bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2617: SUMOylation inhibition attenuates the cancer stem cell population in glioblastoma and basal breast cancer
Authors: Park Jung M. , Wu Tong , Van Dorin Sarah , Weigel Ronald 
Published: August 2015

Abstract
INTRO: TFAP2A and mouse homolog Tcfap2a are transcription factors that play a critical role in development and cancer. We have recently shown that SUMOylation of TFAP2A is a key posttranslational modification that maintains the basal breast cancer phenotype. Treatment with anacardic acid (AA), a SUMOylation inhibitor, led to depletion of the CD44+/hi/CD24-/lo cancer stem cell population. Interestingly, glioblastoma has also been shown to express TFAP2A and demonstrates an expanded cancer stem cell population.
METHODS: Mouse 4T1 basal mammary cancer, IOWA-1T human basal breast cancer and UG118 glioblastoma cell lines were analyzed. MTT was used to measure cell viability. Coulter Counter and hemocytometer were used for cell quantification. Matrigel invasion and western blot were used to further characterize the cell lines.
RESULTS: Treatment of 4T1 and UG118 cells with AA in vitro resulted in a 67% and 65% decrease in cell viability by MTT assay, respectively (p &lt; 0.05 for both). Quantification of cell number confirmed that AA treatment inhibited cell proliferation. At 48 hours, 4T1 cells demonstrated a decrease of 73-77% (p &lt; 0.01), and UG 118 cells decreased by 97 to 98% (p &lt; 0.001). Cell invasiveness assessed by Matrigel invasion assay was attenuated in 4T1 and UG118 cells after treatment (84%, p &lt; 0.01 and 28%, p &lt; 0.05, respectively). Western blot demonstrated a dose-dependent decrease in expression of the cancer stem cell marker CD44 or the mouse homolog CD49f following AA treatment of UG118 and 4T1 cells, respectively. Western blot confirmed that while total TFAP2A levels were unchanged, SUMO conjugated TFAP2A was decreased after AA treatment of 4T1 cells. To further establish relevance to human cancer, an aggressive chemotherapeutic resistant patient-derived xenograft, IOWA-1T, similarly demonstrated a 41% drop (p &lt; 0.007) in cell invasiveness and a concomitant decrease in SUMOylated TFAP2A with AA treatment.
CONCLUSION: Inhibition of the SUMO pathway attenuates the cancer stem cell population in basal breast cancer and glioblastoma. While further investigation is needed, SUMOylation may be a common biological posttranslational modification that defines cancer stem cells. Furthermore, basal breast cancer, brain cancer, and other cancers that express TFAP2A may be amenable to SUMOylation inhibitors such as AA.
Citation Format: Jung M. Park, Tong Wu, Sarah Van Dorin, Ronald Weigel. SUMOylation inhibition attenuates the cancer stem cell population in glioblastoma and basal breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2617. doi:10.1158/1538-7445.AM2015-2617
Abstract 2635: Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum
Authors: Ruiz-Saenz Ana , Sandhu Manbir , Carrasco Yazmin , Maglathlin Rebecca L. , Taunton Jack , Moasser Mark M. 
Published: August 2015

