bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2697: Functional analysis of metastasis-related microRNA induced by the stromal-cell derived factor (SDF)-1/CXCR4 system in oral cancer.
Authors: Kinouchi Makoto , Uchida Daisuke , Kuribayashi Nobuyuki , Tamatani Tetsuya , Nagai Hirokazu , Miyamoto Youji 
Published: August 2014

Abstract
We have previously demonstrated that stromal cell-derived factor (SDF)-1/CXCR4 system is involved in the metastatic process of oral cancer. Recently, small non coding RNAs, microRNAs (miRNAs) are involved in the metastatic process of several types of cancers. However, the miRNAs contributed to metastases induced by the SDF-1/CXCR4 system in oral cancer are largely unknown. Thus, we examined the metastasis-related miRNAs induced by the SDF-1/CXCR4 system, using oral cancer cells, B88-SDF-1, which exhibits functional CXCR4 and distant metastatic potential, in vivo. We examined the metastasis-related miRNAs induced by the SDF-1/CXCR4 system by use of a miRNA microarray representing approximately 1700 miRNA. Consequnetly, we identified 4 kinds of upregulated-miRNAs in B88-SDF-1 cells whose functions are unknown. Among these miRNAs, we confirmed the upregulation of miR-5XX in B88-SDF-1 cells by the real-time PCR analysis. Although LNA-based miR-5XX inhibitor did not affect the growth of the cells, it did significantly inhibit the migration of B88-SDF-1 cells. Thus, we examined the target gene(s) of miR-5XX in the SDF-1/CXCR4 system. cDNA microarray analysis revealed that 6 kinds of mRNA containing the predictive binding site of miR-5XX were upregulated by the treatment with miR-5XX inhibitor. Furthermore, gene A mRNA and protein was downregulated in B88-SDF-1 cells, and upregulated by the treatment with miR-5XX inhibitor. These results indicating that SDF-1/CXCR4 system might regulate the metastases of oral cancer by the downregulation of gene A via upregulation of miR-5XX.
Citation Format: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Tetsuya Tamatani, Hirokazu Nagai, Youji Miyamoto. Functional analysis of metastasis-related microRNA induced by the stromal-cell derived factor (SDF)-1/CXCR4 system in oral cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2697. doi:10.1158/1538-7445.AM2013-2697
Abstract 27: A phase I study of MEK inhibitor BAY 86-9766 in Japanese patients with advanced or reflactory solid tumors.
Authors: Doi Toshihiko , Fuse Nozomi , Yoshino Takayuki , Shitara Kohei , Bando Hideaki , Miyamoto Hideaki , Koyama Susumu , Tsukada Katsuya , Ohtsu Atsushi 
Published: August 2014

Abstract
Background: BAY 86-9766 (RDEA119) is a potent, orally administered,, allosteric inhibitor of mitogen-activated protein (MAP) kinase kinase (MEK) 1/2, a key protein in the MAP kinase signaling pathway, located downstream of RAS and RAF. We conducted a phase I study to evaluate the safety and pharmacokinetics (PK) of BAY 86-9766 in advanced/refractory Japanese cancer patients.
Patients and Methods: BAY 86-9766 was administered at 30 mg bid (cohort 1) and at 50 mg bid (MTD; cohort 2) over a 28-day treatment cycle which was continued until disease progression or unacceptable toxicity. PK samples were collected after single doses (Day 1 to Day 4) and during multiple dosing through Day 22. Tumor response was assessed after every even cycle by RECIST v.1.1.
