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Six-Transmembrane Epithelial Antigen of Prostate 3 Predicts Poor Prognosis and Promotes Glioblastoma Growth and Invasion.

ABSTRACT: Recent evidence suggests that dysregulation of iron regulatory factors may play essential roles in cancer pathophysiology. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a metalloreductase, which is vital for cellular iron uptake and homeostasis. However, the clinical significance and function of STEAP3 in the development of human gliomas remain unclear. Through analysis of publicly available databases, we found that STEAP3 was highly expressed in malignant gliomas, especially in the mesenchymal glioma molecular subtype and isocitrate dehydrogenase 1/2 (IDH1/2) wild-type gliomas. Expression levels of STEAP3 in gliomas correlated inversely with patient overall survival (OS) and served as an independent prognostic marker by multivariate Cox regression analysis. In functional assays performed with RNA knockdown, loss of STEAP3 attenuated aggressive phenotypes in glioma cells, including cell proliferation, invasion, and sphere formation in vitro and tumor growth in vivo. Finally, STEAP3 drives these activities by inducing mesenchymal transition, promoting transferrin receptor (TfR) expression, and activating STAT3-FoxM1 axis signaling. Taken together, these results indicate that STEAP3 functions as an oncogenic mediator in glioma progression and is thus a potential therapeutic target for the treatment of the disease.

SUBMITTER: Han M

PROVIDER: S-EPMC5994776 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Six-Transmembrane Epithelial Antigen of Prostate 3 Predicts Poor Prognosis and Promotes Glioblastoma Growth and Invasion.

Han Mingzhi M Xu Ran R Wang Shuai S Yang Ning N Ni Shilei S Zhang Qing Q Xu Yangyang Y Zhang Xin X Zhang Chao C Wei Yuzhen Y Ji Jianxiong J Huang Bin B Zhang Di D Chen Anjing A Li Wenjie W Bjerkvig Rolf R Li Xingang X Wang Jian J

Neoplasia (New York, N.Y.) 20180503 6

Recent evidence suggests that dysregulation of iron regulatory factors may play essential roles in cancer pathophysiology. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a metalloreductase, which is vital for cellular iron uptake and homeostasis. However, the clinical significance and function of STEAP3 in the development of human gliomas remain unclear. Through analysis of publicly available databases, we found that STEAP3 was highly expressed in malignant gliomas, especially in ...[more]

PMID: 29730475

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Project description:PURPOSE:Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer. METHODS:Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg). RESULTS:Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing. CONCLUSION:DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.

Dataset Information

Six-Transmembrane Epithelial Antigen of Prostate 3 Predicts Poor Prognosis and Promotes Glioblastoma Growth and Invasion.

Publications

Six-Transmembrane Epithelial Antigen of Prostate 3 Predicts Poor Prognosis and Promotes Glioblastoma Growth and Invasion.

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