Abstract
There is increasing evidence implicating HER3 in several types of cancer, as a resilient copartner for HER2 in HER2-amplified cancers, and as a driver of resistance in many other types of cancer. However, the development of targeted therapies to inactivate HER3 function has been a challenging endeavor. Its tumor-driving functions are only sometimes driven by ligand-activation, and targeting its extracellular domain with antibody molecules has only limited effects. Its kinase domain functions in allostery, not catalysis, and we have previously shown that the classical ATP-analog class of tyrosine kinase inhibitors fail to inactivate it. Here we describe a novel approach that eliminates HER3 expression. This involves interfering with mechanisms critical for its cotranslational translocation into the endoplasmic reticulum (ER), resulting in the elimination of HER3 protein expression and loss of HER3 function. The small-molecule cotransin CT8 binds the Sec61 translocon channel in the ER membrane and prevents the signal peptide of the nascent HER3 protein from initiating its cotranslational translocation into the lumen of the ER, resulting in the degradation of HER3. Interestingly, CT8 treatment prevents HER3 translocation while the other HER proteins are unaffected. In addition, CT8 treatment suppresses the compensatory induction of HER3 that accompanies lapatinib treatment of HER2-amplified cancer cells, making for a durable suppression of HER2-HER3 signaling with the lapatinib-CT8 combination. Consistent with the effective inactivation of HER2-HER3 signaling, CT8 treatment synergistically enhances the apoptotic effects of lapatinib in HER2-overexpressing cancer cells. The target selectivities of cotransins are highly dependent on their structure and the signal sequence of targeted proteins and can be narrowed through structure-function studies. Our results thus highlight Sec61-dependent processing as a novel strategy to eliminate HER3 expression and function with considerable potential for the treatment of HER2-amplified and other types of cancers.
Citation Format: Ana Ruiz-Saenz, Manbir Sandhu, Yazmin Carrasco, Rebecca L. Maglathlin, Jack Taunton, Mark M. Moasser. Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2635. doi:10.1158/1538-7445.AM2015-2635
Abstract 2662: A dual PI3K/mTOR inhibitor as potential therapeutic option for vulvar cancer
Authors: Rodrigues Iara , Rodrigues Bruna , Giudice Fernanda , Baiocchi Glauco , Soares Fernando Augusto , Martins Vilma , Rocha Rafael Malagoli 
Published: August 2015

Abstract
Introduction: Epithelial to mesenchymal transition (EMT) is an important process during cancer progression by which epithelial cells acquire mesenchymal phenotype and show reduced intercellular adhesion as well as increased motility. Interfering PI3K/AKT pathway has been considered an anti-EMT target therapy, due to its effect in restoration of E-cadherin function and inhibition of transcription factors that repress the E-cadherin promoter, such as Snail, Slug, and Twist. Aim: Investigate the antitumor effects of treatment with PI3K/mTOR dual inhibitor, NVP-BEZ235, in biological behavior of lymph node metastatic vulva cancer cell line (SW962), as a potential anti-EMT agent in vulvar tumor. Methods: we performed in vitro assays and evaluated the expression of proteins related to PI3K/Akt/mTOR pathway as well as Vimentin and E-cadherin, relevant EMT biomarkers. All results were presented as mean standard deviation and were compared using the unpaired t test or ANOVA followed by the Bonferroni post test using Graph Pad InStat v3.02 software. P values &lt; 0.05 were considered statistically significant. Results: Treatment with NVP-BEZ235 resulted in a significant decrease in cell migration (p&lt; 0.001), proliferation (p&lt; 0.01) and invasion (p&lt;0.05). The phosphorylation of AKT, S6K, 4E-BP1 and p70S6 was markedly reduced by NVP-BEZ235 treatment. In contrast, the levels of p-GSK3β (Ser9) were increased. Our qualitative results demonstrated that the localization pattern of E-cadherin and Vimentin protein was similar between control and treatment groups. We observed Vimentin protein only in isolated cells and, E-cadherin protein was found exclusively in cell clusters, demonstrating EMT-like events in SW962 cells. The expression of E-cadherin in SW962 cells treated was slightly increased and the levels of Vimentin was reduced in these cells. Conclusion: The present study suggests that NVP-BEZ235 is an effective inhibitor of PI3K/mTOR pathway, resulting in the decrease of Vimentin expression, an important EMT marker, as well as of other essential tumor events, such as proliferation, migration and invasion of vulva cancer. Taken together, these findings not only provide a novel insight into the actions of NVP-BEZ235 as inhibitor of EMT process in cancer progression, but also highlight a novel potential therapeutic option for the treatment of aggressive tumors such as vulvar carcinoma.
Citation Format: Iara Rodrigues, Bruna Rodrigues, Fernanda Giudice, Glauco Baiocchi, Fernando Augusto Soares, Vilma Martins, Rafael Malagoli Rocha. A dual PI3K/mTOR inhibitor as potential therapeutic option for vulvar cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2662. doi:10.1158/1538-7445.AM2015-2662
Abstract 2667: FP-208, a novel mTOR inhibitor with potent antitumor activities
Authors: Du Zhenjian , Ji Qi , Chen Bo , Zhang Chunxiao , Zhao Ge , Zhang Xingmin 
Published: August 2015

