bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5449: FP-1039/GSK3052230, an FGF ligand trap, enhances VEGF antagonist therapy in preclinical models of RCC and HCC
Authors: Bellovin David I. , Palencia Servando , Hestir Kevin , Lee Ernestine , DeYoung M. Phillip , Brennan Thomas , Los Gerrit , Baker Kevin 
Published: May 2015

Abstract
An increasing body of evidence has implicated FGF2 as one of the drivers of resistance to various inhibitors of VEGF-mediated angiogenesis. This resistance may play a role as a key limitation to the efficacy of therapies targeted at VEGF and its receptors. We investigated the potential for FP-1039/GSK3052230, a ligand trap that sequesters FGFs and inhibits their signaling, to enhance the activity of VEGF antagonist therapies in certain preclinical models of renal cell (RCC) and hepatocellular (HCC) carcinomas. First, we examined whether FP-1039/GSK3052230 has single agent efficacy against human RCC and HCC xenografts that express relatively high levels of FGF2, a profile that would mimic FGF2-driven resistance to VEGF therapy. We determined that this expression profile represents 34% of clear cell RCC (ccRCC) and 31% of HCC patients, based on the cancer genome atlas (TCGA) data. Human ccRCC xenografts with high FGF2 expression and low VEGFA expression demonstrated a significant inhibition in tumor growth when treated with FP-1039/GSK3052230 alone (TGI: 39-81%). In addition, we show that the high FGF2 expression profile is similarly predictive for the anti-tumor response of a human HCC model to single-agent FP-1039/GSK3052230 (TGI: 31-55%). In contrast, RCC models with low FGF2 expression, representing 66% of all ccRCC in the TCGA, are relatively insensitive to FP-1039/GSK3052230 as a single-agent. However, combination therapy of FP-1039/GSK3052230 with pazopanib in these tumors is significantly more effective than either agent alone. FP-1039/GSK3052230 not only slows tumor growth, but can induce ∼25% tumor regression when administered to mice bearing ccRCC xenografts that have become resistant to pazopanib. Together, our data demonstrate that FP-1039/GSK3052230 may be an effective therapy against RCC and HCC, both as a single agent in disease driven by FGF2 and in combination with VEGF antagonist therapies that represent the current standards of care for advanced disease.
Citation Format: David I. Bellovin, Servando Palencia, Kevin Hestir, Ernestine Lee, M. Phillip DeYoung, Thomas Brennan, Gerrit Los, Kevin Baker. FP-1039/GSK3052230, an FGF ligand trap, enhances VEGF antagonist therapy in preclinical models of RCC and HCC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5449. doi:10.1158/1538-7445.AM2014-5449
Abstract 5455: Resistance to a MEK inhibitor (AZD6244): Its association with increased expression of transcription factor 4
Authors: Goo Bon-Kwan , Hur Eun-Hye , Choi Yunsuk , Kim Sung-Doo , Hwang Jung Jin , Kim Choung-Soo , Bae Kyun Seop , Choi Jene , Cho Suk Young , Yang Sang-Hwa , Lee Je-Hwan 
Published: May 2015

Abstract
The important role of Ras/Raf/MEK/ERK pathway in carcinogenesis has led to clinical development of MEK inhibitors for treatment of various cancers. Although recent studies have demonstrated impressive antitumor activities of the agents, many tumors show intrinsic and acquired resistance to MEK inhibitors. We tried to find biomarkers that were associated with intrinsic or acquired resistance to a MEK inhibitor (AZD6244) by public microarray data acquisition and development of AZD6244-resistance cell lines. First, we analyzed a set of genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines of various tissue origins to identify candidate genes whose expression changes are associated with resistant or sensitive responses to AZD6244. Of 62 differentially expressed genes, we selected Transcription Factor 4 (TCF4) gene as a potential drug resistance marker for further analysis because degree of increased expression of TCF4 in resistance cell lines was relatively high and a previous study suggests that TCF4 functions as an oncogene in human colon cancers. The mRNA levels of TCF4 in AZD6244 resistant cell lines were significantly elevated than those in sensitive cell lines. The siRNA was used for the targeted silencing of TCF4 to elucidate the role of increased expression of TCF4 in intrinsic resistance to AZD6244. TCF4 siRNA significantly enhanced susceptibility of a AZD6244-resistant cell line, LOXIMVI, to AZD6244. Next, we established AZD6244-resistant cell lines, using originally AZD6244-senstive cell lines, M14 and COLO-205. The half maximal inhibitory concentration (IC50) values for AZD6244 in two acquired resistant cell lines were 34 fold and 200 fold higher than those of their parent cell lines, respectively. Protein levels of TCF4 in the acquired resistant cell lines were higher than those in the sensitive parent cell lines. Our study results suggest that increase expression of TCF4 may be associated with both intrinsic and acquired resistance to MEK inhibitors.
