bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3784: The role of the taurine transporter SLC6A6 in promoting prosurvival activity and multidrug resistance of colorectal cancer
Authors: Yasunaga Masahiro , Matsumura Yasuhiro 
Published: July 2016

Abstract
The identification of a novel therapeutic target is desired to improve the treatment of colorectal cancer (CRC). In a comprehensive gene expression analysis, we found that the taurine transporter SLC6A6 was highly expressed in CRC. In the functional analysis, SLC6A6-knocked down (KD) CRC cells showed attenuated cell-survival activity accompanying enhanced sensitivity of the drugs (5-FU, DOX and SN-38). Moreover, the number of side population (SP) cells and their cancer stem cell (CSC)-like properties such as tumor-initiation were abrogated by SLC6A6-KD. Conversely, increased the cell-survival activity, the fraction of SP cells and enhancement of multidrug resistance (MDR) were observed in SLC6A6-overexpressed cells. Furthermore, SLC6A6-siRNA treatment enhanced the cytotoxic effect of all 3 drugs as distinct from ABCG2-siRNA treatment, the efficacy of which was limited to its 2 substrate-drug, DOX and SN-38. Finally, we clarified the prosurvival and anti-apoptotic effects of the taurine transporter SLC6A6 in CRC cells. Moreover, we found that SLC6A6 plays an important role in the maintenance of CSC characteristics promoting cell survival signal and MDR. Our findings indicate that the SLC6A6 may be a novel therapeutic target for refractory CRC.
Citation Format: Masahiro Yasunaga, Yasuhiro Matsumura. The role of the taurine transporter SLC6A6 in promoting prosurvival activity and multidrug resistance of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3784.
Abstract 3802: Evaluation of microfilament-directed cytochalasins as novel antineoplastic agents
Authors: Trendowski Matthew , Christen Timothy D. , Acquafondata Christopher , Fondy Thomas P. 
Published: July 2016

Abstract
Despite inherent differences between the cytoskeletal networks of malignant and normal cells, and the clinical antineoplastic activity of microtubule-directed agents, there has yet to be a microfilament-directed agent approved for clinical use. Cytochalasins are mycotoxins known to potently inhibit the polymerization of filamentous (F)-actin, and have long been used in vitro to examine the importance of microfilaments in fundamental cellular processes. It has previously been demonstrated that cytochalasins preferentially multinucleate malignant cells, suggesting that the congeners may exert novel antineoplastic activity. We have taken these findings, and further expanded upon their potential importance. We have shown in vitro efficacy with multiple congeners, including cytochalasin B, which potentiates substantial sensitivity to clinically approved antineoplastic agents, X-radiation, and low frequency ultrasound. Further, we have shown that cytochalasin B is more cytotoxic against neoplastic cells selected for high metastatic propensity than are their less invasive counterparts. Interestingly, we have also demonstrated that nine cytochalasin congeners may be substantially less affected by drug efflux due to overexpression of ATP-binding cassette (ABC) transporters than are doxorubicin, paclitaxel, or vinblastine, as demonstrated with SK human ovarian carcinoma cell lines of varying levels of drug resistance. Finally, we have shown that cytochalasins B and D elicit substantial antitumor and antimetastatic activity in numerous preclinical mammalian models of malignancy, suggesting that the novel mechanisms by which these congeners exert antineoplastic activity is worth further examination.
Citation Format: Matthew Trendowski, Timothy D. Christen, Christopher Acquafondata, Thomas P. Fondy. Evaluation of microfilament-directed cytochalasins as novel antineoplastic agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3802.
Abstract 3836: Novel conditionally active biologic anti-Axl antibody-drug conjugate demonstrates anti-tumor efficacy and improved safety profile
Authors: Chang Cathy , Frey Gerhard , Boyle William J. , Sharp Leslie L. , Short Jay M. 
Published: July 2016