Results: A total of 12 patients were enrolled, including 6 colorectal cancer, 2 GIST, and one hepatocellular cancer, carcinoid tumor, neuroendocrine tumor and leiomyosarcoma, respectively (5 patients in cohort 1: 30mg bid; 7 patients in cohort 2: 50mg bid). There were no DLTs in Cycle 1 of cohort 1 and cohort 2. The most common adverse event regardless of grade was rash acneiform in 12 subjects (100.0%), followed by elevated AST, creatine phosphokinase (CPK) or hypoalbuminemia in 9 subjects (75.0%), fever or elevated ALP in 7 subjects (58.3%), elevated ALT or decreased platelet count in 6 subjects (50.0%). Of those, the most common drug-related adverse events were rash acneiform (100.0%), followed by elevated CPK (66.7%), laboratory-others (66.7%), elevated AST (58.3%), and elevated ALP (50.0%). There were three cases of serious adverse events - thrombocytopenia, bile duct stenosis and elevated CPK - with only the elevated CPK being regarded as drug-related. There were no deaths on study. In Cohort 2, 7 out of 7 patients had elevated CPK, with 4 patients Grade 3 or higher. None of these were considered clinically significant and were not regarded as DLT's. Three patients had a positive de-challenge and re-challenge and 2 patients experienced muscle-related symptoms (neck pain and muscle weakness of the lower limb). PK parameters were comparable to the non-Japanese population.
Conclusions: BAY 86-9766 was generally well tolerated at both the 30 mg bid dose and the MTD of 50 mg bid. BAY 86-9766 administration increased CPK in a majority of patients but this was manageable by dose reduction.
Citation Format: Toshihiko Doi, Nozomi Fuse, Takayuki Yoshino, Kohei Shitara, Hideaki Bando, Hideaki Miyamoto, Susumu Koyama, Katsuya Tsukada, Atsushi Ohtsu. A phase I study of MEK inhibitor BAY 86-9766 in Japanese patients with advanced or reflactory solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 27. doi:10.1158/1538-7445.AM2013-27
Abstract 2701: Expression and function of CXCR4 in human salivary gland cancers.
Authors: Kuribayashi Nobuyuki , Uchida Daisuke , Kudo Yasusei , Kinouchi Makoto , Tamatani Tetsuya , Nagai Hirokazu , Miyamoto Youji 
Published: August 2014

Abstract
Salivary gland cancers (SGCs) frequently metastasize to cervical lymph nodes and distant organs. Currently, the mechanisms responsible for the metastatic behavior of SGC cells are not fully understood. We previously demonstrated that the stromal cell-derived factor-1 (SDF-1; also known as CXCL12)/CXCR4 system is involved in the establishment of metastasis in oral squamous cell carcinoma. In the present study, we investigated the role of CXCR4 in the metastatic behavior of SGCs. We examined the expression of CXCR4 mRNA and protein in human SGC cell lines by quantitative RT-PCR and western blotting, respectively. The expression of CXCR4 mRNA and protein were frequently upregulated in 5 out of 6 SGC cell lines. On the contrary to the CXCR4 expression, CXCR7, a recently identified second receptor for SDF-1, was detected in all SGC cell lines, expression levels were considerably lower on average compared with that of CXCR4 expression. Functional CXCR4 expression was demonstrated by the ability of these SGC cell lines to migrate toward an SDF-1 gradient. SDF-1 rapidly activated extracellular signal-regulated kinase (ERK)1/2 in SGC cell lines. Immunohistochemical analysis revealed that CXCR4 protein expression was detected in either the nucleus or cytoplasm of cancer cells in 16 out of 20 tissues of adenoid cystic carcinoma (ACC) and in 4 out of 6 tissues of mucoepidermoid carcinoma, which are representative of SGC. Furthermore, ACC cell lines exhibited dramatic metastasis to the lung following intravenous inoculation, whereas AMD3100, a CXCR4 antagonist, significantly inhibited lung metastasis of the cells, ameliorated body weight loss and improved the survival rate of tumor-bearing nude mice. These results indicate that CXCR4 expression contributes to the metastatic potential of SGCs.
Citation Format: Nobuyuki Kuribayashi, Daisuke Uchida, Yasusei Kudo, Makoto Kinouchi, Tetsuya Tamatani, Hirokazu Nagai, Youji Miyamoto. Expression and function of CXCR4 in human salivary gland cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2701. doi:10.1158/1538-7445.AM2013-2701
Abstract 2706: Crizotinib, a selective c-Met inhibitor, prevents metastasis to the liver and lungs in a primary uveal melanoma mouse model.