Abstract
The mammalian target of rapamycin (mTOR) is a master regulator of cell growth, proliferation and survival. The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway is commonly dysregulated in cancer. FP-208, animidazolone derivatives, is a novel small molecule that primarily inhibits mTOR with potent antitumor activity. The compound is soluble with a good oral PK profile and excellent bioavailability in mice and rats. Here we report the in vitro and in vivo effects of FP-208 in multiple cancer cell lines and in xenograft tumor models. FP-208 inhibited mTOR enzymatic activity in vitro (IC50 = 0.3nM) in a kinase assay and cell proliferation in multiple cancer cell lines. Western blot analysis to examine the effect of FP-208 showed significant blockade of phosphorylation of S6 and AKTS473, suggesting inhibition of both mTORC1 and mTORC2 activities. The antitumor activity of FP-208 was evaluated in human cancer xenograft models as well. Oral administration of the compound in tumor bearing mice strongly inhibited tumor growth as a single agent. Further analysis demonstrated that treatment with FP-208 inhibited phosphorylation of mTORC1/2 pathway markers, S6 and AKTS473 in the tumors. Taken together, our data from both in vitro and in vivo studies suggest that FP-208 is a drug candidate for the treatment of human cancers.
Citation Format: Zhenjian Du, Qi Ji, Bo Chen, Chunxiao Zhang, Ge Zhao, Xingmin Zhang. FP-208, a novel mTOR inhibitor with potent antitumor activities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2667. doi:10.1158/1538-7445.AM2015-2667
Abstract 2679: Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma
Authors: Fofaria Neel M. , Frederick Dennie T. , Sullivan Ryan J. , Flaherty Keith T. , Srivastava Sanjay K. 
Published: August 2015

Abstract
Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. The most prevalent mechanisms of acquired resistance appear to reactivate MAPK pathway. Furthermore, relatively little is known about the determinants of de novo resistance. Here, we establish such a mechanism of resistance and subsequently identified a suitable drug combination to overcome the resistance. Single treatment of BRAF mutant melanoma cell lines with vemurafenib or dabrafenib (BRAF inhibitors) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1. Overexpression of Mcl-1 in A375 and SK-MEL-28 by transfection completely blocked BRAF and MEK1/2 inhibitor-mediated inhibition of cell survival. Melanoma cells resistant to BRAF inhibitors showed massive expression of Mcl-1 as compared to respective sensitive cell lines. Silencing of Mcl-1 using siRNA completely sensitized resistant melanoma cells to growth suppression by BRAF inhibitors. In vivo, vemurafenib resistant A375 xenografts implanted in athymic nude mice showed substantial tumor growth inhibition when treated with a combination of vemurafenib and Mcl-1 inhibitor or siRNA. Immunohistochemistry and western blot analyses demonstrated enhanced expression of Mcl-1 and activation of ERK1/2 in vemurafenib-resistant tumors whereas level of Mcl-1 or p-ERK1/2 was diminished in the tumors of mice treated with either of the combination. Biopsied tumors from the patients treated with or resistant to BRAF inhibitors revealed overexpression of Mcl-1. These results suggest that the combination of BRAF inhibitors with Mcl-1 inhibitor may have therapeutic advantage to melanoma patients with acquired resistance to BRAF inhibitors alone or in combination with MEK1/2 inhibitors. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Neel M. Fofaria, Dennie T. Frederick, Ryan J. Sullivan, Keith T. Flaherty, Sanjay K. Srivastava. Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2679. doi:10.1158/1538-7445.AM2015-2679
Abstract 2682: Melanoma phenotype switching to adapt to BRAF inhibition
Authors: Robert Lidia , Tsoi Jennifer , Garcia Diaz Angel , Homet Moreno Blanca , Truong Nhat , Graeber Thomas , Ribas Antoni 
Published: August 2015

