLIP and TNF are androgen regulated. Two other cytokine signaling pathways (triggered by transforming growth factor-b (TGFb) and insulin-like growth factor 1 (IGF1)) have also been implicated in AWIA, and the corresponding genes are also androgen regulated. We will test the following central hypothesis: androgen withdrawal regulates a network of paracrine-acting cytokines (TNF, TGFb, IGF1, IGFBP3) and thereby reduces the expression of the intracellular apoptosis inhibitor FLIP. The net effect is to trigger the apoptotic arm of the TNF signaling pathway. The experimental plan utilizes rodent AWIA models and a prostate-specific PTEN-deficient mouse model resembling human prostate cancer, in conjunction with CHESS-MRI to image both normal and tumorous prostates.
Aim 1 determines the role of TNF, TGFb and IGFBP3 in ADT-induced prostate apoptosis and whether these same cytokines cooperate to induce apoptosis in normal and tumorigenic prostates.
Aim 2 investigates the role of TGFb and NF-kB cross-talk in mediating androgen deprivation induced down-regulation of FLIP. Finally, Aim 3 tests the functional role of FLIP, determining if FLIP down-regulation can cooperate with pro- apoptotic cytokines to induce apoptosis and regression of normal prostate and PrCa in a murine model.

Public Health Relevance

The detection and treatment of prostate cancer, the most prevalent visceral cancer among men in the US, is a complex clinical problem. Androgen-deprivation is used to treat both localized and metastatic prostate cancers, but this treatment is prone to side-effects and, in metastatic cancers, often fails. To identify novel apoptotic medical therapies for prostate cancer, we propose to investigate the cooperative role of multiple cytokines (IGF1, TNF and TGFb) in the mechanism of androgen withdrawal induced apoptosis in normal and tumorigenic prostates.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151753-03
Application #
8549718
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2011-09-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$40,431
Indirect Cost
$14,092
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627