bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1216: Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric cancer
Authors: Kim Hyun Myong , Jeong Inhye , Park Kyu Hyun , Kim Tae Soo , Kwon Woo Sun , Jeung Hei-Cheul , Jung Minkyu , Rha Sun Young 
Published: July 2017

Abstract
Platinum-based antineoplastic drugs are chemotherapeutic agents to usually treat gastric cancer (GC) include cisplatin. However, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Especially, increased DNA repair is drug targetable mechanism and useful in the treatment strategy of cisplatin-resistant cancer. Casein kinase 2 (CK2) has critical role of multiple cellular processes with DNA repair. For this reason, research for CK2 expression correlated with DNA repair mechanism is important in gastric cancer. Combination of cisplatin and CK2 inhibitor (CX-4945, also known as Silmitasertib, Senhwa Biosciences, USA) may improve cisplatin-induced DNA damage for GC treatment. In this study, we screened sensitivity of cisplatin and CX-4945 in 49 GC cell lines by MTT assay. For molecular profiling, we analyzed variants and gene expression using whole exome sequencing and RNA sequencing. RNA and protein expression of CK2 subunits (α/α’) using real-time RT-PCR and Western blot. Also, activity of CK2α was measured by ELISA. Combination treatment performed different schedules including concurrent and sequential. Synergistic effect was analyzed by Bliss Independence model. As CK2 profiling, CK2α’ mRNA expression was a tendency to correlated with CX-4945 sensitivity(p=0.0504). Moreover, CK2α’ protein expression was a correlated with CX-4945 sensitivity(p=0.0252). Other molecular profiling did not reveal any clear correlations. Twenty one (Group1: cisplatin extremely resistant and CK2 high, Group2: cisplatin intermediate resistant regardless of CK2 expression) cell lines were performed combination treatment. Both YCC-21 and YCC-28 cell lines show synergistic effect (+20% and +22%, respectively) in concurrent schedule. Only MKN-74 cell line show synergistic effect (+11%) in Pre-addition. The 4 cell lines (YCC-18, YCC-38, SNU-1 and -216) were show synergistic effect (+10%, +37%, +11% and +19%, respectively) in Post-addition. In conclusion, early inhibition of CK2 shows synergistic effect in group 1, because CK2 is high expression. In group 2, late inhibition of CK2 demonstrated synergistic effect. It means CK2-related DNA repair is up-regulating for repair to cisplatin-induced DNA damage. Personalized the treatment schedule for inhibit CK2-induced DNA repair is a new strategy to restore cisplatin resistant in GC.
Citation Format: Hyun Myong Kim, Inhye Jeong, Kyu Hyun Park, Tae Soo Kim, Woo Sun Kwon, Hei-Cheul Jeung, Minkyu Jung, Sun Young Rha. Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2017-1216
Abstract 1229: RNAi-based β-catenin inhibition in combination with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance
Authors: Ganesh Shanthi , Shui Serena , Chopda Girish , Koser Martin , Craig Kevin , Dutta Chaitali , Lai Cheng , Dudek Hank , Wang Weimin , Brown Bob D. , Abrams Marc 
Published: July 2017

Abstract
Despite recent advances in early detection and therapeutic intervention, colorectal cancer (CRC) remains one of the most deadly cancers in the United States. The Wnt/β-catenin and KRAS/BRAF-driven MAPK pathways were reported to cooperate in inducing CRC initiation and progression. Several studies have also identified Wnt signaling as a resistance mechanism in MAPK pathway-activated CRCs. Thus far, independent targeting of these single oncogenic events in CRC has yielded limited therapeutic success. RNA interference (RNAi) triggers are capable of silencing any expressed mRNA with high potency and specificity, including previously un-druggable targets such as β-catenin, an oncogene frequently dysregulated in CRC. DCR-BCAT is a chemically-optimized DsiRNA targeting CTNNB1, the gene which encodes β-catenin, formulated in a second-generation EnCore lipid nanoparticle. We have previously reported extensive preclinical pharmacology for DCR-BCAT in mouse tumor models of diverse origin. (Ganesh et al, Mol Cancer Ther 2016). Here we demonstrate that the dual inhibition of β-catenin and MEK demonstrates synergistic efficacy in not only primary CRC, but also in aggressive liver metastases of CRC in preclinical models. This combination of DCR-BCAT and the MEK inhibitor trametinib was also efficacious in tumors which are known to be resistant to trametinib, as well as tumors which acquire resistance due to drug exposure. These data support clinical development of these combination approaches for this first-in-class RNAi therapeutic.
Citation Format: Shanthi Ganesh, Serena Shui, Girish Chopda, Martin Koser, Kevin Craig, Chaitali Dutta, Cheng Lai, Hank Dudek, Weimin Wang, Bob D. Brown, Marc Abrams. RNAi-based β-catenin inhibition in combination with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2017-1229
Abstract 1231: Restoration of tumor suppression in vivo by systemic delivery of PTEN mRNA nanoparticles
Authors: Xu Yingjie , Islam Mohammad Ariful , Zope Harshal , Mahmoudi Morteza , Langer Robert S. , Shi Jinjun , Zetter Bruce R. , Farokhzad Omid C. 
Published: July 2017

