Despite advances in surgical and therapeutic approaches, veterans have a 4-times higher risk for developing prostate cancer compared with non-veterans. Therefore novel strategies to prevent or delay development and progression of clinically significant disease in this population are critical for successful management of prostate cancer. The goal of this VA-Merit proposal is to develop a safe and effective strategy for management of clinically significant prostate cancer using a novel bark extract namely NexrutineR. This is based on strong published and preliminary unpublished studies from our laboratory demonstrating (i) NexrutineR intervention inhibits early stage tumor development in a preclinical animal model that develops prostate cancer akin to humans;(ii) NexrutineR treatment reduces Akt activation, transcriptional activity of CREB and NF:B and expression of antiapoptotic protein FLIP in prostate cancer cells and (iii) overexpression of myristoylated Akt protects prostate cancer cells from NexrutineR - induced growth inhibition. Preliminary results also show that reduction in the protein levels of pmTOR (2448) and pAkt (473) within 2h of NexrutineR;implicating a role for Akt/mTOR signaling in NexrutineR-induced biological activities. Despite such promising results, the precise role of mTORC2/Akt signaling and signaling pathways downstream of Akt, including CREB in NexrutineR-induced inhibition of cell proliferation/survival and induction of apoptosis remains to be established. Further it is not known whether NexrutineR is effective only in preventing early stage prostate tumors or it will be effective in other stages of prostate cancer. In addition, published studies from our laboratory and other investigators demonstrate a good correlation between expression of FLIP, CREB, Akt, NF:B and tumor grade in human prostate cancer patients. This data supports the concept that a substantial number of VA patients with high grade prostate cancer may benefit from strategies targeting FLIP, CREB, Akt, NF:B signaling or pathways that activate these molecules. To date no studies have examined the potential for combined targeting of these critical signaling pathways for prostate cancer management. We have designed experiments to fill these critical gaps using state-of-the-art methodologies including magnetic resonance imaging (MRI) for monitoring tumor development in animals, siRNA approaches, ChIP analysis in addition to standard molecular and biochemical approaches. Although multicomponent approach has been successfully applied in the treatment of diseases such as tuberculosis, AIDS and leukemia, such strategies have not been exploited fully for prostate cancer management. Therefore our approach targeting mTORC2/Akt/mTORC1 and Akt/NF:B- mediated signaling pathways simultaneously that play a critical role in prostate cancer progression while using a safe and cost-effective herbal supplement is novel and innovative. Results from these studies will likely provide mechanistic data and a detailed preclinical evaluation, setting the stage for the clinical assessment of NexrutineR against prostate cancer in VA patients.

Public Health Relevance

Project Narrative: A critical health care issue for the aging Veteran population is metastatic hormone refractory prostate cancer which accounts for most of the prostate cancer associated fatality. Although not explored in detail, it has been suggested that Veterans are more susceptible due to extended exposure to various toxic chemicals and smoke from oil well fires during war. In addition with increasing life expectancy of the Veteran population, prostate cancer will continue to be a major health problem. Therefore developing new non toxic treatment modalities are critical for protecting current and future armed forces personnel. Considering these problems and the known heterogeneity of prostate cancer, simultaneously targeting multiple critical signaling pathways that play a critical/major role during prostate carcinogenesis will have tremendous advantage and impact in keeping morbidity and mortality at bay. In addition these data will provide key insights for better design of future clinical trials for Veterans population who has developed prostate cancer.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000766-03
Application #
8391589
Study Section
Oncology A (ONCA)
Project Start
2010-10-01
Project End
2013-09-30
Budget Start
2012-10-01
Budget End
2013-09-30
Support Year
3
Fiscal Year
2013
Total Cost
Indirect Cost
Name
South Texas Veterans Health Care System
Department
Type
DUNS #
078493228
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Chakravarthy, Divya; Muñoz, Amanda R; Su, Angel et al. (2018) Palmatine suppresses glutamine-mediated interaction between pancreatic cancer and stellate cells through simultaneous inhibition of survivin and COL1A1. Cancer Lett 419:103-115
Gong, Jingjing; Muñoz, Amanda R; Pingali, Subramanya et al. (2017) Downregulation of STAT3/NF-?B potentiates gemcitabine activity in pancreatic cancer cells. Mol Carcinog 56:402-411
Batth, Izhar; Yun, Huiyoung; Hussain, Suleman et al. (2016) Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer. Oncotarget 7:14048-63
Yun, Huiyoung; Xie, Jianping; Olumi, Aria F et al. (2015) Activation of AKR1C1/ER? induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity. Oncotarget 6:11600-13
Hambright, Heather G; Batth, Izhar Singh; Xie, Jianping et al. (2015) Palmatine inhibits growth and invasion in prostate cancer cell: Potential role for rpS6/NF?B/FLIP. Mol Carcinog 54:1227-34
Swanson, Gregory P; Jones 3rd, William E; Ha, Chul S et al. (2015) Tolerance of Phellodendron amurense bark extract (Nexrutine®) in patients with human prostate cancer. Phytother Res 29:40-2
Hussain, Suleman S; Patel, Darpan; Ghosh, Rita et al. (2015) Extracting the Benefit of Nexrutine® for Cancer Prevention. Curr Pharmacol Rep 1:365-372
Gong, Jingjing; Muñoz, Amanda R; Chan, Daniel et al. (2014) STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth. Oncotarget 5:2529-41
Gong, Jingjing; Xie, Jianping; Bedolla, Roble et al. (2014) Combined targeting of STAT3/NF-?B/COX-2/EP4 for effective management of pancreatic cancer. Clin Cancer Res 20:1259-73
Li, Guiming; Rivas, Paul; Bedolla, Roble et al. (2013) Dietary resveratrol prevents development of high-grade prostatic intraepithelial neoplastic lesions: involvement of SIRT1/S6K axis. Cancer Prev Res (Phila) 6:27-39