Abstract
Melanoma can adapt to several stress factors, such as TNF treatment, by changing its phenotype from a highly differentiated (MITF and MART-1 positive) to undifferentiated (neural crest markers) states. We studied this phenomenon as a mechanism of adaptive resistance to BRAF inhibition since melanomas with both MITF high and low have been reported to result in BRAF inhibitor resistance. We treated 17 BRAFV600E mutant melanoma cell lines with the BRAF inhibitor vemurafenib for short term (3 days) or long term (17 days), and compared them to no treatment or TNF treated conditions. We profiled them phenotypically for MART1 antigen (differentiated phenotype) and nerve growth factor receptor (NGFR, neural crest phenotype) expression by flow cytometry. Results comparing median fluorescence intensity (MFI) showed a wide spectrum of adaptive responses to short term BRAF inhibition, followed by solidification or further evolution of these changes upon long term exposure and development of drug tolerance. According to each cell line distribution, we calculated a (x,y) value that organized the cell lines and conditions in four quadrants according to MART1 (x axis) or NGFR (y axis) expression. Two double negative (MART1-/NGFR-) cell lines that were unaffected by treatment and stayed in the same quadrant. Seven MART1-/NGFR+ and four MART1+/NGFR- cell lines slightly changed phenotype with vemurafenib exposure but stayed in the same quadrant. Four cell lines with MART1+/NGFR+ phenotype were greatly influenced by treatment, showing wide plasticity with cells shifting towards NGFR+/MART1- and others towards NGFR-/MART1+. Changes in position between baseline and tolerance to vemurafenib after 17days treatment were numerically quantified as an inferred number from plasticity. Cell lines with double positive (MART1+/NGFR+) phenotype had a significant change in plasticity compared to the rest of cell lines in other quadrants (p = 0.0004). This arranges cells in a four-quadrant pattern that could be likened to a U-turn toward de-differentiation. Cells that de-differentiated with BRAF inhibition mimicked the effect induced by TNF. This effect was driven by a decrease in MITF activity confirmed with a tyrosinase promoter-luciferase assay. In conclusion, baseline melanoma differentiation phenotypes guide the phenotype switch response, with those double positive for differentiation and neural crest markers being at a semi-stable state that can be prone to different plastic changes upon BRAF inhibition.
Citation Format: Lidia Robert, Jennifer Tsoi, Angel Garica Diaz, Blanca Homet Moreno, Nhat Truong, Thomas Graeber, Antoni Ribas. Melanoma phenotype switching to adapt to BRAF inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2682. doi:10.1158/1538-7445.AM2015-2682
Abstract 2694: Esophageal cancer exhibits a resistance to the chemical inhibition of IGF-1R with a maintained Ras-MAPK activity
Authors: Takaoka Munenori , Bao XiaoHong , Hao Huifang , Ishida Naomasa , Fukazawa Takuya , Yamatsuji Tomoki , Haisa Minoru , Naomoto Yoshio 
Published: August 2015

Abstract
The type 1 insulin-like growth factor receptor (IGF-1R) and its associated signaling system play a significant role in carcinogenesis and progression of gastrointestinal malignancies, and thus have provoked great interest as a promising target for cancer treatment. The aim of our study was to assess the effects of a novel IGF-1R inhibitor, NVP-AEW541, on the cell proliferation and signal transduction of esophageal squamous cell carcinoma. Five human esophageal squamous carcinoma cell lines (TE-1, TE-4, TE-8, TE-10 and T.Tn) were treated with this inhibitor and the IC50 of NVP-AEW541 for each cell line was more than 1μM, exhibiting that these cells were less sensitive to this compound. The activation of IGF-1R and AKT were dose dependently blocked by NVP-AEW541. However, the activities of the key molecules in Ras-MAPK pathway was not significantly inhibited by NVP-AEW541 without any major mutation of Ras. These results indicate that esophageal squamous cell carcinoma may be resistant to targeting IGF-IR due to its maintenance of Ras-MAPK signaling. Thus, to explore the potential mechanism of resistance will contribute to the therapeutic application for NVP-AEW541.
Citation Format: Munenori Takaoka, XiaoHong Bao, Huifang Hao, Naomasa Ishida, Takuya Fukazawa, Tomoki Yamatsuji, Minoru Haisa, Yoshio Naomoto. Esophageal cancer exhibits a resistance to the chemical inhibition of IGF-1R with a maintained Ras-MAPK activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2694. doi:10.1158/1538-7445.AM2015-2694
Abstract 2696: Arenobufagin targets K-Ras downstream to enhance the efficiency of gemcitabine in human pancreatic carcinoma cells
Authors: Wang Tianjiao , Yuan Yuhui 
Published: August 2015

