bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2044: Down-regulation of YAP sensitizes lung cancer cells to platinum and ionizing radiation.
Authors: Cheng Haiying , Zhang Zhenfeng , Rodriguez-Barrueco Ruth , Yu Jiyang , Silva Jose M. , Cheng Simon , Perez-Soler Roman , Halmos Balazs 
Published: August 2014

Abstract
Platinum compounds are the foundation of chemotherapy regimens for non-small cell lung cancer despite poor response rates and limited response duration. In order to identify novel target genes the modulation of which could influence drug sensitivity of lung cancer cells in response to cisplatin, we performed a high-throughput RNAi screen targeting the majority of genes in the human genome. We first transfected PC9 lung cancer cells with an shRNA library containing ∼60,000 individual shRNAs, then identified depleted versus enriched shRNAs following two weeks of cisplatin treatment versus vehicle in surviving cells. Standard quality control studies suggested good correlation among triplicates. After using strict selection criteria, we selected a narrow list of highly depleted genes- genes the activity of which is expected to be required for cell survival in the face of cisplatin therapy, including YAP (Yes associated protein). YAP shRNAs were depleted 80 fold in the cisplatin screen. YAP was initially identified as a protein interacting with the non-receptor tyrosine kinase c-Yes and is considered a nuclear effector of the Hippo pathway that promotes cell growth as a transcription co-activator. To validate this promising target identified in our screen, we first confirmed that an siRNA pool targeting YAP can efficiently knockdown YAP protein expression in multiple lung cancer cell lines, then next examined the effects of YAP knockdown on drug responses. YAP knockdown indeed quite prominently improved sensitivities not only to cisplatin, but also to ionizing radiation in several cell lines. Furthermore, YAP knockdown also induces prominent apoptosis as measured by induction of PARP cleavage concurrent with platinum therapy. Our findings indicate the YAP inhibition is potentially relevant to improve sensitivities to platinum-based chemotherapy and chemoradiation in lung cancer.
Citation Format: Haiying Cheng, Zhenfeng Zhang, Ruth Rodriguez-Barrueco, Jiyang Yu, Jose M. Silva, Simon Cheng, Roman Perez-Soler, Balazs Halmos. Down-regulation of YAP sensitizes lung cancer cells to platinum and ionizing radiation. [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 2044. doi:10.1158/1538-7445.AM2013-2044
Abstract 2052: WNT/beta-catenin signaling inhibitors improve the anti-proliferative effect of sorafenib against hepatocellular carcinoma (HCC) cells.
Authors: Lin Hsiao-Hui , Feng Wen-Chi , Lu Li-Chun , Shao Yu-Yun , Cheng Ann-Lii , Hsu Chih-Hung 
Published: August 2014

Abstract
[Background] Sorafenib, a multikinase inhibitor targeting Raf kinase and vascular endothelial growth factor receptor, is currently the only indicated therapy for patients with advanced hepatocellular carcinoma (HCC). The aberrant activation of WNT/β-catenin signaling pathway, which is associated with the carcinogenetic process of HCC, has been shown to mediate the resistance to various types of anti-cancer therapy. We hypothesized that inhibition of WNT/β-catenin signaling pathway might improve the anti-tumor effect of sorafenib in HCC.
[Materials and Methods] Huh7, HepG2, PLC5, and Hep3B HCC cells were treated with sorafenib with or without inhibitors of WNT/β-catenin pathway, and evaluated for viability in vitro. WNT/β-catenin signaling inhibitors included ICG-001 which down-regulates β-catenin/TCF signaling by specifically binding to cyclic AMP response element-binding protein, and XAV939 which targets tankyrases and facilitates degradation of β-catenin.
[Results] Sorafenib induced an anti-proliferative effect in HCC cells, with IC50s of 3.5±0.3 μM, 3.7±0.4 μM, 7.7±0.8 μM and 14±0.3 μM for HepG2, Huh7, PLC5, and Hep3B cells, respectively. Upon treated with 10 μM sorafenib for 24 hours, the total cellular amounts of β-catenin were significantly decreased in HepG2 and Huh7 cells, moderately decreased in PLC5 cells, and unchanged in Hep3B cells. In all HCC cells, XAV939 or ICG-001 enhanced the anti-proliferative effect of sorafenib dose-dependently. The median effect analysis showed a synergistic anti-proliferative effect for the combination of ICG-001 plus sorafenib in all HCC cells.
[Conclusion] Inhibitors of WNT/β- catenin signaling pathway in combination with sorafenib resulted in an improved anti-tumor effect against HCC in vitro. (The study was supported by the grant NSC 100-2325-B-002-043 from National Science Council of Taiwan)
Citation Format: Hsiao-Hui Lin, Wen-Chi Feng, Li-Chun Lu, Yu-Yun Shao, Ann-Lii Cheng, Chih-Hung Hsu. WNT/beta-catenin signaling inhibitors improve the anti-proliferative effect of sorafenib against hepatocellular carcinoma (HCC) 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 2052. doi:10.1158/1538-7445.AM2013-2052
Abstract 2060: Metronomic chemotherapy (MCT): comparison of the efficacy of two combinations of drugs for the treatment of murine mammary adenocarcinomas.
Authors: Rico María J. , Mainetti Leandro E. , Perroud Herman A. , Rozados Viviana R. , Scharovsky O. Graciela 
Published: August 2014

Abstract
Metronomic chemotherapy (MCT) refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. We have developed two combined MCT schemes for the treatment of mammary tumors: A) cyclophosphamide (Cy) 30 mg/kg/day p.o. + celecoxib (Cel) 30 mg/kg p.o. 5 times/week, and B) Cy 20 mg/kg/day p.o. + doxorubicin (Dox) 0.5 mg/kg, 3 times/week i.p. They were tested in two experimental models of mammary adenocarcinomas: I) M-406 and II) M-234p syngeneic with inbred CBi and BALB/c mice, respectively. Our present aim was to compare efficacy and toxicity of MCT combined A and B treatments in both tumor-models. There were analyzed antitumor and antimetastatic effects, survival and toxicity. The % of reduction of tumor volume of animals in the treated group with respect to control group without treatment [median (range): AI: 77.9 (50.9-89.9), AII: 84.4 (30-99.4), BI: 95.6 (57-99.6), BII: 75.5 (62.5-96.8)] didn't differ between treatments or between tumor-models (non parametric ANOVA). The % of reduction of lung metastatic burden [AI: 99.8 (97.1-99.2) AII: 99.7 (98.7-100), BI: 90.6 (35.9-96.6), BII: 90 (48.4-99.3)] was significantly different among all the groups (P&lt;0.01); Dunn's post-test showed differences in AII vs BII (P&lt;0.05). The analysis of survival showed higher values in treated groups, being the % of survival increase with respect to controls [AI: 56.5 (4.3-56.5) AII: 77.6 (5.3-84.2), BI: 110.9 (60-308.2), BII: 36.1 (12.4-113)] did not reach statistical significance (P=0.054). The treatments toxicity, evaluated by evolution of body weight and total leucocytes count, was similar in both tumor-models and treatments. The antitumor therapeutic efficacy was comparable in both MCT schemes and so was the toxicity generated by them. The combination Cy + Cel was superior than Cy + Dox related to antimetastatic power, suggesting its potential use at the adjuvant setting. That observation, together with the advantage that represents the oral administration of the Cy + Cel drug combination, thus leading to a better quality of life for tumor bearers, points at its election for the treatment of mammary tumors with metronomic chemotherapy.
Citation Format: María J. Rico, Leandro E. Mainetti, Herman A. Perroud, Viviana R. Rozados, O. Graciela Scharovsky. Metronomic chemotherapy (MCT): comparison of the efficacy of two combinations of drugs for the treatment of murine mammary adenocarcinomas. [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 2060. doi:10.1158/1538-7445.AM2013-2060
Abstract 2068: Combination erlotinib and cisplatin causes decrease angiogenesis in lung adenocarcinoma.
Authors: Lee Jasmine G. , Wu Reen 
Published: August 2014

