Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series.

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer. EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. RESULTS: The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets. CONCLUSIONS: We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.

[Corrigendum] Role of the EZH2/miR­200 axis in STAT3­mediated OSCC invasion.

Following the publication of the above article, an interested reader drew to the authors' attention that, in Figs. 7A and 8A. apparently the same mouse had been featured to represent two different experimental groups, albeit displaying distinct fluorescence values. Moreover, following an independent investigation in the Editorial Office, an additional instance of probable data duplication was also noted, comparing between the 'SCC15 / si­NC' cell migration image in Fig. 2D and the 'SCC15­EV' migration assay image in Fig. 1C. After having consulted their original data, the authors realized that these errors arose during the process of assembling the images for Figs. 2 and 8. First, the image for the DZNep (42d) experiment in Fig. 7A had inadvertently been used for the mimic NC (7d) experiment in Fig. 8A; moreover, the 'SCC15 / si­NC' cell migration image in Fig. 2D had been selected incorrectly. The revised versions of Figs. 2 and 8, showing the correct data for the the 'SCC15 / si­NC' cell migration image in Fig. 2D and the mimic NC (7d) experiment in Fig. 8A, are shown on the next two pages. The authors regret that these errors went unnoticed prior to publication, and thank the Editor of International Journal of Oncology for allowing them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they also apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 52: 1149­1164, 2018; DOI: 10.3892/ijo.2018.4293].

Structure-activity relationship studies on O-alkylamino-tethered salicylamide derivatives with various amino acid linkers as potent anticancer agents.

In our continued SAR study efforts, a series of O-alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast cancer (BC) and triple-negative breast cancer (TNBC) cell lines with low micromolar IC50 values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC50 = 3.38 ± 0.37 µM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC50 > 60 µM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising anticancer drug candidate for further clinical development.

Fibroblast Growth Factor Receptor 1 Drives the Metastatic Progression of Prostate Cancer.

BACKGROUND: No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation. OBJECTIVE: To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/ß) in the pathogenesis of PCa bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In mice, bone metastases (chi-square/Fisher's test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher's test). RESULTS AND LIMITATIONS: FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p < 0.0001; ß, p = 0.032) and increased the incidence of bone metastases (α, p < 0.0001; ß, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005). CONCLUSIONS: FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa. PATIENT SUMMARY: We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.

A novel STAT3 inhibitor, HJC0152, exerts potent antitumor activity in glioblastoma.

Aberrant expression and activation of signal transducer and activator of transcription 3 (STAT3) is implicated in several malignancies, including glioblastoma, and is correlated with poor outcomes in patients with glioblastoma, rendering STAT3 a potential therapeutic target. However, few STAT3 inhibitors have been approved for clinical use. We recently developed an orally active small-molecule compound with anti-STAT3 activity, HJC0152. This study aimed to test the effect of this novel drug on glioblastoma cell lines, and provide possibility to improve clinic prognosis of patients with glioblastoma in the future. In the present study, we aimed to determine the effects of HJC0152 on the growth, proliferation, and chemosensitivity of glioblastoma cell lines and xenograft tumors. We found that HJC0152 inactivated STAT3 via inhibiting phosphorylation of the Tyr705 residue. In vitro, HJC0152 suppressed the proliferation and motility of glioblastoma cells, induced apoptosis, and enhanced the chemosensitivity of glioblastoma cells. Furthermore, HJC0152 inhibited the growth of glioblastoma xenograft tumors in vivo. This study provides a rationale for developing HJC0152 as a STAT3-targeting therapy for treating human glioblastoma in the future.

Role of the EZH2/miR-200 axis in STAT3-mediated OSCC invasion.

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) serves a pivotal role in oral squamous cell carcinoma (OSCC) tumor cell invasion into normal tissues or distant organs. However the downstream regulatory network of STAT3 signaling remains unclear. The present study aimed to investigate the potential mechanism underlying how STAT3 triggers enhancer of zeste homolog 2 (EZH2) expression and inhibits microRNA (miR)-200a/b/429 expression in SCC25 and SCC15 cells in vitro and in vivo. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect expression, and numerous functional tests were conducted to explore cancer metastasis. The results indicated that when STAT3 signaling activity was attenuated by Stattic or enhanced with a STAT3 plasmid, the EZH2/miR-200 axis was markedly altered, thus resulting in modulation of the invasion and migration of OSCC cell lines. In addition, loss of function of EZH2 compromised the oncogenic role of STAT3 in both cell lines. F-actin morphology and the expression of epithelial-mesenchymal transition markers were also altered following disruption of the STAT3/EZH2/miR-200 axis. An orthotopic tumor model derived from SCC15 cells was used to confirm that targeting STAT3 or EZH2 suppressed OSCC invasion in vivo. In conclusion, the EZH2/miR-200 axis was revealed to mediate antitumor effects by targeting STAT3 signaling; these findings may provide a novel therapeutic strategy for the treatment of OSCC.

Targeting the NRF-2/RHOA/ROCK signaling pathway with a novel aziridonin, YD0514, to suppress breast cancer progression and lung metastasis.

Metastasis is a major cause of breast cancer-associated mortality. Natural products extracted from herbs provide rich bioactive compounds with anticancer efficacy but may have limited or moderate potency and considerable toxicity. We developed a novel aziridonin, YD0514, by aziridinating oridonin, a natural product of the medicinal herb Rabdosia rubescens. In this study, we found that YD0514 significantly inhibited proliferation, motility, and adhesion of metastatic breast cancer cell lines MDA-MB-231, GI101, GILM2, and GILM3. YD0514 also decreased the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9), focal adhesion kinase (FAK), and integrin family members. Importantly, YD0514 suppressed the growth of metastatic breast cancer xenograft tumors and significantly inhibited lung metastasis in vivo. Lastly, we showed that YD0514's anti-metastatic effect on highly aggressive breast cancer is mediated via regulating the NRF-2/RHOA/ROCK signaling pathway. These results demonstrate that YD0514, the first active analog based on an oridonin D-ring modification, has the potential to be developed as an anti-metastasis therapy for patients with metastatic cancers.

Suppression of the Growth and Invasion of Human Head and Neck Squamous Cell Carcinomas via Regulating STAT3 Signaling and the miR-21/ß-catenin Axis with HJC0152.

Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both in vitro and in vivo via inactivating STAT3 and downstream miR-21/ß-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G0-G1 phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines. Moreover, HJC0152 inhibited nuclear translocation of phosphorylated STAT3 at Tyr705 and decreased VHL/ß-catenin signaling activity via regulation of miR-21. Loss of function of VHL remarkably compromised the antitumor effect of HJC0152 in both cell lines. In our SCC25-derived orthotopic mouse models, HJC0152 treatment significantly abrogated STAT3/ß-catenin expression in vivo, leading to a global decrease of tumor growth and invasion. With its favorable aqueous solubility and oral bioavailability, HJC0152 holds the potential to be translated into the clinic as a promising therapeutic strategy for patients with HNSCC. Mol Cancer Ther; 16(4); 578-90. ©2017 AACR.

[Anti-sense miRNA-21 oligonucleotide inhibits Tb 3.1 human tongue squamous cell carcinoma growth in vitro].

OBJECTIVE: To investigate the effect of micro RNA-21 (miRNA-21) knocking on the Tb3.1 human tongue squamous cell carcinoma growth. METHODS: Anti-sense miRNA-21 oligonucleotide was delivered with oligofectamine to suppress Tb 3.1 tongue cancer cell growth in vitro. Real-time polymerase chain reaction (PCR) was conducted to detect the miRNA-21 expression after transfection. Methyl thiazolyl tetrazolium (MTT) assay was used to determine Tb 3.1 cell survival rate. Apoptosis were examined by flow-cytometry. Matrigel matrix and transwell assay were used to determine Tb 3.1 cell colony formation and migration ability. Antigen KI-67 (Ki67), B cell lymphoma (Bcl-2), phosphatase and tensin homolog (PTEN), matrirx metalloproteinase 2 (MMP-2, MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) protein expression in Tb 3.1 cell were measured by Western blotting. RESULTS: miRNA-21 expression was decreased in miRNA-21 antisense oligonucleotide (ASODN) group. The survival rate of Tb 3.1 cells with AS-miRNA-21 transfection was significantly suppressed (F = 27.02, P = 0.00) and early phase apoptosis (F = 26.641, P = 0.001) induced in Tb 3.1 cell. Ki67, Bcl-2, MMP-2 and MMP-9 protein were down regulated while PTEN and TIMP-1 protein expression was increased. CONCLUSIONS: Blocking miRNA-21 expression in Tb3.1 cell could suppress cancer cell growth in vitro and miRNA-21 can serve as a novel target candidate for human tongue cancer gene therapy.