Abstract
PTEN (phosphatase and tensin homolog on chromosome ten) is one of the most common lost or mutated tumor suppressor genes in human cancers, including ~50% of metastatic castration-resistant prostate cancer (mCRPC). By catalyzing PIP3 dephosphorylation, PTEN negatively regulates the PI3K-AKT-mTOR pathway, which is frequently altered in mCRPC. Reintroduction of functional PTEN for mCRPC treatment has proven difficult. By employing self-assembled lipid-polymer hybrid nanoparticle platforms, we successfully reintroduced PTEN mRNA to PTEN-null prostate cancer cells both in vitro and in vivo. These mRNA-loaded nanoparticles demonstrate high protein expression efficiency, low toxicity and good stability in serum and tumor accumulation. We confirmed that restoration of PTEN in PTEN-null prostate cancer cells inhibits the PI3k-AKT pathway, reduces cell viability and enhances apoptosis in vitro. Systemic delivery of PTEN mRNA-loaded nanoparticles in prostate xenograft tumors results in ~85% inhibition of tumor growth and leads to tumor cell death without toxic side effects in vivo. In summary, this work provides proof of concept of mRNA-based gene therapy for systemic restoration of functional PTEN for tumor suppression in vivo. It represents a novel approach to PI3K-AKT pathway inhibition, with the potential to specifically target cancers with loss of PTEN function.
Citation Format: Yingjie Xu, Mohammad Ariful Islam, Harshal Zope, Morteza Mahmoudi, Robert S. Langer, Jinjun Shi, Bruce R. Zetter, Omid C. Farokhzad. Restoration of tumor suppression in vivo by systemic delivery of PTEN mRNA nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1231. doi:10.1158/1538-7445.AM2017-1231
Abstract 1237: PDGF induces cell growth and changes in glucose metabolism in colon cancer in the absence of PDGF receptors
Authors: Moench Romana , Grimmig Tanja , Germer Christoph-Thomas , Waaga-Gasser Ana Maria , Gasser Martin 
Published: July 2017

Abstract
Background: The Platelet derived growth factor (PDGF) and its receptors play a major role in inducing proliferation, migration, and angiogenesis by activating intracellular PI3K/Akt/mTOR signaling events in different solid tumors and therefore represent attractive targets in tumor therapy. Recently we showed a PDGF-induced activation of metabolism and proliferation in HT29 colon cancer cells in the absence of specific PDGF receptors. The aim of this study was to analyze PDGFR and VEGFR expression and possible alternative PDGF binding partners in colorectal cancer (CRC).
Methods: Human HT29 colon cancer cells were cultured and stimulated with PDGF in a time-dependent manner. Additionally, VEGFR2 and EGFR inhibition was performed to analyze alternative PDGF signaling events. Whole cell or RNA extracts were analyzed by Western Blot and RT-q-PCR for receptors and PI3K/Akt/mTOR signaling. To investigate the effects of specific receptor inhibition on proliferation, MTS proliferation assays were performed. Moreover, mRNA levels of PDGFR and VEGFR in tumors from patients with CRC were analyzed by RT-qPCR.
Results: Human UICC stage I-IV tumors exhibited a significantly increased PDGFRβ and VEGFR1,2 gene expression. As observed previously, HT29 colon cancer cells showed only positivity for VEGFR1,2, but no PDGFR protein expression. Despite that, stimulation with PDGF resulted in increased proliferation and metabolic changes. In contrast, Caco-2 and SW480 colon cancer cells showed PDGFR and VEGFR expression on protein level. Interestingly, PDGF stimulation increased VEGFR1 and 2 gene expression in HT29 colon cancer cells and secondly inhibition of VEGFR2 and EGFR showed alterations in proliferation and Akt signaling in PDGF stimulated cancer cells.
Conclusion: Despite the absence of PDGF receptors in HT29 colon cancer cells, PDGF induced proliferating and metabolic effects in the tumor cells, suggesting an alternative binding partner on the tumor cell surface. Further investigation of the alternative PDGF binding partners could be of clinical relevance in CRC.
Note: This abstract was not presented at the meeting.
Citation Format: Romana Moench, Tanja Grimmig, Christoph-Thomas Germer, Ana Maria Waaga-Gasser, Martin Gasser. PDGF induces cell growth and changes in glucose metabolism in colon cancer in the absence of PDGF receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1237. doi:10.1158/1538-7445.AM2017-1237
Abstract 1247: Identifying novel regulators of the Unfolded Protein Response (UPR) by genome-scale CRISPR-Cas9 knockout screens
Authors: Leli Nektaria Maria , Dey Souvik , Brady Lauren , Koumenis Constantinos 
Published: July 2017