Citation Format: Bon-Kwan Goo, Eun-Hye Hur, Yunsuk Choi, Sung-Doo Kim, Jung Jin Hwang, Choung-Soo Kim, Kyun Seop Bae, Jene Choi, Suk Young Cho, Sang-Hwa Yang, Je-Hwan Lee. Resistance to a MEK inhibitor (AZD6244): Its association with increased expression of transcription factor 4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5455. doi:10.1158/1538-7445.AM2014-5455
Abstract 546: CD44 variant expression is a poor prognostic marker in early gastric cancer and well-differentiated gastric cancer
Authors: Lee Won Sup , Go Se-Il , Lee Jeong-Hee , Jeong Sang-Ho , Lee Young-Joon , Hong Soon Chan , Ha Woo Song , Ko Gyung Hyuck 
Published: May 2015

Abstract
The present study is to investigate the significance of the expression of CD44 variant (CD44v), a functional cancer stem cell marker, in the primary gastric cancer. We first tested whether CD44v is selectively expressed in gastric cancer tissue. With the tissue microarray samples containing the 6 normal tissue, 6 H. pylori associated gastritis, 12 intestinal metaplasia, 12 low-grade adenoma, 12 high-grade adenoma, 25 early gastric cancer and 26 advanced gastric cancer. The positive expression rates in tumor were 65.3% (49/75) whereas the positive rates in normal and gastritis tissue were 30.4% (p = 0.003). Next, we investigated the clinical significance of gastric cancer with the tissue microarray containing 333 gastric cancer tissue derived from the patients who underwent radical gastrectomy for gastric cancer from 1999 to 2007. The positive expression rates of CD44v (55%, 134/242) were higher in intestinal type gastric cancer than in diffuse type (28%, 21/76). Intestinal type gastric cancer among the CD44v-positive gastric cancer accounted for 82% (134/164). The 5-year survival rate of CD44v-positive gastric cancer was 67.7% whereas that of CD44v-negative gastric cancer was 62.9%. The survival difference was higher as time passed, but it was statistically insignificant (p = 0.219). However, in the subgroup analysis we found that the survival differences were significantly higher in early gastric cancer and well-differentiated gastric cancer (p = 0.013, 5-YSR ; p = 0.046, 5-YSR , respectively). We also investigated the correlation between the expressions of CD44v and EGFR along with the well-known proliferative molecular biomarkers, cylin D1 and Ki-67. Only the expression of Ki-67 were some correlation with CD44v expression in gastric cancer; CD44v-positive rates of the cancers with negative or 1 positive Ki-67 expression were 37% (47/127) whereas those with 2 or 3 positive Ki-67 expression were 57.4% (116/202). This study demonstrates that CD44v can be a good biomarker for early gastric cancer and well-differentiated gastric cancer. [This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare & Family Affairs, Republic of Korea. (0820050).]
Citation Format: Won Sup Lee, Se-Il Go, Jeong-Hee Lee, Sang-Ho Jeong, Young-Joon Lee, Soon Chan Hong, Woo Song Ha, Gyung Hyuck Ko. CD44 variant expression is a poor prognostic marker in early gastric cancer and well-differentiated gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 546. doi:10.1158/1538-7445.AM2014-546
Abstract 5469: Trastuzumab resistant HER2+ breast cancer cells retain sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition
Authors: Wielgos Monica E. , Cooper Tiffiny , Forero Andres , Bonner James A. , Esteva Francisco J. , Osborne C K. , Schiff Rachel , LoBuglio Albert F. , Yang Eddy S. 
Published: May 2015

Abstract
Background: Overexpression of HER2 in breast cancer is associated with aggressive tumor features and poor patient survival. Current therapeutic agents targeting this receptor have increased the survival rate of patients with HER2+ breast cancer; however some patients eventually develop resistance to these therapies. We have previously reported that HER2+ breast cancers are susceptible to poly (ADP-Ribose) polymerase inhibitors (PARPi) alone independent of a basal or induced DNA repair deficiency but instead via suppression of NF-κB signaling. In this study, we investigated PARPi sensitivity in HER2+ breast cancer cells that are resistant to the HER2 targeted agent trastuzumab.
Materials and Methods: HER2+ breast cancer cell lines BT-474, UACC812, SKBRR3 and their trastuzumab resistant counterparts were used in this study. Cells were treated with vehicle or 10µM ABT-888 or transfected with scrambled or PARP1 siRNA. NF-κB transcriptional activity was measured using a NF-κB-driven luciferase reporter assay. Protein expression was measured by Western blot analysis. Cellular cytotoxicity and viability following PARPi was assessed with colony formation and ATPlite assays, respectively.
Results: HER2+ parent and trastuzumab resistant breast cancer cells showed similar susceptibility to the PARPi ABT-888. There was a dose response reduction in survival fraction (greater than 70% at 10μM) and a greater than 40% decrease in cell viability with 10μM ABT-888. This cytotoxicity was associated with more than 50% attenuation of NF-κB transcriptional activity and reduced expression of the NF-κB activator IKKα. Suppression of NF-κB signaling was also observed utilizing PARP1 siRNA.
Conclusions: HER2+ breast cancer cells resistant to trastuzumab continue to be sensitive to PARP inhibition through attenuation of the NF-κB signaling pathway. These results support the use of PARPi as part of a therapeutic strategy for patients with HER2+ breast cancer.
Citation Format: Monica E. Wielgos, Tiffiny Cooper, Andres Forero, James A. Bonner, Francisco J. Esteva, C K. Osborne, Rachel Schiff, Albert F. LoBuglio, Eddy S. Yang. Trastuzumab resistant HER2+ breast cancer cells retain sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5469. doi:10.1158/1538-7445.AM2014-5469
Abstract 5470: LKB1 loss sensitizes non-small cell lung cancer cells to aggravation of ER stress
Authors: Inge Landon J. , Friel Jacqueline M. , Fowler Aaron , Richer Amanda , Whitsett Timothy , Tran Nhan L. , Bremner Ross M. 
Published: May 2015

Abstract
Five-year survival rates for non-small cell lung cancer (NSCLC) have seen minimal improvement despite aggressive therapy with standard chemotherapeutic agents, indicating a need for new treatment approaches. Studies show inactivating mutations to the LKB1 tumor suppressor are common in NSCLC and are concurrent with activating mutations to the KRas oncogene. Genetic and mechanistic analyses of KRas/LKB1-null NSCLC tumors suggest these tumors are a phenotypically distinct subpopulation of NSCLC and the unique features of KRas/LKB1-null tumors have potential for therapeutic gain. In the exploration of the mechanism(s) behind increased cytotoxicity of KRas/LKB1-null NSCLC cells to 2-D-Deoxyglucose (2DG), we find that loss of LKB1 in NSCLC cells imparts increased sensitivity to pharmacological aggravation of ER stress. In a panel of NSCLC cell lines, LKB1 expression status correlated to differential expression of the ER stress markers, BiP and CHOP, with 2DG treatment. Treatment of isogenic LKB1-null NSCLC cells ectopically expressing LKB1 or a nonfunctional LKB1 with the ER stress activators, tunicamycin (Tm) or brefeldin A (BFA), revealed that expression of LKB1 increased cell viability and phosphorylation of AMPK. Conversely, isogenic LKB1-null NSCLC cells expressing nonfunctional LKB1 displayed increases in phosphorylation of the ER stress marker, eif2α and markers of ER stress mediated cell death (reactive oxygen species and cleaved caspase-9) following aggravation of ER stress with 2DG, Tm or BFA. The use of 2DG was effective in controlling the growth of KRas/LKB1-null tumors compared to KRas/LKB1-expressing tumors in transgenic NSCLC models and 2DG-treated KRas/LKB1-null NSCLC tumors displayed features consistent with 2DG treatment of in vitro KRas/LKB1-null NSCLC cell lines. Based upon these findings, we suggest that KRas/LKB1-null NSCLC tumors are more sensitive to pharmacological aggravation of ER stress and this approach has potential as a treatment for NSCLC patients whose tumors are defined as KRas/LKB1-null.
Citation Format: Landon J. Inge, Jacqueline M. Friel, Aaron Fowler, Amanda Richer, Timothy Whitsett, Nhan L. Tran, Ross M. Bremner. LKB1 loss sensitizes non-small cell lung cancer cells to aggravation of ER stress. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2014-5470
Abstract 5479: Antitumor effect of KX-01, a novel Src and tubulin inhibitor, in triple negative breast cancer cells
Authors: Kim Seongyeong , Im Seock-Ah , Min Ahrum , Lee Miso , Jang Heymin , Lee Kyung-Hun , Kim Hee-Jun , Kim Tae-Yong , Han Sae-Won , Oh Do-Youn , Kim Tae-You , Yoon Young-Kwang , Hangauer David , Lau Johnson , Bang Yung-Jue 
Published: May 2015

Abstract
Background: Src kinases have been involved in cell proliferation, invasion, and metastasis and is one of the highly expressed oncogenes in breast cancer. Therefore, it could be a reasonable target for therapeutic strategy. Although several Src inhibitors, targeting the ATP binding site, were developed, none of them have shown remarkable responses as monotherapeutic agents in breast cancer clinical trials. KX-01 (KX2-391) is a novel peptidomimetic agent, and a non ATP-competitive Src inhibitor, which has potent efficacy for inhibiting both Src as well as tubulin polymerization. Its dual inhibition effects could potentially overcome the limitations of the Src inhibitors that have been evaluated previously.
Materials & Methods: We determined the anti-tumor effects of KX-01 on breast cancer cell lines using a cytotoxicity assay, cell cycle analysis, a wound healing assay and western blotting following KX-01 treatment.
Results: KX-01 effectively inhibited cell growth in most breast cancer cells including ER/PR/HER2 negative breast cancer cells. Short exposure of KX-01 down-regulated the expression level of Src phosphorylation. Phosphorylated FAK, ERK, AKT and STAT3 were also down-regulated by KX-01 treatment in MDA-MB-231, MDA-MB-468 and BT-549 cells. By wound healing assay, we confirmed migration inhibitory effect of KX-01 in BT-549 cells. Increase of G2/M cell cycle arrest was observed in dose dependent manner. In addition, mitotic catastrophes were also observed in KX-01 sensitive cell lines. Consistent with induction of mitotic catastrophe, the increased levels of aneuploidy in sensitive cell lines were examined following the treatment of KX-01.
Conclusion: Inhibition of cell growth and migration, as well as an induction of mitotic catastrophy, were observed in triple negative breast cancer cell lines treated with KX-01. Our data strongly supports utilizing KX-01 as a new therapeutic agents for treating triple negative breast cancer.
Citation Format: Seongyeong Kim, Seock-Ah Im, Ahrum Min, Miso Lee, Heymin Jang, Kyung-Hun Lee, Hee-Jun Kim, Tae-Yong Kim, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Young-Kwang Yoon, David Hangauer, Johnson Lau, Yung-Jue Bang. Antitumor effect of KX-01, a novel Src and tubulin inhibitor, in triple negative breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5479. doi:10.1158/1538-7445.AM2014-5479
Abstract 548: CEP 3/CEP 17 in the genetic diagnosis and its prognostic relevance of Kazakh esophageal cancer patients
Authors: Awut Edris 
Published: May 2015

Abstract
To investigate the clinical application value of centromere of chromosome 3 and 17 (CEP 3, CEP 17) DNA probes in Kazakh esophageal squamous cell carcinoma (ESCC) patients’ molecular pathological diagnosis and prognosis.
Forty patients with ESCC who received radical surgical treatment and 10 cases of normal specimen in control group were enrolled in this study. Touch preparations of fresh cancer and normal tissue were made and fluorescence in situ hybridization (FISH) technique were used to count the copy numbers of CEP 3 and CEP 17, abnormalities were analyzed comparing with routine pathological diagnosis.