Abstract
Axl is a TAM family receptor tyrosine kinase that has been implicated in the pathogenesis of many cancer types. The high level of expression on the cancer cell surface has made it an attractive target for antibody therapeutics. However, Axl is expressed on many normal tissues and has been implicated in wide ranging requisite biological processes including response of endothelial cells to vascular injury, hematopoiesis, and regulation of immune responses. This normal tissue expression may limit Axl as a target for antibody-drug-conjugates (ADC). Conditionally Active Biologics (CAB) technology is a proprietary platform that selects antibodies that bind to target antigen in the context of diseased tissues, but not normal tissues, by taking advantage of the unique cancer microenvironment that is produced largely as a result of the Warburg effect. Using our CAB technology, we have identified anti-Axl Abs that reversibly bind to recombinant Axl and Axl expressing cells under conditions that are present in the tumor microenvironment but not in normal tissues.
CAB-Axl antibodies were then conjugated to a model toxin payload to generate CAB-Axl-ADCs. The CAB-Axl-ADCs were active against Axl positive human tumor xenografts with tumor stasis observed at 1mg/kg weekly and tumor regressions observed at 1 mg/kg twice a week dose levels. A non-specific IgG-ADC showed minimal efficacy at the same dose levels. Single dose studies in cynomolgus macaques have demonstrated that CAB-Axl-ADC has reduced liver toxicity and immune system effects compared to Axl-ADCs that bind to Axl under normal conditions.
In conclusion, our data is consistent with our work on CAB-EGFR antibodies, and suggests that ADCs generated using the CAB technology provides biologics with increased therapeutic index. Specifically, the CAB-Axl-ADC is an excellent candidate for evaluation as a treatment for human cancers that are Axl positive.
Citation Format: Cathy Chang, Gerhard Frey, William J. Boyle, Leslie L. Sharp, Jay M. Short. Novel conditionally active biologic anti-Axl antibody-drug conjugate demonstrates anti-tumor efficacy and improved safety profile. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3836.
Abstract 3902: Novel selective estrogen receptor downregulators developed using endocrine-independent breast cancer cell lines
Authors: Xiong Rui , Zhao Jiong , Gutgesell Lauren , Tonetti Debra , Thatcher Gregory 
Published: July 2016

Abstract
Approximately 70% of breast cancer patients are estrogen receptor positive (ER+). Aromatase inhibitors and the selective estrogen receptor modulator (SERM), tamoxifen, are the first line treatments for these patients; however, almost 50% of patients either do not respond or acquire resistance. Multiple mechanisms, including mutations of the ESR1 gene, contribute to resistance via ligand-independent constitutive activation of ER. Selective estrogen down-regulators (SERDs) that block ligand-dependent and independent ER signaling by ablation of ER, offer a therapeutic approach to treatment-resistant, advanced stage and early stage ER+ breast cancer. Therapeutic use of the first generation SERD, fulvestrant (Faslodex), has largely remained 2nd and 3rd line, because of poor physiochemical/pharmacokinetic properties. Novel benzothiophene based SERDs were designed, synthesized, and optimized and assayed in three tamoxifen-resistant (TR), endocrine-independent ER+ MCF-7 and T-47D cell lines. Cell viability, ERE-luciferase response, and ER degradation was measured and compared to parent endocrine-dependent MCF-7 and T-47D cell lines in 2D and/or 3D spheroid cell cultures and compared to SERDs, fulvestrant and GDC-0810. Pharmacokinetic analysis was used to select novel SERDs for xenograft studies.
Citation Format: Rui Xiong, Jiong Zhao, Lauren Gutgesell, Debra Tonetti, Gregory Thatcher. Novel selective estrogen receptor downregulators developed using endocrine-independent breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3902.
Abstract 3949: Rapid 5-marker multiplex phenotyping of breast cancer subtypes & tumor-infiltrating leukocytes “in situ” in FFPE sections
Authors: Levin Matt , Kron Stephen J. , Schwartz David , Snyder Helen 
Published: July 2016