Abstract
Development and growth of a tumor as well as its ability to metastasize involves a complex relationship with its tissue microenvironment. A proliferating tumor encounters several microenvironmental stress conditions such as hypoxia, lack of nutrients and acidosis. To cope with these conditions, cancer cells have developed elaborate cytoprotective mechanisms which provide them with distinct advantages to thrive. Thus, deciphering the signaling pathways which get activated in the tumor microenvironment has been paramount to develop new therapeutic strategies for treatment. The Unfolded Protein Response (UPR) is an adaptive prosurvival pathway elicited by stresses in the tumor microenvironment (e.g., hypoxia, low glucose) and involves translational and transcriptional activation of effector genes which act to relieve cellular stress and block cancer cell death. We developed a strategy to comprehensively analyze critical mediators of cell fate in response to UPR activation. We have delivered a lentiviral genome-scale CRISPR Cas9 knockout (GeCKOv2) library to Sq20B cells (human squamous head and neck carcinoma) and A375 (human melanoma) cells. The library is targeting 19,050 genes with 123,411 unique guide sequences and enables both negative and positive selection screening. We used the GeCKO v2 library to identify genes essential for triggering the UPR in response to thapsigargin and tunicamycin, known specific activators of ER stress. Our highest-ranking candidates include BIRC5/Survivin, a well-studied molecule that acts as an inhibitor of apoptosis and is highly expressed in cancer cells and eukaryotic translation initiation factor eIF6, whose overexpression increases motility and invasiveness of cancer cells. Our preliminary results indicate that loss of Survivin and eIF6 dramatically enhance sensitization of cells to various ER stress conditions. Moreover, this synergistic outcome is observed when cells are treated with YM155, a small molecule that selectively suppresses Survivin and is used in phase I/II clinical trials. Lastly, morphological changes like endoreduplication are observed after long term absence of Survivin indicating its endogenous ER stress inducing role. Taken together, Survivin and eIF6 are important mediators of survival following ER stress and characterizing the pathways involved can lead to the development of novel targeted agents and therapeutic approaches.
Citation Format: Nektaria Maria Leli, Souvik Dey, Lauren Brady, Constantinos Koumenis. Identifying novel regulators of the Unfolded Protein Response (UPR) by genome-scale CRISPR-Cas9 knockout screens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1247. doi:10.1158/1538-7445.AM2017-1247
Abstract 1251: Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice
Authors: Miyazawa Miki , Subbaramaiah Kotha , Bhardwaj Priya , Zhou Xi Kathy , Wang Hanhan , Falcone Domenick J. , Giri Dilip D. , Dannenberg Andrew J. 
Published: July 2017

Abstract
Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and poor prognosis for PC patients. Recently, we showed that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade PC in men. It’s possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the natural history of PC. Pioglitazone, a ligand of PPARγ, is used to treat diabetes and possesses anti-inflammatory properties. Here our main objectives were to determine if pioglitazone inhibited obesity-related periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Mice were fed either a high fat (HF) diet or low fat (LF) diet to determine if obesity caused periprostatic WAT inflammation as defined by the presence of CLS. To determine if pioglitazone inhibited obesity-associated periprostatic WAT inflammation, obese HF diet fed mice were either continued on HF diet alone or treated with HF diet containing two doses (0.005% or 0.05% w/w) of pioglitazone. Treatment with pioglitazone reduced the density of CLS in periprostatic WAT, and suppressed levels of TNF-α, TGF-β and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knock out mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obese mice. Pioglitazone blocked TNF-α-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone-mediated induction of adiponectin suppressed the elevation in MCP-1 levels thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPARγ-adiponectin-MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade PC or improve outcomes for men with PC.
Citation Format: Miki Miyazawa, Kotha Subbaramaiah, Priya Bhardwaj, Xi Kathy Zhou, Hanhan Wang, Domenick J. Falcone, Dilip D. Giri, Andrew J. Dannenberg. Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1251. doi:10.1158/1538-7445.AM2017-1251
Abstract 1262: Aspirin inhibits the carcinogenesis of esophageal squamous cell carcinoma and enhances its responses to cisplatin
Authors: Zou Zhigeng , Fan Hongjun , Yu Xiying , Zhang Shuming , Guo Liping , Jiang Wei , Lu Shih-Hsin 
Published: July 2017