Authors: Surriga Oliver , Vinagolu Rajasekhar , Ambrosini Grazia , Schwartz Gary 
Published: August 2014

Abstract
Uveal melanoma is the most common primary intraocular malignant tumor in adults. About half of patients with uveal melanoma will develop metastatic disease to the liver and the lung. These tumors are characterized by mutations in G-proteins (GNAQ and GNA11) and also the over-expression of c-Met. Crizotinib is a selective inhibitor for c-Met as well as anaplastic lymphoma kinase (ALK). We found that crizotinib inhibited cell proliferation of uveal melanoma cell lines in a dose dependent manner with an IC50 in the range of 0.75 μM to 2 μM. Phospho-c-Met was inhibited by crizotinib starting at 10 nM with inhibition of downstream signaling including p-ERK1/2, p-AKT and p-STAT. In our xenograft model there was only a modest inhibition of tumor growth after treatment with doses of ≥ 50 mg/kg crizotinib. As crizotinib also prevented cell migration regardless of G-protein status, we established a primary metastatic uveal mouse model in which we created a GFP-luciferase expressing uveal melanoma cell line that developed liver and lung metastases 6 weeks after primary implantation into the eye. At a dose of 50 mg/kg daily, starting 4 weeks after primary implantation, there was a dramatic reduction in the liver and lungs metastases when compared to untreated controls. These results indicate that the inhibition of c-Met alone may be sufficient to prevent metastasis of uveal melanoma and suggest there may be a potential for using crizotinib as an adjuvant therapy in uveal melanoma.
Citation Format: Oliver Surriga, Rajasekhar Vinagolu, Grazia Ambrosini, Gary Schwartz. Crizotinib, a selective c-Met inhibitor, prevents metastasis to the liver and lungs in a primary uveal melanoma mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2706. doi:10.1158/1538-7445.AM2013-2706
Abstract 2708: The TWEAK-FN14 pathway promotes prostate cancer bone metastasis through the NFκB pathway.
Authors: Yin Juan Juan , Liu Yen-Nien , Barrett Ben , Fang Lei , Lake Ross , Casey Orla , Tillman Heather , Ward Yvona , Kelly Kathleen 
Published: August 2014

Abstract
Advanced prostate cancer is highly associated with castration resistance and the development of bone metastases. Understanding the mechanisms contributing to prostate cancer bone metastasis is needed in order to develop novel therapeutic agents. NFκB signaling has been implicated in prostate cancer progression. The Tweak-Fn14 axis, which activates both canonical and non-canonical NFκB pathways, has been shown to be up-regulated in many cancer types. However, the role of the Tweak-Fn14 signaling in prostate cancer progression has not been investigated. In this study, we show that oncogenic Ras transformation of the AR negative, DU145 cell line led to the acquisition of bone metastatic capability and associated increased expression of TWEAK and FN14. Knocking down FN14 using shRNAs, as well as blocking the NFκB pathway using an IKBα super repressor, in DU145/Rasb1 cells, significantly inhibited bone metastasis and improved survival. This inhibitory effect of FN14shRNA was fully rescued by activating the NFκB canonical pathway, but not the NFκB non-canonical pathway. FN14 expression is also high in the bone metastatic, AR negative prostate cancer PC3 cell line. Similarly, knocking-down FN14 in PC3 cells inhibited bone metastatic capacity following intracardiac inoculation in a xenograft model. TWEAK and FN14 are relatively low or undetectable in AR positive prostate cancer cell lines including Lncap and 22RV1. AR binding was detected in both TWEAK and FN14 promoters as determined by chromatin immunoprecipitation analysis in Lncap. Reporter assays demonstrated that AR binding inhibited FN14 and TWEAK transcription. The above experimental models were further supported by analyses of publically available expression data sets for clinical prostate cancer samples that showed FN14 expression was inversely correlated with AR gene expression signatures. In addition, individual FN14 RNA mean expression was higher in clinical metastasis of castrate (n=11) as compared to non-castrate (n=8) patients. We propose that down-regulation of AR activity under castrate conditions may lead to increased FN14 expression and NFκB activation, which provides a survival benefit for prostate cancer cells associated with disease progression. Therefore, targeting the TWEAK-FN14 pathway in prostate cancer patients provides potential, new preventive and therapeutic approaches.
