bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1598: Grainyhead-like 2 (GRHL2) regulates the expression of forkhead box transcription factor M1 (FoxM1) in human oral cancer cells and determines tumorigenicity
Authors: Chen Wei , Yi Jin-Kyu , Shin Ki-Hyuk , Kim Reuben , Mehrazarin Shebli , Park No-Hee , Kang Mo K. 
Published: May 2015

Abstract
GRHL2 is a proto-oncogene that regulates epithelial proliferation and differentiation through transcriptional regulation of large number of target genes. The current study was performed to determine its role in oral carcinogenesis through regulation of forkhead box 1 (FoxM1), which is a known oncogene for many solid tumors. GRHL2 expression was highly elevated in oral squamous cell carcinoma (OSCC) tissues compared with normal oral epithelium (NHOM), and its protein expression is localized in the proliferative cells at the outer border of invasive islands of OSCC. In cultured OSCCs, GRHL2 and FoxM1 levels were both highly upregulated compared with normal human oral keratinocytes (NHOK), supporting their roles in oral carcinogenesis. When GRHL2 was knocked down in SCC4 cells by RNA interference, the cells have lost their proliferative capacity and colony formation when plated at low density. GRHL2 knockdown also resulted in marked loss of tumor spheroid formation, which is hallmark of cancer self-renewal. GRHL2 knockdown also led to loss of tumorigenic ability of cells upon xenograft transplantation in immunocompromised mice. GRHL2 appeared to determine the epithelial phenotype in OSCC cells. GRHL2 knockdown led to loss of E-cadherin and miR-200 family genes, which are epithelial markers. These data indicate that GRHL2 is required to maintain the transformed phenotype in OSCC. We also noted that GRHL2 knockdown led to drastic loss of FoxM1 expression, suggesting that GRHL2 may regulate FoxM1. To test this possibility, we performed in vivo binding assay by chromatin immunoprecipitation (ChIP), which showed GRHL2 binding at the proximal promoter of FoxM1. Luciferase reporter plasmid under FoxM1 promoter showed that GRHL2 directly regulates the gene promoter activity. FoxM1 knockdown resulted in loss of OSCC proliferation and tumor spheroid formation, while its overexpression conferred transformed phenotype in non-tumorigenic human oral keratinocytes (HOKs). Therefore, our data indicate that GRHL2 is required for the maintenance of transformed phenotype and that it plays a role in oral carcinogenesis through regulation of FoxM1. This study was supported in part by the grants from NIDCR/NIH (DE18295 and DE18959) and Jack Weichman Endowed Fund.
Note: This abstract was not presented at the meeting.
Citation Format: Wei Chen, Jin-Kyu Yi, Ki-Hyuk Shin, Reuben Kim, Shebli Mehrazarin, No-Hee Park, Mo K. Kang. Grainyhead-like 2 (GRHL2) regulates the expression of forkhead box transcription factor M1 (FoxM1) in human oral cancer cells and determines tumorigenicity. [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 1598. doi:10.1158/1538-7445.AM2014-1598
Abstract 1606: Global mapping of tyrosine kinase signalling in breast cancer by combined use of RNAi and SILAC quantitative proteomics
Authors: Zhang Hua , Stebbing Justin , Xu Yichen , Giamas Georgios 
Published: May 2015

Abstract
Dysregulation of protein tyrosine kinases (TKs) signalling can contribute to tumorigenesis. However, less than half of the 90 TKs described so far have been thoroughly studied and even in these cases a global functional analysis is still lacking. A combined use of RNA interference (RNAi) and stable isotope labelling by amino acids in cell culture (SILAC) was applied in breast cancer MCF7 cells. After knocking down individually each TK, a proteomic map consisting of ∼3,000 regulated proteins per TK was acquired.
Quantitative and statistical analyses resulted in the clustering of the significantly modulated proteins/TK into various biological and molecular categories.
Further use of mathematical modelling tools resulted in a new classification and phylogeny of the TK family members depending on connections between their regulated proteomes. This taxonomy has little overall correlation when compared to their catalytic domain sequence grouping. These data suggest that despite the primary structure homology of kinases, their regulated proteomic landscapes can significantly vary and may depend on other factors, notably their dynamic interactions with other proteins.
Our results and bionformatic analyses will be presented.
Citation Format: Hua Zhang, Justin Stebbing, Yichen Xu, Georgios Giamas. Global mapping of tyrosine kinase signalling in breast cancer by combined use of RNAi and SILAC quantitative proteomics. [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 1606. doi:10.1158/1538-7445.AM2014-1606
Abstract 1607: Quantitative membrane proteome profiling to discover therapeutic targets for adult T-cell leukemia (ATL)
Authors: Ishihara Makoto , Araya Natsumi , Sato Tomoo , Fujii Risa , Tatsuguchi Ayako , Saichi Naomi , Nakagawa Hidewaki , Yamano Yoshihisa , Ueda Koji 
Published: May 2015

Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is one of retroviruses known as the causative agent of adult T-cell leukemia (ATL), which is infected within 20 million people in the world. ATL develops at the prevalence of only 5% among HTLV-1-infected individuals after a long latency period over 30 years. However, the outcomes of conventional treatment for ATL are not satisfactory, exhibiting overall 5-year survival rate of 20%. To discover novel therapeutic targets for ATL, we performed label-free quantitative membrane proteome analysis for CD4+ T-cell subpopulation in which HTLV-1 infected cells are enriched. Tryptic digests of CD4+ T-cells were prepared from 14 normal donors (ND), 21 asymptomatic carriers (AC), and 13 ATL patients. To focus on the membrane derived peptides, glycosylated peptides were enriched by lectin column chromatography (Mol Cell Proteomics. 2010,9(9),1819) since most of membrane proteins are glycosylated. The eluates were analyzed by LC/MS/MS and 8,658 N-glycosylated peptides derived from 1,134 N-glycosylated proteins were identified.
The therapeutic targets were subsequently extracted by a couple of criteria as follows. The all-or-nothing analysis explored peptides detected in none or 1 case of ND+AC group, resulting in identification of 31 peptides derived from 19 proteins. Additionally Welch's t-test (ATL vs. ND+AC) identified 33 peptides derived from 14 proteins (p &lt; 0.05 and fold change &gt; 2.0).
The identified therapeutic target molecules above included cell adhesion molecule 1 (CADM1 or TSLC1) which overexpresses in ATL cells and induces organ infiltration of tumor cells. Programmed cell death 1 ligand 1 (PD1L1) was also found in our therapeutic target list, which was known to be up-regulated in ATL cells and involved in induction of immune tolerance. These facts strongly emphasize the credibility of our quantitative profiling results. We would like to show the results of functional inhibitory experiments for novel therapeutic targets and discuss the uncovered molecular mechanisms of ATL progression.
Note: This abstract was not presented at the meeting.
Citation Format: Makoto Ishihara, Natsumi Araya, Tomoo Sato, Risa Fujii, Ayako Tatsuguchi, Naomi Saichi, Hidewaki Nakagawa, Yoshihisa Yamano, Koji Ueda. Quantitative membrane proteome profiling to discover therapeutic targets for adult T-cell leukemia (ATL). [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 1607. doi:10.1158/1538-7445.AM2014-1607
Abstract 1608: Profiling c-Met and EGFR kinase inhibitor resistance pathways in non-small lung cancer cells
Authors: Bomgarden Ryan D. , Jacobs Ryan , Fong Jason , Moravec David , Botting Gregory M. , Blank Michael , Viner Rosa I. , Rogers John C. , Puri Neelu 
Published: May 2015

Abstract
Tyrosine kinase inhibitors (TKIs) against c-MET and EGFR have positive therapeutic effects in a subset of Non-Small Cell Lung Cancer (NSCLC) patients; however, their clinical efficacies are limited due to the development of TKI resistance. To determine mechanisms of TKI resistance, two NSCLC model cell lines H2170 and H358 were made resistant to the c-Met/EGFR TKIs SU11274, erlotinib or a combination of both by exposing the cells to progressively increasing concentrations of inhibitor. Initial characterization of these cell lines using phospho-specific antibodies showed that phospho-c-Met was found to be downregulated 4- and 1.5- fold