FISH analysis revealed that abnormal copy numbers of CEP 3, CEP 17 (aneuplody) were observed in 40 cases. CEP 3 and CEP 17 polyploidy rates were 42%, 40.5% in well-differentiated, 62.9%, 46.8% in moderately differentiated, and 76.95%, 63.5% in poorly differentiated ESCC respectively. These were significantly different between poorly differentiated, moderately differentiated and well-differentiated groups (p&lt;0.05, p&lt;0.05), and the polyploidy rates were also significantly higher in the group with lymph node metastasis comparing to the group without lymph node metas-tasis (CEP 3, p=0.0001; CEP 17, p=0.012).
The CEP 3, 17 variations were shown to be correlated with the level of differentiation and lymph node metastasis in ESCC. Therefore, there DNA probes may be the predictive biological marker in the prognosis of patients with ESCC. In addition, being an objective and qualitative method, the technology of FISH can detect CEP 3, 17 variations in the genetic diagnosis of Kazakh ESCC.
Note: This abstract was not presented at the meeting.
Citation Format: Edris Awut. CEP 3/CEP 17 in the genetic diagnosis and its prognostic relevance of Kazakh esophageal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 548. doi:10.1158/1538-7445.AM2014-548
Abstract 5480: NSCLC cells with LKB1 mutation are vulnerable to energetic and oxidative stresses induced by 8-Chloroadenosine
Authors: Yang Chao , Cortez Maria Angelica , Giri Uma , Gudikote Jayanthi , Wierda William G. , Gandhi Varsha , Byers Lauren Averett , Heymach John V. 
Published: May 2015

Abstract
Background: It has been demonstrated that loss of LKB1 is associated with a higher likelihood of tumor recurrence after surgery and shorter overall survival in early stage NSCLC. We sought to determine whether NSCLC tumor cells with loss of LKB1 are preferentially sensitive or resistant to various therapeutic agents. We tested 23 NSCLC cell lines, and observed that LKB1 mutant NSCLC cells are highly resistant to standard chemotherapy as well as EGFR inhibitors. In contrast, LKB1 mutant NSCLC cells are highly sensitive to 8-Chloroadenosine (8-Cl-Ado). 8-Cl-Ado is an RNA-directed nucleoside analogue, which depletes cellular ATP and triggers apoptosis in sensitive cells. LKB1 is known to play a key role in balancing cellular energy consumption and production. Therefore, we hypothesize that LKB1 mutant NSCLC cells are vulnerable to 8-Cl-Ado induced energetic stress. Method: Cellular ATP level was determined by LC-MS and luminescent based methods. Cell proliferation was measured by Celltiter-Glo assay. IC50 values were calculated by Calcusyn. Oxidative stress was measured by CellRox assay. Result: NSCLC cell lines with LKB1 mutation were significantly more sensitive to 8-Cl-Ado than wild type cell lines (p=0.024). We transfected H460 and A549 cells (both harboring mutant LKB1) with wild-type LKB1. Re-expression of LKB1 rendered cells resistant to 8-Cl-Ado (P&lt;0.05). Knockdown LKB1 resulted in increased sensitivity to 8-Cl-Ado in Calu6 cells (p&lt;0.05). Moreover, 8-Cl-Ado treatment caused a significant decrease in cellular ATP levels in LKB1 mutant cells. However, in A549 and H460 cells overexpressing wild-type LKB1, ATP levels were not decreased. Similarly, in H661 cells (wild-type LKB1) 8-Cl-Ado treatment did not affect ATP levels, whereas when LKB1 was knocked down by shRNA 8-Cl-Ado treatment reduced intracellular ATP levels. Furthermore, 8-Cl-Ado increased ROS levels in A549 cells but not in A549 cells overexpressing wild-type LKB1. Conclusion: Our result indicates that LKB1 mutant NSCLC cells are vulnerable to energetic and oxidative stresses induced by 8-Cl-Ado. LKB1 played a protecting role in cells under 8-Cl-Ado treatment.
Citation Format: Chao Yang, Maria Angelica Cortez, Uma Giri, Jayanthi Gudikote, William G. Wierda, Varsha Gandhi, Lauren Averett Byers, John V. Heymach. NSCLC cells with LKB1 mutation are vulnerable to energetic and oxidative stresses induced by 8-Chloroadenosine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5480. doi:10.1158/1538-7445.AM2014-5480