Abstract
Breast cancer can be divided into four subgroups HER2+, Luminal A, Luminal B and triple negative using multiple clinically validated monoclonal antibodies. Each subtype presents a different prognosis and treatment option. It is also increasingly clear that immune subsets within the tumor microenvironment may also have a bearing on prognosis, with certain subsets being associated with increased patient survival. Determining the tumor and immunologic phenotype of initial tumor biopsies both in the composition of cells and their relative spatial distribution is becoming key in selecting optimal treatment. The aim of our research has been to develop a multiplex immunofluorescence technology that can rapidly and simultaneously detect 5+ markers on a single section, allowing multiparametric quantitative analysis of cell phenotype and tissue composition as well as providing important spatial information of cells relative to each other. Our multiplex immunofluorescence (mxIF), modified-hapten based technology allows the simultaneous detection of multiple biomarkers using a standard two-step procedure. The technology is antibody species independent and produces signals 3-4X stronger than direct fluor-labeled secondary antibodies. It can detect multiple co-localized markers and while it has been engineered to detect four biomarkers and DAPI, it has the potential for significantly higher multiplexing. In addition it is modular and can be readily modified for any multiplex panel. The data generated from a staining experiment can be readily exported into any image analysis program. In comparison to existing technologies from GE and PerkinElmer, our technology allows multiple targets to be interrogated rapidly and simultaneously without the need for multiple rounds of stripping and imaging. The breast cancer phenotyping panel (BC-1) provides rapid phenotyping information allowing identification of Luminal A, Luminal B, HER2+ or triple negative cancer. Our immuno-oncology panel (IO-1) identifies CD4 and CD8 T cells, CD20+ B cells and CD68+ macrophages. Application of each panel to one of two sequential sections and then image overlay allows both tumor and immunophenotyping. The modular and non-species specific nature of this technology means that panels can be modified and expanded to characterize multiple different tumors and immune cell subpopulations in a rapid, sensitive and quantitative manner.
Citation Format: Matt Levin, Stephen J. Kron, David Schwartz, Helen Snyder. Rapid 5-marker multiplex phenotyping of breast cancer subtypes & tumor-infiltrating leukocytes “in situ” in FFPE sections. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3949.
Abstract 4094: Exosomes secreted from the noncancerous microenvironment promote proliferation, migration, and invasion in breast cancer cells
Authors: Yearby Letitia A. , Cunningham Terri , Matthews Jacenta , Lemieux. KiTani Parker 
Published: July 2016

Abstract
Introduction: Triple negative breast cancer (TNBC) is one of the most aggressive forms of five major types of breast cancer. Because TNBC mortality disproportionately affects premenopausal African American women, a health disparity exists within this group. Our research has provided insight on how the noncancerous microenvironment plays a role in TNBC proliferation, migration, and invasion. Exosomes, extracellular vesicles (30-300 nm) produced ubiquitously by mammalian cells, are secreted by noncancerous breast epithelial cells, and have been noted to enhance proliferation, migration and invasion in TNBC. Therefore, the purpose of this study is to determine if exosome-free conditioned media (EFCM), which contains noncancerous MCF10A exosomes, enhances proliferation, migration and invasion in TNBC.
Methods: MDA-MB-231 and MCF10A breast epithelial cells were used as cell line models. Proliferation was measured by the alamar blue proliferation assay. The transwell migration assay was used to assess migration, and the Matrigel invasion assay was used to measure migration. ExoELISA assays were also used to detect exosomes in exosome-free conditioned media (EFCM) from MCF10A cells. MCF10A cells were serum-starved for 24 hours, using DMEM/F-12 with 0.5% standard or exosome-depleted FBS (edFBS), to produce exosomal conditioned media (CM) and EFCM. This media was harvested and sterile filtered before use. MDA-MB-231 cells were treated with EFCM in each of the bioassays, and RPMI-1640 was used as a control.
Results: MCF10A exosomes introduced via EFCM enhanced proliferation, migration and invasion of MDA-MB-231 cells.
Conclusions: Taken together, our findings demonstrate that secreted factors from noncancerous MCF10A cells that have been stressed as a direct result of serum starvation are exosomes. These exosomes recruit TNBC cells to increase proliferation, migration, and invasion. The role of these exosomes in the noncancerous microenvironment is poorly understood, but these data suggest that exosomes from the noncancerous microenvironment have potential to be used in targeted therapies against triple negative breast disease.
Citation Format: Letitia A. Yearby, Terri Cunningham, Jacenta Matthews, KiTani Parker Lemieux. Exosomes secreted from the noncancerous microenvironment promote proliferation, migration, and invasion in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4094.
Abstract 4123: Thymoquinone inhibits bone metastasis in a breast cancer mouse model by modulating CXCR4/CXCL12 signaling axis
Authors: Shanmugam Muthu K. , Hsu Annie , Hui Kam Man , Tan Benny K.H. , Sethi Gautam 
Published: July 2016

