Search

// Cheng-Lung Hsu 1 , Jai-Shin Liu 2 , Ting-Wei Lin 3 , Ying-Hsu Chang 4 , Yung-Chia Kuo 1 , An-Chi Lin 1 , Huei-Ju Ting 5 , See-Tong Pang 4 , Li-Yu Lee 6 , Wen-Lung Ma 7 , Chun-Cheng Lin 3 and Wen-Guey Wu 2 1 Division of Hematology-Oncology, Departments of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan 2 Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan 3 Department of Chemistry, National Tsing-Hua University, Hsinchu 300, Taiwan 4 Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan 5 Department of Biological Science and Technology, National University of Tainan, Tainan 700, Taiwan 6 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan 7 Sex Hormone Research Center, China Medical University Hospital, Taichung 104, Taiwan Correspondence to: Cheng-Lung Hsu, email: hsu2221@adm.cgmh.org.tw Wen-Guey Wu, email: wgwu@life.nthu.edu.tw Chun-Cheng Lin, email: cclin66@mx.nthu.edu.tw Keywords: FxxLF, RIPK1, androgen receptor, prostate cancer, oxadiazole Received: November 04, 2016 Accepted: April 27, 2017 Published: May 13, 2017 ABSTRACT Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.

// Bo-Ru Lai 1, * , Yu-Tung Wu 1, * , Yung-Chia Kuo 2 , Hung-Chih Hsu 2 , Jen-Shi Chen 2 , Tse-Ching Chen 3 , Ren-Chin Wu 3 , Cheng-Tang Chiu 4 , Chun-Nan Yeh 1 , Ta-Sen Yeh 1 1 Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan 2 Department of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan 3 Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan 4 Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Ta-Sen Yeh, email: tsy471027@adm.cgmh.org.tw Keywords: GIST, second primary cancer, cancer driver gene, c kit, colorectal cancer Received: June 08, 2016 Accepted: September 17, 2016 Published: October 28, 2016 ABSTRACT The association of non-hereditary (sporadic) gastrointestinal stromal tumors (GISTs) and second primary malignancies is known to be nonrandom, although the underlying molecular mechanisms remain unknown. In this study, 136 of 749 (18.1%) patients with sporadic GISTs were found to have additional associated cancers, with gastrointestinal and genitourinary/gynecologic/breast cancers being the most prevalent. Gene mutations in GISTs and their associated colorectal cancers (CRCs) (n=9) were analyzed using a panel of 409 cancer-related genes, while a separate group of 40 sporadic CRCs not associated with GISTs served as controls. All 9 of the GISTs had either KIT (8 of 9) or PDGFRA (1 of 9) mutations that were not present in their associated CRCs. Conversely, all but one of the 9 GIST-associated CRCs exhibited an APC mutation, a TP53 mutation or both, while none of their corresponding GISTs harbored either APC or TP53 mutations. The genetic profile of CRCs with and without associated GISTs did not differ. Although population-based studies and case series worldwide, including ours, have unanimously indicated that the GIST-CRC association is nonrandom, our targeted ultra-deep sequencing unveiled a lack of driver-gene mutations linking sporadic GISTs to highly prevalent second primaries. Further studies are needed to elucidate other genetic alterations that may be responsible for this puzzling contradiction.

// Hung-Ming Wang 1, * , Tung-Liang Lin 1, * , Yung-Chia Kuo 1 , Hsin-Pai Li 2 , Kai-Ping Chang 3 , Chien-Yu Lin 4 , Hsien-Chi Fan 1 , An-Chi Lin 1 , Chia-Hsun Hsieh 1 , Ngan-Ming Tsang 4 , Li-Yu Lee 5 , Sheng-Chieh Chan 6 , Kar-Wai Lui 7 , Yu-Sun Chang 2 , Cheng-Lung Hsu 1 1 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 2 Department of Cell and Molecular Biology, Chang Gung University, Taoyuan, Taiwan, ROC 3 Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 4 Department of Radiation Oncology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 5 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 6 Department of Nuclear Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 7 Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC * These authors contributed equally to this work Correspondence to: Cheng-Lung Hsu, email: hsu2221@adm.cgmh.org.tw Keywords: nasopharyngeal carcinoma, metastasis, EB virus, EBV DNA, IP-10 Received: March 10, 2016 Accepted: June 09, 2016 Published: July 18, 2016 ABSTRACT Differential overall survival of nasopharyngeal carcinoma (NPC) with different organ site metastases has been documented. Here, we attempted to determine the underlying mechanisms by assessing plasma and tumor tissue markers in relation to patient survival. Pretreatment plasma Epstein-Barr virus (EBV) DNA concentrations, cytokines and tissue macrophages, proliferation and apoptosis markers were determined in 178 patients with metastatic NPC. The median overall survival (OS) was 19 months. Patients with single organ metastases had better outcomes than those with multiple organ metastases (median OS: 26 months vs. 16 months), with statistical significance. Among the single organ involvement cases, patients with lung metastasis only showed longer survival than those with bone or liver involvement (median OS: 50 months vs. 21 months vs. 18 months; P < 0.001). Pretreatment plasma EBV DNA concentrations were lower in patients with lung metastasis than bone or liver metastasis among single organ site groups. Plasma interferon-γ-inducible protein-10 (IP-10) and monocyte chemotactic protein-1 (MCP-1) expression levels were correlated with differential single organ site metastasis OS and EBV DNA load. Liver metastatic tissue had higher density of infiltrating macrophages and proliferative index than the lung metastatic group. Low pretreatment plasma EBV DNA load, expression of cytokines, such as IP-10 and MCP-1, tissue macrophage infiltration, and proliferative index may contribute to the differences in overall survival.

Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC.