bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-011: Arginine deprivation using ADI-PEG20 leads to regression of an ASS1-ve intracranial GBM tumor in mice and potentiates gamma irradiation of ASS1+ve GBM in vitro
Authors: Abaitua Fernando , Przystal Justyna , Hajitou Amin , Syed Nelofer 
Published: August 2015

Abstract
Patients with Gliobastoma Multiforme (GBM) have an extremely poor overall survival rate. Novel molecular targeted therapies have failed to provide further improvements in these rates and as such the standard of care for GBM patients remains unchanged, consisting of radical surgery followed by chemo and radiotherapy. In light of this, novel therapeutic approaches have to be tested in combination with current protocols for their efficacy. We have previously demonstrated the metabolic dependency of ∼30% of de novo GBM to extracellular arginine. Using ADI-PEG20 to deplete arginine, we showed a marked reduction in the proliferation of primary GBM explants that exhibited methylation in their ASS1 gene, the rate-limiting enzyme in the arginine biosynthetic pathway.
We have validated these findings in an animal model where we have demonstrated that ADI-PEG20 treatment induces a profound delay in the growth of ASS1-ve intracranial human GBM tumors in mice. In cell culture models, we show that ADI-PEG20 has comparable cell growth inhibition efficiencies as conventional chemotherapies namely temozolomide, lomustine and chloroquine. Moreover, these agents exhibited inhibitory effects on proliferation in hypoxic conditions (1% O2) representing activity in a more physiological environment. Importantly, combination with ADI-PEG20 did not reduce efficiency of these conventional drugs. Although no synergistic effects of ADI-PEG20 with these chemotherapeutic agents was observed, synergy was detected in combination with irradiation. Here, we showed the ADI-PEG20 radio-sensitized GBM cell lines to photon irradiation regardless of their ASS1 methylation status: In clonogenic assays, there was a 50% enhanced decrease in colony formation with pre-treatment of ADI-PEG20 and subsequent photon irradiation when compared to irradiation alone.
These results suggest arginine deprivation therapy as a novel therapeutic strategy for ASS1-ve GBM. Moreover, we show that when combined with irradiation, ADI-PEG20 can be used to treat GBM irrespective of their ASS1 status.
Citation Format: Fernando Abaitua, Justyna Przystal, Amin Hajitou, Nelofer Syed. Arginine deprivation using ADI-PEG20 leads to regression of an ASS1-ve intracranial GBM tumor in mice and potentiates gamma irradiation of ASS1+ve GBM in vitro. [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 LB-011. doi:10.1158/1538-7445.AM2015-LB-011
Abstract LB-015: VAMP2-NRG1 fusion gene is a novel oncogenic driver of non-small cell lung adenocarcinoma
Authors: Jung Yeonjoo , Yong Seunghui , Kim Pora , Lee Hee-Young , Jung Yeonhwa , Keum Juhee , Kim Suyeon , Lee Sanghyuk , Kim Jhingook , Kim Jaesang 
Published: August 2015

Abstract
Neuregulin 1 (NRG1) has been discovered as the tail moiety of fusion genes with several distinct partner head genes in lung cancers. These fusion genes activate ERBB2/ERBB3 receptor-mediated cell signaling and thereby function as oncogenic drivers. We have carried out whole-transcriptome sequencing of 100 non-small cell lung carcinoma (NSCLC) tumors and isolated a novel fusion gene consisting of Vesicle-Associated Membrane Protein 2 (VAMP2) and NRG1. RT-PCR and genomic DNA analysis were used to demonstrate inter-chromosomal translocation. Immunoblotting and soft agar assays were used to examine stimulating activity of the fusion gene through ERBB2/ERBB3 signaling pathway. The most highly expressed splice variant of VAMP2-NRG1 fusion gene was shown to be membrane-bound and display EGF-like domain of NRG1 extracellularly. VAMP2-NRG1 promotes anchorage-independent colony formation of H1568 lung adenocarcinoma cells. Ectopic expression of the fusion gene stimulates phosphorylation of ERBB2 and ERBB3 as well as down-stream targets, AKT and ERK, confirming activation of the signaling pathway. VAMP2-NRG1 is a novel oncogenic fusion gene representing a new addition to the list of NRG1 fusion genes which together may form an important diagnostic and clinical category of lung adenocarcinoma cases.
Citation Format: Yeonjoo Jung, Seunghui Yong, Pora Kim, Hee-Young Lee, Yeonhwa Jung, Juhee Keum, Suyeon Kim, Sanghyuk Lee, Jhingook Kim, Jaesang Kim. VAMP2-NRG1 fusion gene is a novel oncogenic driver of non-small cell lung adenocarcinoma. [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 LB-015. doi:10.1158/1538-7445.AM2015-LB-015
Abstract LB-024: Inhibition of bone morphogenetic protein (BMP) type I receptors in lung cancer cells activates the TGFβ signaling cascades which increases Id1 expression by TAK1
Authors: Langenfeld John E. , Langenfeld Elaine , Castle Monica 
Published: August 2015

Abstract
Bone morphogenetic protein (BMP) signaling increases Id1 expression while the transforming growth factor (TGF) signaling typically decreases Id1 expression. BMP antagonists decrease growth of cancer through the inhibition of Id1. Both the BMP and TGF signaling pathways activate TGF activated kinase1 (TAK1). TAK1 has been shown to phosphorylate and activate the BMP transcription factor Smad1/5. The purpose of this study was to understand the cross regulation between the BMP and TGFβ signaling pathways in lung cancer cell lines that occurs following the inhibition of BMP signaling. Antagonists targeting the BMP (DMH2, DMH1), TGFβ (SB-505124), and TAK1 ((5Z)-7-Oxozeaenol) signaling cascades were used to examine the cross regulation between these pathways.
Here, we show using siRNA and BMP antagonists targeting the type I receptors that upon inhibition of BMP signaling in lung cancer cells, the TGFβ signaling cascade is activated. SB-505124 alone increases Id1 expression in H1299 cells. However, when BMP signaling was inhibited, SB-505124 decreases Id1 expression, which is associated with a decrease expression in pTAK1. When BMP signaling is inhibited, the TGFβ constitutively active alk5 receptor activates TAK1 and increases Id1 expression, which is attenuated with (5Z)-7-Oxozeaenol. A BMP antagonist together with a TGFβ antagonist further enhanced growth suppression. This study reveals that TGFβ signaling can increase the expression of Id1 when BMP signaling is inhibited in lung cancer cells, which is mediated by TAK1. The data suggests that the inhibition of both the BMP and TGF signaling pathways enhances growth suppression of lung cancer cells that involves the downregulation of Id1.
Citation Format: John E. Langenfeld, Elaine Langenfeld, Monica Castle. Inhibition of bone morphogenetic protein (BMP) type I receptors in lung cancer cells activates the TGFβ signaling cascades which increases Id1 expression by TAK1. [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 LB-024. doi:10.1158/1538-7445.AM2015-LB-024
Abstract LB-027: Inhibition of mammalian target of rapamycin by Torin2, an ATP-competitive inhibitor, induces growth inhibition in adult T cell leukemia
Authors: Watanabe Tatsuro , Aragane Naoko , Sueoka Eisaburo 
Published: August 2015

Abstract
Adult T cell leukemia (ATL) is one of the aggressive malignant lymphomas induced by the infection of human T-cell Lymphotropic virus-1. Advanced stages of ATL patients still have a poor prognosis and novel therapeutic approaches are needed. Since mammalian target of rapamycin (mTOR) is a key molecule in cell growth and survival in a number of hematological malignancies, we here focused on mTOR signaling pathway consisting from mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). It has been already reported that inhibition of mTOR with rapamycin, a classical mTOR inhibitor, or its derivatives induces growth inhibition in ATL cells, and we found that Torin2, a second generation ATP-competitive mTOR inhibitor, has more beneficial effects than rapamycin does. Although Torin2 showed weaker growth inhibitory effect against ATL cell lines than rapamycin did at low concentrations (&lt; 10 nM), its effect exceeded at higher concentrations (&gt; 10nM) in CCK-8 assay and Trypan blue staining assay. To understand differences of mechanism of action between Torin2 and rapamycin, we first studied apoptosis and cell cycle arrest of the ATL cell line stained with annexin-FITC; Although both Torin2 and rapamycin caused G1 cell cycle arrest, a small number of ATL cells died in apoptotic manner at higher concentration of Torin2 but not of rapamycin. It is important to note that inhibition of mTOR pathway with rapamycin induced feedback activation of Akt (phosphorylation of Akt at Ser471), down stream of mTORC2, at high concentrations (&gt; 50 nM) but Torin2 inhibited phosphorylation of Akt dose-dependently. Based on these results, we think Torin2 inhibits mTORC1 and mTORC2 followed by G1 cell cycle arrest, however rapamycin inhibits only mTORC1 and it induces feedback activation of Akt at high concentration resulting in resistance to apoptotic cell death. Thus, inhibition of mTOR pathway with Torin2 is new potent therapeutic approach in the treatment of ATL.
Citation Format: Tatsuro Watanabe, Naoko Aragane, Eisaburo Sueoka. Inhibition of mammalian target of rapamycin by Torin2, an ATP-competitive inhibitor, induces growth inhibition in adult T cell leukemia. [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 LB-027. doi:10.1158/1538-7445.AM2015-LB-027
Abstract LB-030: Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs
Authors: Wong Nathalie , He Mian 
Published: August 2015