Abstract
Introduction: Platinum based agents such as cisplatin have been traditionally used to for the treatment of lung cancer, and tyrosine kinase inhibitors such as erlotinib are being used more readily. Combinations of anti-cancer agents are becoming more popular due to the anticipation that combination treatment is more effective than individual drug treatments. In this study, we evaluate the anti-cancer effects of combination erlotinib and cisplatin in in vitro cell lines and in in vivo mice models. In addition, as studies of cisplatin and erlotinib in other cancer types show potential to inhibit angiogenesis, we examine whether these agents are able to target angiogenesis in lung adenocarcinoma.
Method: Three individual lung adenocarcinoma cell lines (PC9, A549, and H292) were utilized. Each cell line had four treatment groups: control, erlotinib only, cisplatin only, and combination erlotinib and cisplatin. Alamar Blue Assay was utilized to evaluate for in vitro cell death following two day treatments. PC9 cells were injected into the left flank of nude mice for in vivo experiments. Erlotinib and/or cisplatin treatments were injected directly into the tumor and tumor measurements were made every 2 days for a total of 14 days. Western blot analysis of VEGFR, p-VEGFR, and CD31was performed for both in vitro and in vivo samples. Hematoxylin and eosin (H&E) staining and 3,3′-Diaminobenzidine (DAB) staining for CD31 were done on tumor samples.
Results: Combination treatment in EGFR mutated PC9 cells led to significantly higher cell death compared to other treatment groups (P&lt;0.0001); the effect was synergistic. In EGFR wild type A549 and H292 cell lines there were no significant differences. Similar to results from cell cultures, in vivo studies of combination treatment showed significant inhibition of tumor growth compared to other treatment groups (p=0.001). On western blot analysis, there were significantly lower levels of p-VEGFR (p&lt;0.0001) and CD31 (p=0.0291) in the combination group compared to all other groups. H&E staining shows significantly lower density of blood vessel and DAB staining of CD31in the combination group compared to other groups.
Conclusions: Combination low dose erlotinib and cisplatin is able to induce synergistic cell death. This effect, however, may be specific to EGFR mutated lung adenocarcinoma. Combination treatment also demonstrated the ability to inhibit tumor growth in mice. The inhibition of tumor growth may be secondary to inhibition of angiogenesis.
Citation Format: Jasmine G. Lee, Reen Wu. Combination erlotinib and cisplatin causes decrease angiogenesis in lung adenocarcinoma. [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 2068. doi:10.1158/1538-7445.AM2013-2068
Abstract 2073: The parp inhibitor olaparib (AZD2281) greatly enances the effect of temozolomide in soft tissue sarcoma cell lines.
Authors: Musi Elgilda , Ambrosini Grazia , Schwartz Gary K. 
Published: August 2014

Abstract
Sarcomas are heterogeneous mesenchymal neoplasms which have very limited treatment options. Chemotherapies for advanced sarcoma include DNA damaging agents such as doxorubicin, dacarbazine and gemcitabine with very low response rates. We elected to study the effects of olaparib (AZD2281), a novel, potent orally active PARP inhibitor in combination with standard chemotherapy Temozolomide (TMZ) in various sarcoma subtypes. We examined the effects of olaparib and TMZ in a panel of 7 sarcoma cell lines including leiomyosarcoma (SK-LMS, SK-UT1, SK-UT1b), liposarcoma (LS141, DDLS) and malignant peripheral nerve sheath tumors (MPNST, ST8814). In vitro results have shown inhibition of cell viability with combination treatment in all cell lines at concentrations of 300uM TMZ and 1 uM olaparib. After 48 hrs of drug treatment, we also examined biochemical effects showing PAR inhibition, p53 induction and γH2AX increase, indicative of DNA damage. Flow cytometric analysis of each cell line indicated G2/M cell cycle arrest with combination treatment. These observations correlated with enhanced apoptosis as measured by biochemical PARP cleavage and DNA content (sub-G1 population). Taking these observations and results, there is strong evidence to support combining standard chemotherapy TMZ with the PARP inhibitor olaparib in various sarcoma subtypes.
Citation Format: Elgilda Musi, Grazia Ambrosini, Gary K. Schwartz. The parp inhibitor olaparib (AZD2281) greatly enances the effect of temozolomide in soft tissue sarcoma cell lines. [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 2073. doi:10.1158/1538-7445.AM2013-2073
Abstract 2077: Downregulation of miR-21 induces differentiation of chemo-resistant colon cancer cells and enhances susceptibility to therapeutic regimens.
Authors: Yu Yingjie , Sarkar Fazlul H. , Majumdar Adhip P.N. 
Published: August 2014