Abstract
Pancreatic carcinoma (PC) is a deadly form of cancer with poor overall survival. Currently, chemotherapeutic such as gemcitabine and 5-fluorouracil (5-FU) are the most popular medication that can slightly improve survival, but rapid drug-resistance makes it urgent to search for more effective drugs. In hunting for natural components that cure PC, we found that arenobufagin, a cardiac glycosides-like compound, showed significant effects on the gemcitabine-resistant cell line Panc-1, the gemcitabine-sensitive cell line ASPC-1 and K-Ras activating HPNE cells at nanomolar concentrations. We used MTT and clonogenic survival assays to examine survival and proliferation and western blotting to assess changes of K-Ras downstream and apoptosis related proteins. We also detected the cell cycle and migration by flow cytometry and wound healing assay. Arenobufagin inhibited cellular survival and proliferation, decreased the phosphorylation of key proteins of K-Ras downstream such as Akt, Erk and nuclear factor kappa B (NF-κB), induced cell cycle G2/M arrest and apoptosis, and downregulated the level of phosphorylated epidermal growth factor receptor (EGFR). Most importantly, our data showed that arenobufagin can enhance the sensitivity of PC cells to gemcitabine and 5-fluorouracil (5-FU). Arenobufagin could enhance the effect of gemcitabine and 5-FU on PC cells through targeting multiple key proteins. All above makes arenobufagin a novel agent for combination therapy of pancreatic carcinoma.
Citation Format: Tianjiao Wang, Yuhui Yuan. Arenobufagin targets K-Ras downstream to enhance the efficiency of gemcitabine in human pancreatic carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2696. doi:10.1158/1538-7445.AM2015-2696
Abstract 2700: The IAP inhibitor Debio 1143 reverses carboplatin resistance in ovarian cancer cells by inducing both apoptosis and necroptosis
Authors: Thibault Benoît , Genre Ludivine , Broca Clothilde , Barbier Maryse , Zanna Claudio , Vuagniaux Grégoire , Delord Jean-Pierre , Couderc Bettina 
Published: August 2015

Abstract
Ovarian cancer remains the most lethal gynecological cancer. The efficacy of conventional chemotherapy with a combination of platinum salts and taxanes is transient because 70 to 80% of patients initially responding to platinum finally relapse. Mechanisms of resistance to carboplatin include a disruption of the balance between key pro-and anti-apoptotic proteins such as the inhibitor of apoptosis protein (IAP) family. Drug mimetics of the endogenous IAP inhibitor SMAC constitute a novel therapeutic approach to overcome apoptosis resistance and are currently in clinical development for cancer treatment.
In this study we tested the ability of the oral IAP inhibitor Debio 1143 to revert carboplatin resistance in three carboplatin-sensitive (OVCAR-3, IGROV-1, A2780S) and three carboplatin-resistant (SKOV-3, A2780R, EFO-21) human ovarian tumor cell lines.
We demonstrated that in vitro Debio 1143 was able to sensitize SKOV-3, EFO-21 and A2780R ovarian tumor cells to carboplatin. In addition, we demonstrated that the combination allowed a full recovery of carboplatin sensitivity in A2780R similar to the sensitive cell line A2780S. The sensitization to carboplatin correlated with an increased induction of apoptosis (Annexin V/PI assay and PARP cleavage) in SKOV-3 and A2780R cells. In EFO-21 cells, Debio 1143 triggered necroptosis as shown by the necroptosis inhibitor necrostatin-1 which was able to suppress Debio 1143-induced cell death with or without carboplatin. Our study shows that in the above human ovarian tumor cell lines Debio 1143 induces degradation of cIAP1 while XIAP levels remain unchanged.
Using a carboplatin-resistant in vivo ovarian tumor mouse model, we further showed that Debio 1143 alone or in combination with carboplatin causes marked regression of subcutaneous SKOV-3 tumors.
Together, our results suggest that Debio 1143 in combination with carboplatin could provide considerable benefit to patients with innate or acquired resistance to carboplatin by acting as a sensitizing agent. Debio 1143 is currently evaluated in combination with carboplatin and paclitaxel in patient with advanced solid malignancies including platinum-refractory ovarian cancer (NCT01930292).
Citation Format: Benoît Thibault, Ludivine Genre, Clothilde Broca, Maryse Barbier, Claudio Zanna, Grégoire Vuagniaux, Jean-Pierre Delord, Bettina Couderc. The IAP inhibitor Debio 1143 reverses carboplatin resistance in ovarian cancer cells by inducing both apoptosis and necroptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2700. doi:10.1158/1538-7445.AM2015-2700