Citation Format: Juan Juan Yin, Yen-Nien Liu, Ben Barrett, Lei Fang, Ross Lake, Orla Casey, Heather Tillman, Yvona Ward, Kathleen Kelly. The TWEAK-FN14 pathway promotes prostate cancer bone metastasis through the NFκB pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2708. doi:10.1158/1538-7445.AM2013-2708
Abstract 2712: Identification of tumor initiating genes RPL39 and MLF2 that mediate lung metastasis through nitric oxide signaling and mesenchymal to epithelial transition.
Authors: Dave Bhuvanesh , Granados Sergio , Mai Junhua , Choi Dong Soon , Gao Ding Cheng , Mitra Sucharita , Shen Haifa , Muthuswamy Senthil , Mittal Vivek , Ferrari Mauro , Chang Jenny 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) is the most aggressive and lethal form of cancer characterized by lack of estrogen, progesterone and Her2 receptors. It is prevalent in women of African American descent, often present in younger and premenopausal women. It shows high risk of recurrence and frequently metastasizes to lungs and brain, resulting in poor overall prognosis. There is no targeted therapy for TNBC as it does not respond to hormonal therapy and is intrinsically resistance to conventional chemotherapy. It is therefore imperative to understand the mechanism of survival of these cancers and unravel its biological pathways and modes of progression. We have previously described breast cancer stem cells (BCSC) to be intrinsically resistant to treatment which is further confirmed by recent publications by other groups that describe direct functional evidence for the same. Using genomic assays, we traced a BCSC gene signature comprising of 477 genes derived from patient biopsies. On selective shRNA knockdown of these genes we identified RPL39 and MLF2 as the top two candidates that affect BCSC self-renewal. Selective siRNA knockdown of RPL39 and MLF2 in human cancer xenografts, showed reduced tumor volume and lung metastases with a concomitant decrease in BCSC markers. Thus, targeting BCSCs in combination with chemotherapy should eliminate the heterogeneous populations within a tumor. Additionally, next generation RNA-seq confirmed mutations in RPL39 and MLF2 in 50% of lung metastases from breast cancer patients. In vitro and in vivo siRNA knockdown of RPL39 and MLF2 showed decrease in nitric oxide synthase, suggesting that these genes are driven by nitric oxide signaling. In conclusion this study reveals novel tumor initiating genes, RPL39 and MLF2 that target the breast cancer stem cells and also show impact on lung metastasis. Our findings enhance the understanding of treatment resistant breast cancer stem cells, the mutations that cause metastases and also lay foundation for developing new therapies for such cancers with poor prognosis.
Citation Format: Bhuvanesh Dave, Sergio Granados, Junhua Mai, Dong Soon Choi, Ding Cheng Gao, Sucharita Mitra, Haifa Shen, Senthil Muthuswamy, Vivek Mittal, Mauro Ferrari, Jenny Chang. Identification of tumor initiating genes RPL39 and MLF2 that mediate lung metastasis through nitric oxide signaling and mesenchymal to epithelial transition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2712. doi:10.1158/1538-7445.AM2013-2712
Abstract 2727: Sulfiredoxin is required for AOM/DSS induced mouse colon carcinogenesis and invasiveness of human colon cancer cells.
Authors: Wei Qiou , Jiang Hong , Baker Alyson , Dodge Lisa K. , Gerard Matthieu , Young Matthew R. , Toledano Michel B. , Colburn Nancy H. 