Abstract
Exosomes are increasingly recognized as important mediators of cell-cell communication in cancer progression through the horizontal transfer of RNAs and proteins to neighboring or distant cells. Hepatocellular carcinoma (HCC) is a highly malignant cancer, whose metastasis is largely influenced by the tumor microenvironment. The possible role of exosomes in the interactions between HCC tumor cell and its surrounding hepatic milieu are however largely unknown. In this study, we comprehensively characterized the exosomal RNA and proteome contents derived from three HCC cell lines (HKCI-C3, HKCI-8 and MHCC97L) and an immortalized hepatocyte line (MIHA) using Ion Torrent sequencing and mass spectrometry, respectively. RNA deep sequencing and proteomic analysis revealed exosomes derived from metastatic HCC cell lines carried a large number of pro-tumorigenic RNAs and proteins, such as MET proto-oncogene, S100 family members and the caveolins. Of interest, we found exosomes from motile HCC cell lines could significantly enhance the migratory and invasive abilities of non-motile MIHA cell. We further demonstrated that uptake of these shuttled molecules could trigger PI3K/AKT and MAPK signaling pathways in MIHA with increased secretion of active MMP-2 and MMP-9. Our study showed for the first time that HCC-derived exosomes could mobilize normal hepatocyte, which may have implication in facilitating the protrusive activity of HCC cells through liver parenchyma during the process of metastasis.
Citation Format: Nathalie Wong, Mian He. Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs. [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 LB-030. doi:10.1158/1538-7445.AM2015-LB-030
Abstract LB-031: Biochemical profiling of cancer-associated KRAS mutants: clues towards an understanding of differential clinical outcomes
Authors: Hunter John C. , Gurbani Deepak , Carrasco Martin , Manandhar Anuj , Gondi Sudershan , Westover Kenneth 
Published: August 2015

Abstract
As one of the first identified and most commonly activated oncogenes, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) has been a focus of cancer research for many decades. Despite progress in our understanding of RAS biology, significant questions remain unanswered regarding observed differences in clinical outcomes between tumors harboring different KRAS mutations. In an attempt to understand these clinical differences we characterized the pertinent biochemical properties of the most commonly observed KRAS mutants including, nucleotide exchange rate, intrinsic and GTPase activating protein (GAP)-stimulated GTP hydrolysis rate and affinity for one of the enzyme's primary downstream effectors, Raf kinase. We additionally solved high resolution crystal structures of four of these mutants and attempt to explain the observed biochemical differences between the mutants in the context of these structures. Based on the individual biochemical properties of each KRAS mutant, we propose a classification scheme to predict the propensity of the various mutants to activate Raf-kinase and respond to therapies targeting this downstream signaling pathway.
Citation Format: John C. Hunter, Deepak Gurbani, Martin Carrasco, Anuj Manandhar, Sudershan Gondi, Kenneth Westover. Biochemical profiling of cancer-associated KRAS mutants: clues towards an understanding of differential clinical outcomes. [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 LB-031. doi:10.1158/1538-7445.AM2015-LB-031
Abstract LB-032: Soluble E-cadherin as a microenvironmental factor that enhances tumor progression
Authors: Patil Pratima , Mason Robert W. , Ambrosio Julia D' , Rajasekaran Ayyappan K. 
Published: August 2015