Abstract
Several lines of evidence(s) indicate that CXCR4 overexpression has been correlated with distant site metastasis and poor overall survival rate in patient with breast cancer. The tumor metastasis promoting molecule CXCR4 is considered as a potential therapeutic target for inhibiting breast cancer metastasis. Thus, novel agents that can down-regulate CXCR4 expression have potential against breast cancer metastasis. In the present report we investigated the effect of thymoquinone (TQ), derived from the seeds of medicinal plant Nigella sativa, on the expression and regulation of CXCR4 in breast cancer cells. In addition, we evaluated the effect of TQ in a metastasis mouse model established by intracardiac injection of luciferase tagged MDA-MB-231 breast cancer cells that metastasize to the bones. We observed that TQ could inhibit the expression of CXCR4 in MCF-7 and MDA-MB-231 cells in a dose and time dependent manner. TQ (2 mg/kg or 4 mg/kg) treatment for four weeks significantly inhibited tumor growth and significantly reduced metastasis to multiple vital organs, including lungs, brain and bone. Immuno-histochemical analysis of the lung and brain tissue showed significant reduction in CXCR4, Ki67, MMP9, VEGFR2 and COX2 expression compared to control tissues. TQ treatment also reduced the overall bone tumor burden. Overall, our results show that TQ exerts its antitumor and anti-metastatic effects by downregulation of CXCR4 expression both in vitro and in vivo thus may have possible potential for the treatment of breast cancer.
Acknowledgement: This work was supported by NUHS Basic Seed Research grant to Prof. Benny Tan.
Citation Format: Muthu K. Shanmugam, Annie Hsu, Kam Man Hui, Benny K.H. Tan, Gautam Sethi. Thymoquinone inhibits bone metastasis in a breast cancer mouse model by modulating CXCR4/CXCL12 signaling axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4123.
Abstract 4187: Loss of SLFN11 or gain of TWIST1 promote chemotherapy resistance in small cell lung cancer
Authors: Gardner Eric E. , Lok Benjamin H. , Schneeberger Valentina E. , de Stanchina Elisa , Poirier John T. , Rudin Charles M. 
Published: July 2016