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Over 70% of ESCC cases occur in China. Unfortunately, the treatment of ESCC has hardly been improved all these years. Several studies suggested that aspirin (ASA) might decrease the risk of ESCC and prolonged the survival of patients with ESCC. However, it is unclear if ASA could prevent ESCC and/or enhance ESCC treatment by chemotherapy. In this study, a N-nitroso-N-methylbenzylamine (NMBzA) - induced ESCC model was employed to prove that aspirin could prevent the growth of esophageal tumor. F344 rats were treated with NMBzA by subcutaneous injection with or without ASA in drinking water (2mg/ml). After 35 week ASA-NMBzA or NMBzA alone treatment, rats were killed and esophageal tumor development were examined. The results showed that F344 rats treated with NMBzA and receiving a daily intake of ASA developed much less tumors than F344 rats treated with NMBA alone both in amount and in size (Tumor count: 2.40 ± 1.57 vs 10.85 ± 3.86 , P &lt; 0.001; Tumor volume: 11.10 ± 13.38 mm3 vs 70.79 ± 41.65 mm3, P &lt; 0.001). Immunohistochemical analysis indicated that a higher rate of apoptosis was observed in the basal layer of esophageal epithelium in ASA-NMBzA treated rats than in NMBzA alone treated rats. These results indicated that ASA prevented development of esophageal tumors in rats induced by NMBzA. Moreover, using in vitro human ESCC cell culture and in vivo xenograft models, we showed that ASA has strong beneficial effects on inhibition of ESCC cell proliferation and colony formation, reduction of ESCC cancer stem cells and enhance of ESCC cell cytotoxicity induced by cisplatin treatment. Biochemical analysis revealed that these effects of ASA on human ESCC cells in vitro and in vivo were due to inhibiting the repairing of DNA damage, decreasing the efflux activity and ALDH1 activity of the tumor cells, and blockades of PI3K/Akt pathway. Thus, our results demonstrated a positive role of aspirin in the prevention and treatment of ESCC.
Note: This abstract was not presented at the meeting.
Citation Format: Zhigeng Zou, Hongjun Fan, Xiying Yu, Shuming Zhang, Liping Guo, Wei Jiang, Shih-Hsin Lu. Aspirin inhibits the carcinogenesis of esophageal squamous cell carcinoma and enhances its responses to cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1262. doi:10.1158/1538-7445.AM2017-1262
Abstract 1266: Metformin represses esophageal carcinogenesis in NMBzA-treated rat model through inhibiting AMPK/mTOR and Stat3 signaling pathways
Authors: Fan Hongjun , Zou Zhigeng , Yu Xiying , Guo Liping , Jiang Wei , Lu Shih-Hsin 
Published: July 2017

Abstract
Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Metformin is one of the most used diabetic drugs for the management of type 2 diabetes mellitus in the world. The role of metformin in prevention of the development and progression of a variety of human tumors has been studied. However, the detailed mechanisms have not yet been fully understood. In the present study, we investigated the effects of metformin on the suppression of esophageal carcinogenesis in a rat model, in which F344 rats were treated with N-nitroso-N-methylbenzylamine (NMBzA 0.30 mg/kg s.c.) three times per week for 35 weeks to induce esophageal tumors. To monitor the effects of metformin in this model, one group of rats were administered with metformin (3 g/L) in the drinking water at the first NMBzA injection. Our results showed that although there was no significant difference in body weight in rats of different groups, rats treated with NMBzA and metformin together significantly reduced the tumor formation and tumor volume when compared with rats treated with NMBzA alone. Statistic analyses demonstrated that the tumor numbers was reduced in NMBzA-treated rats received metformin to an average of 1.85 ± 1.09 tumors per rat when compared with 10.85 ± 3.86 (P &lt; 0.001) in rats without metformin, while the tumor volume was decreased from 70.79 ± 41.65 mm3 per rat without metformin administration to 8.64 ± 13.45 mm3 (P &lt; 0.001) with metformin administration. In addition, 7 out of 24 rats in the NMBzA-treated group died before week 35 but no rats died in the other groups. Furthermore, immunoblotting analysis indicated that p-mTORSer2448, p-Stat3Tyr705, and Cyclin D1 protein levels significantly decreased, while p-AMPKThr172 significantly increased in tumors obtained from rats treated with NMBzA and metformin when compared with tumors obtained from rats treated with NMBzA alone. Thus, our results indicated that metformin suppressed NMBzA-induced esophageal carcinogenesis via inhibition of the AMPK/mTOR and Stat3 signaling pathways. Together, our study suggested that metformin might have a potential use for treatment and prevention of esophageal cancer.
Citation Format: Hongjun Fan, Zhigeng Zou, Xiying Yu, Liping Guo, Wei Jiang, Shih-Hsin Lu. Metformin represses esophageal carcinogenesis in NMBzA-treated rat model through inhibiting AMPK/mTOR and Stat3 signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2017-1266