Abstract
During malignant transformation of epithelial cells, their well-organized architecture is disrupted. A key event observed during epithelial cancer progression is down regulation of E-cadherin (E-cad), a central adherens junction protein that plays a crucial role in directing cell polarity, epithelial architecture and cell-cell adhesion. One mechanism by which tumor cells downregulate E-cad is by the proteolytic cleavage of its extracellular domain by proteases such as the matrix metalloproteinases (MMPs). This proteolytic cleavage results in the shedding of the E-cad ectodomain as an 80 kDa fragment known as soluble E-cadherin (sE-cad). Elevated levels of sE-cad are found in the serum and urine of cancer patients. In tumor cells physiological consequences include enhanced tumor cell migration and invasion, induction of MMP secretion, and increased cell signaling; all of which ultimately result in tumor progression. sE-cad also causes morphological changes in epithelial cells, including disruption of the adherens junction. However, the influence of elevated sE-cad levels on normal tissue architecture is not well understood. Specifically, the mechanism by which sE-cad in the tumor microenvironment interacts with cellular E-cad in normal epithelium is yet to be elucidated.
We used a three-dimensional (3D) cell-culture system to determine the effects of sE-cad on normal epithelial cyst morphology. In this study, we show that recombinant, purified sE-cad can induce lumen-filling in normal non-tumorigenic Madin-Darby canine kidney (MDCK) epithelial cysts. The acinar luminal filling and multiple lumen formation induced by purified sE-cad represent changes in epithelial tissue structure that are characteristic of premalignant lesions reported in human epithelial glandular tumors. We further demonstrate that co-culturing of tumor cells with epithelial MDCK cysts results in disruption of 3D epithelial architecture and filling up of the hollow lumen. Our results also show that tumor cell-induced lumen filling is trigged by sE-cad shedding, with a concomitant increase in MMP-9. Using an inhibitor of MMP-9, we provide evidence that MMP-9 is crucial for lumen filling. Together, these novel findings indicate that invasive carcinoma cells can induce structural alterations in adjacent normal epithelium, and that elevated sE-cad levels disrupt epithelial architecture and activate signaling pathways in normal epithelial cells.
Citation Format: Pratima Patil, Robert W. Mason, Julia D' Ambrosio, Ayyappan K. Rajasekaran. Soluble E-cadherin as a microenvironmental factor that enhances tumor progression. [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 LB-032. doi:10.1158/1538-7445.AM2015-LB-032
Abstract LB-042: MCPIP1 suppresses breast tumor progression by targeting anti-apoptosis pathway
Authors: Liu Jianguo , Lu Wenbao , Ning Huan , Peng Hui , Wang Qinghong , Hou Rong 
Published: August 2015

Abstract
The ability to evade apoptosis is a hallmark of cancer and also plays a significant role in cancer resistance to conventional therapy. While recent progress has broadened our understanding of the apoptosis-evasion mechanisms by cancer cells, how apoptosis resistance develops in cancer cells through posttranscriptional mechanisms, especially by the newly discovered RNA-binding protein monocyte chemotactic protein induced protein 1 (MCPIP1), remains unknown. Here, we report that MCPIP1 expression is impaired in breast tumors and breast tumor cell lines, with the severest impairment in highly metastatic tumors. Ectopic expression of MCPIP1 causes apoptosis of breast tumor cells through selectively suppression of anti-apoptotic gene transcripts, including Bcl2L1, Bcl2A1, RelB, Birc3 and Bcl3. This suppression is medicated through a physical interaction between the PIN domain of MCPIP1 and the 3′UTRs of anti-apoptotic transcripts, resulting in mRNA degradation and tumor cell apoptosis. In difference from the RNA-binding protein tristetraprolin which binds to the ARE in the 3′UTR of target genes for mRNA decay, MCPIP1 specially recognizes a stem-loop structure in the 3′UTR of anti-apoptotic genes for binding and mRNA decay. Furthermore, induction of MCPIP not only ameliorates breast tumor formation but also completely shrinks the established tumors within six days. Lung metastasis is also significantly reduced by MCPIP1 induction. The tumor suppressive effect of MCPIP1 acts through activation of apoptosis. Importantly, by analysis of the excised breast tumors of 251 patients, we found that low MCPIP1 levels in tumors are strongly associated with poor survival of patients over 13 years of follow up. Taken together, we demonstrate that MCPIP1 is a novel potent tumor suppressor which induces tumor apoptosis through tipping the balance between pro-apoptotic and anti-apoptotic genes via selectively targeting the mRNAs of anti-apoptotic genes for degradation. MCPIP1 can serve as a new therapeutic target for treatment of breast cancer and other cancers as well.
Citation Format: Jianguo Liu, Wenbao Lu, Huan Ning, Hui Peng, Qinghong Wang, Rong Hou. MCPIP1 suppresses breast tumor progression by targeting anti-apoptosis pathway. [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 LB-042. doi:10.1158/1538-7445.AM2015-LB-042
Abstract LB-045: Detection of keratin fusions in oral squamous cell carcinoma
Authors: Sheu Jim Jinn-Chyuan 
Published: August 2015