in SU11274-resistant (SR) H2170 and SR H358 cells, respectively. Phospho-EGFR was found to be constitutively autophosphorylated (upregulated 19-fold) in erlotinib-resistant (ER) H2170 cells, but downregulated 6-fold in ER H358 cells. Interestingly, c-Met/EGFR downstream signaling proteins p-mTOR, p-p70S6K and p-ERK were found to be 2-4-fold upregulated, 2-fold upregulated and 2-5-fold upregulated, respectively, in ER H2170 and H358 cells. Phospho-p70S6K was also found to be upregulated 20-fold in SR H2170 cells. These results indicate that alternative signaling pathways may confer TKI resistance in these cell lines. To identify which signaling pathways may be responsible for TKI resistance, H358 parental and resistant cell lines were analyzed by mass spectrometry (MS). Differences in protein expression in cell lines treated with and without EGF and/or erlotinib were measured using higher multiplexing Thermo Scientific™ Tandem Mass Tag™ (TMT™) reagents. More than 1500 protein groups were identified and quantified using a Thermo Scientific™ Orbitrap™ Fusion™ platform with HCD-MS2 and MS3 fragmentation methods. Protein expression in ER H358 cells showed a marked increase in expression of DNA replication proteins, transcription factors, apoptosis inhibitors and some Ras-associated signal transduction pathways. To further investigate the mechanism of TKI resistance, phospho-peptide enrichment was also used in combination with TMT quantitation to profile changes in protein phosphorylation state. Overall, the combination of phospho-peptide enrichment coupled with higher multiplexing TMT and high resolution MS analysis enabled deeper global profiling of TKI resistance signaling pathways compared to previous studies without enrichment.
Citation Format: Ryan D. Bomgarden, Ryan Jacobs, Jason Fong, David Moravec, Gregory M. Botting, Michael Blank, Rosa I. Viner, John C. Rogers, Neelu Puri. Profiling c-Met and EGFR kinase inhibitor resistance pathways in non-small lung 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 1608. doi:10.1158/1538-7445.AM2014-1608
Abstract 1609: Proline-directed kinase signaling in human hepatocellular carcinomas developed on non-fibrotic liver
Authors: Taouji Saïd , Leong Kristen , Beausang Lee A. , Arma Daniela , Moreau Violaine , Balabaud Charles , Bioulac-Sage Paulette , Zucman-Rossi Jessica , Latterich Martin , Rosenbaum Jean , Chevet Eric 
Published: May 2015

Abstract
Ten to 40% hepatocellular carcinoma (HCC) arise on non-cirrhotic liver, including 5% on non-fibrotic liver (nfHCC). These tumors provide an interesting model for the analysis of the hepatocarcinogenesis pathways without the confounding factors associated with cirrhosis. Carcinogenesis has been often associated with the deregulation of phosphorylation-dependent signaling pathways. Quantitative phosphoproteomics recently allowed us to unravel the specific activation of proline-directed kinases (PDK) in nfHCC. Our aim was then to use medium throughput analytical tools (Alphascreen® and AMMP®) to evaluate the activation status of PDK dependent signaling pathways in a series of nfHCC samples. We have used a phosphoproteomics set comprising surgical samples from nfHCC (METAVIR F0 or F1) and samples of histologically normal livers. Proteins were extracted and analyzed for the activation status of select signaling pathways such as MAPK using both Alphascreen® and AMMP® technologies. Because MAPK are prototypic PDKs and are deregulated in many cancers, we analyzed their activation in a series of 25 nfHCC as compared to 6 non-tumor samples and found an overall increased activity in nfHCC samples. Moreover the phosphorylation status of Calnexin, a MAPK substrate found in the phosphoproteomics analysis was monitored and compared in nfHCC samples. In conclusion, we have identified phosphopeptide signatures in human samples of nfHCC that led to the identification of a deregulated PDK-dependent network in those tumors. The elucidation of the functional causes and consequences of such deregulation is ongoing.
Citation Format: Saïd Taouji, Kristen Leong, Lee A. Beausang, Daniela Arma, Violaine Moreau, Charles Balabaud, Paulette Bioulac-Sage, Jessica Zucman-Rossi, Martin Latterich, Jean Rosenbaum, Eric Chevet. Proline-directed kinase signaling in human hepatocellular carcinomas developed on non-fibrotic liver. [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 1609. doi:10.1158/1538-7445.AM2014-1609
Abstract 161: Activation of mTOR pathway in myeloid-derived suppressor cells with lysosomal acid lipase deficiency stimulates cancer cell proliferation and metastasis
Authors: Zhao Ting , Du Hong , Ding Xinchun , Walls Katlin , Yan Cong 
Published: May 2015

Abstract
Inflammation plays crucial roles at all stages of tumor development, from tumor initiation to metastatic progression, during which myeloid-derived suppressor cells (MDSCs) are an important participant. Although MDSCs are known to suppress immune surveillance, their roles in directly stimulating cancer cell proliferation and metastasis currently remains unclear. Lysosomal acid lipase (LAL) deficiency causes systemic expansion and infiltration of MDSCs in multiple organs and subsequent inflammation. In the LAL-deficient (lal-/-) mouse model, we found that melanoma metastasized massively in allogeneic lal-/- mice, which was suppressed in allogeneic lal+/+ mice due to immune rejection. Therefore, we hypothesized that MDSCs with LAL deficiency directly stimulate cancer cell proliferation and metastasis. Bone marrow-derived MDSCs from lal-/- mice directly stimulated B16 melanoma cell proliferation in vitro by co-culture analysis and in vivo by co-implantation in the Matrigel plugs. These tumor cell-stimulatory effects were diminished when myeloid-specific human LAL (hLAL) was expressed in myeloid cells in lal-/- mice. In addition, lal-/- MDSCs facilitated B16 melanoma cell metastasis in the lungs of recipient lal+/+ mice via tail vein injection. Furthermore, the mammalian target of rapamycin (mTOR) and its downstream gene products were significantly up-regulated in lal-/- MDSCs. Knockdown of mTOR in lal-/- MDSCs suppressed their stimulation on B16 melanoma cell proliferation, growth and metastasis, indicating the tumor-promoting function of lal-/- MDSCs is mediated, at least in part, through over-activation of the mTOR pathway. Finally, lal-/- MDSCs stimulated proliferation and growth of Lewis lung carcinoma (LLC), and transgenic mouse prostate cancer (TRAMP-C2) cells, and these effects were impaired after mTOR inhibition. Our results indicate that LAL plays a critical role in regulating MDSCs ability to directly stimulate cancer cell proliferation, and overcome immune rejection of cancer metastasis in allogeneic mice through modulation of the mTOR pathway, which provides a mechanistic basis for targeting MDSCs to reduce the risk of cancer metastasis. Therefore, MDSCs possess dual functions to facilitate cancer metastasis: suppress immune surveillance, and stimulate cancer cell proliferation and growth.
Citation Format: Ting Zhao, Hong Du, Xinchun Ding, Katlin Walls, Cong Yan. Activation of mTOR pathway in myeloid-derived suppressor cells with lysosomal acid lipase deficiency stimulates cancer cell proliferation and metastasis. [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 161. doi:10.1158/1538-7445.AM2014-161
Abstract 1622: Design and preclinical evaluation of single agents with tubulin and multiple receptor tyrosine kinase inhibition
Authors: Gangjee Aleem , Pavana Roheeth K. , Ihnat Michael , Hamel Ernest 
Published: May 2015

Abstract
Vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors lead to the reduction of angiogenesis but are cytostatic, not tumoricidal. These inhibitors have shown significant promise in the clinic when used in combination with cytotoxic agents, and several clinical trials with such combinations are in progress. We have previously reported preclinical studies on AG119, a compound that inhibits both VEGFR2 and tubulin, thereby affording antiangiogenic and cytotoxic effects in a single agent. Structural modifications of AG119 afforded AG321, a unique compound with four separate mechanisms of action in a single agent. AG321 inhibits platelet derived growth factor receptor-β (PDGFRβ) and epidermal growth factor receptor (EGFR), in addition to VEGFR2 and tubulin. AG321 is a colchicine site binding agent with potency comparable with that of combretastatin A-4 against bovine brain tubulin assembly. AG321 has potency comparable with that of erlotinib in tumor cell lines overexpressing EGFR and potency comparable with those of erlotinib, PD153035 and DMBI and in cell lines overexpressing PDGFRβ. It also has potency comparable with those of sunitinib and semaxinib in cell lines overexpressing VEGFR2. AG321 reduced tumor size (control: 15.7 ± 2.9 mm3/day; AG321 treated: 5.7 ± 0.7 mm3/day; p &lt; 0.01 by one way ANOVA with Tukey multiple comparisons post test) and the number of lung metastases in the 4T1 triple negative mouse breast cancer allograft model and was superior to docetaxel, without overt systemic toxicity. A range of potential therapies that target EGFR are currently in development or in clinical trials for the treatment of glioblastoma. Targeting both VEGFR2 and PDGFRβ, which are two key mediators of tumor angiogenesis, increases the antiangiogenic effect even in the often intractable late stage of solid tumors. Hence, AG321, a multiple receptor tyrosine kinase (RTK) inhibitor which may also be effective against EGFR-amplified glioblastoma [AG119 reduced tumor size and vascularity in vivo in the U251 glioma model]. In summary, AG321 with antiangiogenic effects via multiple RTK inhibition and cytotoxic effects via tubulin inhibition in a single entity may delay or prevent tumor cell resistance, circumvent pharmacokinetic problems that can occur with multiple agents, avoid drug-drug interactions, be used at lower doses to alleviate toxicity and be and have reduced toxicity.