Abstract
MicroRNAs (miRNAs) are endogenous posttranscriptional modulators that negatively control the expression of their target genes and play an important role in the development and progression of colorectal carcinoma. In particular, microRNA-21 (miR-21), whose expression is greatly increased in chemotherapy-resistant (CR) colon cancer cells that are enriched in undifferentiated cancer stem/stem-like cells (CSCs/CSLCs). We hypothesize that miR-21 plays a critical role in regulating differentiation of colon cancer (CR cells). Indeed, we observed that downregulation of miR-21 in CR colon cancer HCT-116 cells by anti-sense-miR-21 induced differentiation, as evidenced by marked increases in CK-20 (cytokeratin-20) expression and alkaline phosphatase activity. These changes were accompanied by a significant reduction in the expression of colon CSC/CSLCs marker CD44, colonospheres formation and TCF/LEF activity and increased expression of the pro-apoptotic gene PDCD4. Induction of differentiation greatly increased the sensitivity of CR cells to the growth inhibitory effects of all three regimens tested: 5- FU+ Oxaliplatin (FUOX), difluorinated curcumin (CDF), an analog of curcumin and the combination of CDF and FUOX. However, the magnitude of inhibition of growth by either CDF (75%) alone or CDF + FUOX (80%) was much higher than that observed with FUOX (40%). Growth inhibition by CDF and CDF + FUOX in differentiating CR colon cancer cells was associated with a 98-99% reduction in the expression of CD44 and EGFR. The current observation suggest that CDF as well as CDF + FUOX are highly effective in inhibiting growth and reducing colon CSCs/CSLCs in anti-miR-21-induced differentiating CR colon cancer cells, which supports our contention that differentiating cells become susceptible to conventional and non-conventional therapeutic regimen.
Citation Format: Yingjie Yu, Fazlul H. Sarkar, Adhip P.N. Majumdar. Downregulation of miR-21 induces differentiation of chemo-resistant colon cancer cells and enhances susceptibility to therapeutic regimens. [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 2077. doi:10.1158/1538-7445.AM2013-2077
Abstract 2079: Antitumoral activity of INC280 against adult glioblastoma brain tumors xenografts.
Authors: Keir Stephen T. , Roskoski Martin A. , Wagner Sabrina , Tiedt Ralph , Bigner Darell D. , Friedman Henry S. 
Published: August 2014

