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.
|Jin, J-K; Tien, P-C; Cheng, C-J et al. (2015) Talin1 phosphorylation activates ?1 integrins: a novel mechanism to promote prostate cancer bone metastasis. Oncogene 34:1811-21|
|Han, Ying; Signorello, Lisa B; Strom, Sara S et al. (2015) Generalizability of established prostate cancer risk variants in men of African ancestry. Int J Cancer 136:1210-7|
|Yu, Guoyu; Lee, Yu-Chen; Cheng, Chien-Jui et al. (2015) RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival. Mol Cancer Res 13:348-57|
|Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I et al. (2014) A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 46:1103-9|
|Satcher, Robert L; Pan, Tianhong; Cheng, Chien-Jui et al. (2014) Cadherin-11 in renal cell carcinoma bone metastasis. PLoS One 9:e89880|
|Jiang, Xianhan; Li, Xun; Huang, Hai et al. (2014) Elevated levels of mitochondrion-associated autophagy inhibitor LRPPRC are associated with poor prognosis in patients with prostate cancer. Cancer 120:1228-36|
|Tien, Jean Ching-Yi; Liao, Lan; Liu, Yonghong et al. (2014) The steroid receptor coactivator-3 is required for developing neuroendocrine tumor in the mouse prostate. Int J Biol Sci 10:1116-27|
|Li, Likun; Chang, Wenjun; Yang, Guang et al. (2014) Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer. Sci Signal 7:ra47|
|Li, Hongge; Tao, Chenqi; Cai, Zhigang et al. (2014) Frs2* and Shp2 signal independently of Gab to mediate FGF signaling in lens development. J Cell Sci 127:571-82|
|Lin, Zhuo-Yuan; Huang, Ya-Qiang; Zhang, Yan-Qiong et al. (2014) MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1. Int J Cancer 135:541-50|
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