Abstract
The majority of patients with small cell lung cancer (SCLC) who are treated with first-line platinum/etoposide chemotherapy develop therapeutic resistance, but little is mechanistically understood how resistance develops in patients. This is partly due to limited access to historic paired tissue samples, few investigational re-biopsy programs and the aggressive nature of this disease.
In this study we used a collection of 10 treatment-naïve, patient-derived xenograft (PDX) models of SCLC to determine how resistance to chemotherapy can be acquired in vivo, by cycling weekly cisplatin and etoposide, followed by serial passaging of tumor cells capable of surviving and proliferating through treatment. Applying whole transcriptome (RNAseq), exome and high-depth targeted sequencing approaches to paired parental and resistant populations revealed minimal recurrent mutations; however, two consistent gene expression changes were observed, implicating either a decrease in SLFN11 or an increase in TWIST1 transcript levels may promote resistance. We validated both mechanisms in vitro using conditional gain and loss of function experiments in SCLC cell lines of human and mouse origin. Where suppression of SLFN11 was associated with resistance to select classes of DNA damaging agents, gaining TWIST1 produced a broad resistance phenotype, consistent with an epithelial-to-mesenchymal transition.
Increased sensitivity to chemotherapy through overexpression of SLFN11 was observed only in cell lines with low levels of TWIST1. Importantly, TWIST1 knockdown or knockout did not dramatically change the sensitivity to chemotherapy in multiple TWIST1-high cell lines tested, suggesting that directly targeting TWIST1 may be of limited utility in SCLC. We extended these results by modeling acquired resistance to cisplatin and etoposide in a triple knockout (p53/Rb/p130) mouse allograft model of SCLC, finding that increased expression of TWIST1 was associated with chemotherapy resistance, but did not confer a greater metastatic potential in a tumor type with an already high predilection for metastasis. Understanding the relative expression of SLFN11 and TWIST1 at baseline and upon clinical relapse may be informative in determining therapeutic options for SCLC patients that no longer respond to platinum and etoposide.
Citation Format: Eric E. Gardner, Benjamin H. Lok, Valentina E. Schneeberger, Elisa de Stanchina, John T. Poirier, Charles M. Rudin. Loss of SLFN11 or gain of TWIST1 promote chemotherapy resistance in small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4187.
Abstract 4192: The association between gastric Mucin 5AC (MUC5AC) expressions, transforming growth factor-β (TGF-β) signal, and histopathological phenotypes of lung cancer in xenograft models
Authors: Sato Ryo , Semba Takashi , Kohrogi Hirotsugu , Saya Hideyuki , Arima Yoshimi 
Published: July 2016

Abstract
According to the 2015 World Health Organization (WHO) classification of lung tumors, invasive lung adenocarcinomas are pathologically classified as lepidic, acinar, papillary, micropapillary, or solid types. Adding the cribriform pattern as an additional subtype to the original WHO classification has recently been proposed, because patients with cribriform predominant tumors have a poorer prognosis than that for patients with acinar or papillary predominant tumors. Understanding the molecular mechanisms contributing to the pathological subtypes may provide a basis for the development of new therapeutic strategies and an improved prognosis for lung cancer patients.
We found that the human lung adenocarcinoma A549 cells developed distinct histological types of tumors; acinar types and mucinous cribriform types, when cells were inoculated into immunodeficient mice. Acinar type tumors showed a gland-like pattern containing stromal cells, and cribriform type tumors contained abundant acidic mucins stained with Alcian blue. We also found that the cribriform type tumors, but not acinar type tumors, expressed Mucin 5AC (MUC5AC), which is one of the common mucin core proteins. In contrast, acinar type tumors upregulated the phosphorylation of Smad3, which is the downstream of the transforming growth factor-β (TGF-β) signal, indicating that the TGF-β/Smad pathway is activated in acinar type tumors. We went on to culture A549 cells in several conditions and found that MUC5AC is upregulated in serum-free floating culture conditions. To determine the relationship between TGF-β and MUC5AC expressions, TGF-β1 was added to the culture medium, and we found that TGF-β1 completely inhibited MUC5AC induction.
These data imply that cancer cells and/or cancer associated fibroblasts (CAFs) release TGF-β1 and inhibit MUC5AC expressions, leading to acinar type tumor formations.
Citation Format: Ryo Sato, Takashi Semba, Hirotsugu Kohrogi, Hideyuki Saya, Yoshimi Arima. The association between gastric Mucin 5AC (MUC5AC) expressions, transforming growth factor-β (TGF-β) signal, and histopathological phenotypes of lung cancer in xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4192.