Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer-related deaths in the US. While prognosis for localized PCa is favorable, 5-year survival for metastatic disease is lower than 30%. Current standard of treatment for advanced PCa is androgen deprivation, but most cancers recur as castration-resistant within two years. Precise factors that mediate transformation of normal prostatic epithelium to intraepithelial neoplasia to cancer, metastasis, and castration resistance are poorly understood. However, growing evidence suggests that histologic inflammation of the prostate is positively associated with subsequent high-grade PCa diagnosis and elevated circulating pro-inflammatory cytokines correlate with shorter times to castration-resistance and lower survival. Indeed, inflammation has been implicated in initiation and progression of many cancers, but no mechanistic relationship in PCa has been established to date. We are therefore interested in studying the contribution of infiltrating immune cells to PCa and propose that proteases derived from these cells activate proliferative pathways and sensitize prostatic epithelium to more robustly respond to growth factors and androgens within the tumor microenvironment. We are especially interested in neutrophil elastase (NE) - a serine protease that we find to be abundantly active in PC3 PCa xenografts. NE has been shown to play a pathogenic role in several cancers, but it has never before been studied in the context of PCa. Based on preliminary data, we propose to elucidate mechanisms by which NE activates proliferative pathways in PCa cells, focusing on receptor tyrosine kinase (RTK)-mediated ERK activation. Furthermore, we propose to determine the physiological role of NE in PCa xenografts and examine expression patterns of NE and its endogenous inhibitors in human PCa samples. We will utilize novel in vivo imaging modalities to visualize NE activity and determine whether pharmacologic inhibition of NE can reduce tumor burden in `castration-resistant' and `castration-sensitive' PCa models. Finally, our laboratory has recently reported that the scaffolding protein paxillin is a key mediator of PCa growth; importantly, it is required for RTK mediated ERK activation as well as subsequent ERK- and androgen-mediated transcriptional signals. Preliminary data also indicate that paxillin negatively regulates the expression of endogenous NE inhibitors such as SERPINB1, PI3 (elafin), and SLPI, which may be important for dampening NE activity within the prostate. Because ERK activation lies at the crossroads of this project, we propose a proteomic-based approach to identify novel paxillin binding proteins that facilitate its role as mediator of PCa growth. Ultimately, our goal is to better understand how the assortment of signals present within the tumor microenvironment can work synergistically to activate proliferative pathways in PCa and open avenues for establishment of new biomarkers and therapeutic interventions.

Public Health Relevance

Prostate cancer is the most common cancer in men in the United States, with up to 80% of those over the age of 80 showing histologic signs of disease. Advanced prostate cancer will become an even greater public health concern as the population ages since it carries a very poor prognosis and limited effective treatment options. There is growing evidence that inflammation contributes to prostate carcinogenesis and poor patient outcomes; as such, this research project will investigate the role of a previously unstudied inflammatory mediator, neutrophil elastase, in the context of prostate cancer. These studies will enable establishment of new biomarkers and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA203517-03
Application #
9440380
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Lerman, Irina; Garcia-Hernandez, Maria de la Luz; Rangel-Moreno, Javier et al. (2017) Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase. Mol Cancer Res 15:1138-1152
Lerman, Irina; Hammes, Stephen R (2017) Neutrophil elastase in the tumor microenvironment. Steroids :