Published: August 2014

Abstract
Sulfiredoxin (Srx) is the enzyme that reduces the overoxidized inactive form of peroxiredoxins (Prxs). To study the function of Srx in carcinogenesis in vivo, we tested whether loss of Srx protects mice from cancer development. Srx null mice were generated and colon carcinogenesis was induced by an azoxymethane (AOM) and dextran sulfate sodium (DSS) protocol. Compared to either wildtype or heterozygotes, Srx-/- mice had significantly reduced rates in both tumor multiplicity and volume. Mechanistic studies reveal that loss of Srx did not alter tumor cell proliferation; however, increased apoptosis and decreased inflammatory cell infiltration were obvious in tumors from Srx null mice compared to those from wildtype control. In addition to the AOM/DSS model, examination of Srx expression in human reveals a tissue-specific expression pattern. Srx expression was also demonstrated in tumors from colorectal cancer patients and the levels of expression were associated with patients’ clinic stage. These data provide the first in vivo evidence that loss of Srx renders mice resistance to AOM/DSS-induced colon carcinogenesis, suggesting that Srx has a critical oncogenic role in cancer development, and Srx may be used as a marker for human colon cancer pathogenicity.
Citation Format: Qiou Wei, Hong Jiang, Alyson Baker, Lisa K. Dodge, Matthieu Gerard, Matthew R. Young, Michel B. Toledano, Nancy H. Colburn. Sulfiredoxin is required for AOM/DSS induced mouse colon carcinogenesis and invasiveness of human colon cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2727. doi:10.1158/1538-7445.AM2013-2727
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2752: Novel inhibitor of HSP90- PU-H71 exhibits significant activity in Ewing sarcoma pre-clinical models.
Authors: Ambati Srikanth R. , Caldas Lopes Eloisi , Mony Ullas , Kosugi Kohji , Moreira Andre , Meyers Paul , Chiosis Gabriela , Moore Malcolm 
Published: August 2014

Abstract
Ewing sarcoma is characterized by multiple deregulated pathways that mediate cell survival and proliferation. Heat shock protein-90 (HSP90) is a critical component of the multi-chaperone complexes that regulate the disposition and activity of a large number of proteins responsible for the assembly and regulation of cell-signaling systems. We tested the efficacy of PU-H71, a novel purine scaffold HSP90 inhibitor developed at Memorial Sloan-Kettering Cancer Center in several Ewing sarcoma cell lines and primary cultures established from patient samples. We investigated its effect on cell proliferation and cell viability on multiple Ewing cell lines, benign epithelial, endothelial and mesenchymal stromal cells and its effect on colony forming assay using CD34 hematopoietic stem cells . We performed cell cycle analysis, clonogenic assay, immunoblot analysis and in vivo experiments in NOD scid gamma (NSG) mice using A673 cell line transduced with GFP luciferase for bioimaging. We also established a metastatic model by calculating the mean fluorescence intensity (MFI) in various organs. Our results show that there is a significant therapeutic window in its activity against Ewing cell lines and benign cells. PU-H71 treatment resulted in arrest in G2 phase and diminished S phase in Ewing cell lines. We also noted that many of the deregulated pathway proteins including IGF1R, AKT, ERK, MYC, hTERT and EWS-FLI1 are stabilized by HSP90 and exposure to PU-H71 resulted in depletion of the above proteins. We also noted an increase in cleaved PARP and proapoptotic proteins and a decrease in antiapoptotic proteins on immunoblot analysis. Based on earlier PK and MTD studies, we treated mice at a dose of 75mg/kg by intraperitoneal injection, three times a week for 4 weeks. Our results indicated that Ewing's sarcoma tumor growth was significantly inhibited and metastatic burden was significantly decreased in the mice injected with PU-H71 compared to the mice injected with vehicle, based on MFI, weight and size of the tumors. Immunohistochemical staining showed that CD31 expression was significantly reduced in PU-H71 treated mice tumors. Our results suggest that PU-H71 has the ability to affect multiple critical oncogenic pathways simultaneously resulting in decreased tumor growth and metastases and has a strong rationale for clinical evaluation in Ewing sarcoma.
Citation Format: Srikanth R. Ambati, Eloisi Caldas Lopes, Ullas Mony, Kohji Kosugi, Andre Moreira, Paul Meyers, Gabriela Chiosis, Malcolm Moore. Novel inhibitor of HSP90- PU-H71 exhibits significant activity in Ewing sarcoma pre-clinical models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2013-2752