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 . 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.
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.
|Velazquez-Torres, Guermarie; Shoshan, Einav; Ivan, Cristina et al. (2018) A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. Nat Commun 9:461|
|Zanoaga, Oana; Jurj, Ancuta; Raduly, Lajos et al. (2018) Implications of dietary ?-3 and ?-6 polyunsaturated fatty acids in breast cancer. Exp Ther Med 15:1167-1176|
|Zhang, Wei; Liu, Bo; Wu, Wenhui et al. (2018) Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer. Clin Cancer Res 24:696-707|
|Monroig-Bosque, Paloma Del C; Shah, Maitri Y; Fu, Xiao et al. (2018) OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers. Sci Rep 8:13106|
|Basourakos, Spyridon P; Davis, John W; Chapin, Brian F et al. (2018) Baseline and longitudinal plasma caveolin-1 level as a biomarker in active surveillance for early-stage prostate cancer. BJU Int 121:69-76|
|Pan, Tianhong; Lin, Song-Chang; Yu, Kai-Jie et al. (2018) BIGH3 Promotes Osteolytic Lesions in Renal Cell Carcinoma Bone Metastasis by Inhibiting Osteoblast Differentiation. Neoplasia 20:32-43|
|Yu-Lee, Li-Yuan; Yu, Guoyu; Lee, Yu-Chen et al. (2018) Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGF?RIII-p38MAPK-pS249/T252RB Pathway. Cancer Res 78:2911-2924|
|Luo, Yong; Azad, Abul Kalam; Karanika, Styliani et al. (2018) Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models. Int J Cancer 142:2163-2174|
|Soundararajan, Rama; Aparicio, Ana M; Logothetis, Christopher J et al. (2018) Function of Tumor Suppressors in Resistance to Antiandrogen Therapy and Luminal Epithelial Plasticity of Aggressive Variant Neuroendocrine Prostate Cancers. Front Oncol 8:69|
|Class, Caleb A; Ha, Min Jin; Baladandayuthapani, Veerabhadran et al. (2018) iDINGO-integrative differential network analysis in genomics with Shiny application. Bioinformatics 34:1243-1245|
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