Citation Format: Aleem Gangjee, Roheeth K. Pavana, Michael Ihnat, Ernest Hamel. Design and preclinical evaluation of single agents with tubulin and multiple receptor tyrosine kinase 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 1622. doi:10.1158/1538-7445.AM2014-1622
Abstract 1627: The novel camptothecin analog and antiapoptotic protein inhibitor FL118 appears to be a great backbone platform for development of personalized anticancer drugs
Authors: Li Fengzhi , Ling Xiang , Westover David , Liu Xiaojun , Jin Chunyang , Wani Mansukh 
Published: May 2015

Abstract
We recently characterized a novel camptothecin analog FL118. Interestingly, different from the two clinically used camptothecin analogs irinotecan and topotecan, which are topoisomerase 1 (Top1) inhibitors, FL118 appears to be a poor Top1 inhibitor at its therapeutic dose range. Instead, FL118 selectively inhibits multiple cancer survival and proliferation-associated antiapoptotic proteins including survivin, Mcl-1, XIAP, and cIAP2. We have demonstrated that genetic knockdown or overexpression of survivin, Mcl-1, XIAP, or cIAP2 modulates FL118's ability to inhibit cancer cell growth and induce apoptosis. FL118 is able to eliminate both small and large human tumor xenografts in animal models. Importantly, FL118 effectively overcomes topotecan treatment-induced resistance of human colon tumor in animal models. Pharmacokinetics (PK) studies indicated that FL118 prefers to be accumulated in tumor and rapidly cleared in blood stream in animal models. Furthermore, our most recent studies demonstrated that maintenance of a free hydroxyl group in the lactone ring of FL118 is critical for its antitumor activity, and the superior antitumor efficacy of FL118 heavily depends on its steric configuration (Zhao et al., Molecular Pharmaceutics). Based on the current observation of FL118 properties, we hypothesize that FL118 is an ideal lead for development of novel analogs that may possess distinct antitumor selectivity to overcome different treatment resistance. In this regard, we tested 146 new camptothecin analogs, which were synthesized based on either the FL118 core structure or the camptothecin core structure, in four cancer cell lines and two normal cell lines. We identified 19 top candidates that showed inhibition of cancer cell growth and induction of apoptosis that are better than or comparable to FL118. Intriguingly, all of the 19 top compounds possess the FL118 core structure. Further investigation of the 19 compounds using cancer cells with distinct treatment resistant backgrounds indicated that these compounds showed distinct antitumor selectivity among different treatment resistant cancer cells. Therefore, while our finding would need further investigation using in vivo human tumor animal models, we propose to develop a series of FL118 analogs for personalized cancer treatment to overcome different treatment resistance.
Citation Format: Fengzhi Li, Xiang Ling, David Westover, Xiaojun Liu, Chunyang Jin, Mansukh Wani. The novel camptothecin analog and antiapoptotic protein inhibitor FL118 appears to be a great backbone platform for development of personalized anticancer drugs. [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 1627. doi:10.1158/1538-7445.AM2014-1627