Abstract
INTRODUCTION: INC280 is an oral, highly selective c-Met receptor tyrosine kinase inhibitor. The hepatocyte growth factor (HGF)-c-Met pathway is one of the most frequently dysregulated pathways in human cancers. Aberrant HGF-c-Met signaling has been documented in a wide range of human malignancies. The c-Met pathway can be activated by abnormal HGF and c-Met expression levels, c-Met activating mutations and gene amplifications. At this time, INC280 is in development for the treatment of solid tumors with activation of the c-Met pathway. As a part of this study, we looked at the antitumoral activity of INC280 in adult glioblastoma (GBM) brain tumor xenografts with elevated levels of Met or HGF expression.
METHODS: Met expression and copy number was determined by ELISA and qPCR, HGF mRNA by RT-qPCR. Adult GBM tumor xenografts were grown subcutaneously in athymic BALB/c mice. After tumor size reached 200-500 mm3 subcutaneously, groups of 10 mice were randomly treated with either drug vehicle/control or INC280 (10mg/kg BID) PO for 30 days. Tumor responses for subcutaneous xenografts were assessed by tumor growth delay and regression.
RESULTS: Based on activation of the c-Met pathway, the following two xenograft lines were selected for treatment with INC280: D-09-0337 MG and D-09-0477 MG. As a single agent, INC280 demonstrated statistically significant (p&lt;0.001) growth delays of 40.23 and 30.13 days in D-09-0337 MG and D-09-0477 MG, respectively. In addition, when treated with INC280, tumors implanted with D-09-0337 MG (10 out of 10) or D-09-0477 MG (4 out of 10) regressed.
CONCLUSION: Our results demonstrate the therapeutic efficacy of the inhibition of a c-Met receptor tyrosine kinase in adult brain tumor xenografts with activation of the c-Met pathway. These results warrant further exploration of INC280 in clinical trials for the treatment of adult brain tumor patients with dysregulated proto-oncogene c-Met and its ligand HGF.
Citation Format: Stephen T. Keir, Martin A. Roskoski, Sabrina Wagner, Ralph Tiedt, Darell D. Bigner, Henry S. Friedman. Antitumoral activity of INC280 against adult glioblastoma brain tumors xenografts. [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 2079. doi:10.1158/1538-7445.AM2013-2079
Abstract 2096: Gefitinib analogue V1801 induces apoptosis of T790M EGFR-harboring lung cancer cells by up-regulation of the BH-3 only protein Noxa .
Authors: Zhang Bo , Yao Zhujun , Zhou Guangbiao 
Published: August 2014

Abstract
Treatment of non-small cell lung cancer (NSCLC) with drugs targeting the epidermal growth factor receptor (EGFR), e.g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategies to overcome this resistance are therefore an urgent need. In this study, we synthesized a dozen of novel gefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-romo-5-(trifluoromethyl)phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)uinazolin-4-amine (hereafter, V1801), triggered apoptosis of the NSCLC cells and overcame gefitinib-resistance in mice inoculated with NCI-H1975 cells. Though V1801 only moderately inhibited EGFR kinase activity, it markedly induced the expression of the BH3-only protein Noxa, and Noxa silencing significantly reduced V1801-induced apoptosis of NCI-H1975 cells. It is showed that V1801 interfered with the expression of the transcription factor c-Myc and the extracellular signal regulated kinase (Erk) pathway. V1801 in combination with proteasome inhibitor bortezomib exerted enhanced cytotoxicity in NCI-H1975 cells possibly due to potentiated induction of Noxa expression. These data indicate that gefinitib analogues with weak EGFR inhibitory activity may overcome drug-resistance via activation of BH-3 only pro-apoptotic proteins, and V1801 may have therapeutic potentials for NSCLC.
Citation Format: Bo Zhang, Zhujun Yao, Guangbiao Zhou. Gefitinib analogue V1801 induces apoptosis of T790M EGFR-harboring lung cancer cells by up-regulation of the BH-3 only protein Noxa . [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 2096. doi:10.1158/1538-7445.AM2013-2096
Abstract 2099: Novel inhibitors of NFkB inducing kinase (NIK) are cytotoxic for myeloma cell lines with NIK-dependent activation of NFkB.
Authors: Demchenko Yulia N. , Kuehl Walter Michael 
Published: August 2014

Abstract
NFkB activity is critical for survival and proliferation of normal lymphoid cells and many kinds of B-cell tumors, including multiple myeloma (MM). NFkB activating mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NFkB. Mutations that activate NFkB-inducing kinase (NIK) protein are the most prevalent among the many kinds of NFkB mutations in MM tumors. NIK is the main activating kinase of the alternative NFkB pathway, although over-expression of NIK also can activate the classical pathway. Three Amgen compounds (two NIK inhibitors and an isomeric control) were tested with human myeloma cell lines. These specific NIK inhibitors are selectively cytotoxic for cells with NIK-dependent activation of NFkB. The combination of NIK-inhibitors with IKKβ-inhibitors or dexamethasone show a synergistic effect that might more efficiently target some MM tumors.
Citation Format: Yulia N. Demchenko, Walter Michael Kuehl. Novel inhibitors of NFkB inducing kinase (NIK) are cytotoxic for myeloma cell lines with NIK-dependent activation of NFkB. [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 2099. doi:10.1158/1538-7445.AM2013-2099
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.