Extensive studies have defined GLIPRI (glioma pathogenesis-related protein) as a secreted, cytostatic/pro- apoptotic tumor suppressor protein that is down-regulated during prostate cancer progression through epigenetic mechanisms. Mechanistic studies have shown that GLIPRI manifests tumor suppressor functions through coordinated cell type specific activities, including direct, tumor cell selective, pro-apoptotic activities mediated through reactive oxygen species (R0S)-c-jun-NH2 kinase (JNK) signaling. Recently we showed that GLIPRI expression leads to down-regulation of specificity protein 1 (Spl). Additional analysis showed that GLIPR1 expression suppressed c-myc through transcriptional repression that was dependent on Spl responsive GC/GT sites in the c-myc promoter and resulted in down-regulation of additional Spl target genes including copper/zinc superoxide dismutase (CuZnSOD/SODI) and manganese superoxide dismutase (MnS0D/S0D2). These data are in agreement with previous findings that Spl directly stimulates expression of multiple anti-oxidant proteins including CuZnSOD, MnSOD, and extracellular superoxide dismutase (ECSOD/SOD3). Western blotting analysis of c-myc targets showed that GLIPRI overexpression resulted in significant suppression of key cell cycle regulatory proteins and also y-Qlutamyl-cysteine synthetase, which catalyzes the first rate-limiting step in the synthesis of glutathione [1]. Overall, GLIPRI suppression of Spl activities represents a molecular switch that debilitates the anti-oxidant mechanisms/pathways that prevent cancer cells from ROS mediated """"""""self-destruction"""""""" and inhibits c-myc- mediated cancer cell proliferation. In preclinical studies we have found that recombinant GLIPRI protein treatment results in tumor cell selective growth arrest and/or apoptotic cell death in multiple prostate cancer cell lines in vitro. Further preclinical studies using VCaP and/or PC-3 xenograft models demonstrated that recombinant GLIPRI protein suppressed tumor growth and increased tumor cell apoptosis when administered intratumorally or intraperitoneally. In addition, effects on stromal cells effects were observed in treated tumors including significant suppression of angiogenesis and macrophage infiltration. Our first step in developing GLIPRI protein therapy for prostate cancer is to test in situ delivery of a modified GLIPRI protein (GLIPR1-ATM). This Phase lb clinical trial will accomplish two important goals: (1) Establish the safety of this therapeutic protein in a clinical setting (intraprostatic treatment prior to radical prostatectomy);(2) Establish proof of principle for systemic use of GLIPRI-ATM.

Public Health Relevance

This project will further analyze the mechanism of action of a novel cancer protein therapeutic, GLIPRI-ATM, and use this information to develop predictive biomarkers for local and systemic response. Further clinical studies that involve intraprostatic injection of GLIPRI-ATM will test its toxicity and efficacy through extensive tissue analysis. GLIPRI-ATM has the potential for local and systemic use for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA140388-04
Application #
8380586
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$252,416
Indirect Cost
$87,464
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Tao; Tseng, Chieh; Zhang, Yan et al. (2016) CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat Commun 7:11674
Sun, Sheng; Sun, Le; Zhou, Xi et al. (2016) Phosphorylation-Dependent Activation of the ESCRT Function of ALIX in Cytokinetic Abscission and Retroviral Budding. Dev Cell 36:331-43
Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P et al. (2016) Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release. Proc Natl Acad Sci U S A 113:1877-82
Maity, Sankar N; Titus, Mark A; Gyftaki, Revekka et al. (2016) Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer. Sci Rep 6:35354
Saha, Achinto; Blando, Jorge; Fernandez, Irina et al. (2016) Linneg Sca-1high CD49fhigh prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo. Oncotarget 7:25194-207
Han, Ying; Rand, Kristin A; Hazelett, Dennis J et al. (2016) Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst 108:
Varkaris, Andreas; Corn, Paul G; Parikh, Nila U et al. (2016) Integrating Murine and Clinical Trials with Cabozantinib to Understand Roles of MET and VEGFR2 as Targets for Growth Inhibition of Prostate Cancer. Clin Cancer Res 22:107-21
Fong, Eliza L S; Wan, Xinhai; Yang, Jun et al. (2016) A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials 77:164-72
Weiderhold, Kimberly N; Fadri-Moskwik, Maria; Pan, Jing et al. (2016) Dynamic Phosphorylation of NudC by Aurora B in Cytokinesis. PLoS One 11:e0153455
Qiao, Yuanyuan; Feng, Felix Y; Wang, Yugang et al. (2016) Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer. Neoplasia 18:1-9

Showing the most recent 10 out of 167 publications