Abstract
Keratin cytoskeleton proteins form intermediate filaments in epithelial cells to regulate cell shape, mobility, membrane trafficking and cellular signaling. Although keratin-6 (K6) and -14 (K14) are highly expressed in certain squamous cell carcinomas and have been suggested as tumor markers, molecular mechanisms of how keratins contribute to cancer development still remain elusive. Here, we demonstrated novel K6-K14 chimeras in oral squamous cell carcinomas (OSCCs) by pair-ended transcriptome sequencing and subsequent validation by fluorescence in situ hybridization and junction site mapping. Two unique fusion types (type-1 and type-2) were identified with a total of 23 in-frame fusion variants verified in OSCCs. Clinical screening confirmed high detection rate of K6-K14 fusions in tumor samples: 33% for type-1 and 25% for type-2. Notably, K6-K14 fusions could be only detected in tumor lesions at late carcinoma stage, but not the ones at early stages, suggesting potential benefits of K6-K14 fusions in promoting aggressive tumors. Functional domain analyses revealed a potent role involved in EMT and metastasis.
Citation Format: Jim Jinn-Chyuan Sheu. Detection of keratin fusions in oral squamous cell carcinoma. [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 LB-045. doi:10.1158/1538-7445.AM2015-LB-045
Abstract LB-060: A phosphoproteomic comparison of BRAF(V600E) and MKK1/2 inhibition in melanoma
Authors: Stuart Scott , Ahn Natalie , Houel Stephane , Old William 
Published: August 2015

Abstract
Inhibitors of oncogenic B-RAF(V600E) and MKK1/2 have yielded remarkable responses in B-RAF(V600E)-positive melanoma patients. However, the efficacy of these inhibitors is limited by the inevitable onset of resistance. Despite the fact that these inhibitors target the same pathway, combination treatment with B-RAF(V600E) and MKK1/2 inhibitors has been shown to improve both response rates and progression-free survival in B-RAF(V600E) melanoma patients. To provide insight into the molecular nature of the combinatorial response, we used quantitative mass spectrometry to characterize the inhibitor-dependent phosphoproteome of human melanoma cells treated with the B-RAF(V600E) inhibitor PLX4032 (vemurafenib) or the MKK1/2 inhibitor AZD6244 (selumetinib). In three replicate experiments, we quantified changes at a total of 23,986 phosphosites on 4,722 proteins. This included 1,317 phosphosites that reproducibly decreased in response to at least one inhibitor. Phosphosites that responded to both inhibitors grouped into networks that included the nuclear pore complex, growth factor signaling, and transcriptional regulators. While the majority of phosphosites were responsive to both inhibitors, we identified 16 sites that decreased only in response to PLX4032, suggesting rare instances where oncogenic B-RAF signaling occurs in an MKK1/2-independent manner. Only two phosphosites were identified that appeared to be uniquely responsive to AZD6244. When cells were treated with the combination of AZD6244 and PLX4032 at subsaturating concentrations (30 nM), responses at nearly all phosphosites were additive. We conclude that AZD6244 does not substantially widen the range of phosphosites inhibited by PLX4032 and that the benefit of the drug combination is best explained by their additive effects on suppressing ERK1/2 signaling. Comparison of our results to another recent ERK1/2 phosphoproteomics study revealed a surprising degree of variability in the sensitivity of phosphosites to MKK1/2 inhibitors in human cell lines, revealing unexpected cell specificity in the molecular responses to pathway activation.
Citation Format: Scott Stuart, Natalie Ahn, Stephane Houel, William Old. A phosphoproteomic comparison of BRAF(V600E) and MKK1/2 inhibition 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 LB-060. doi:10.1158/1538-7445.AM2015-LB-060