bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3952: Selective high affinity MYC-binding compound inhibits MYC-MAX interaction and MYC-dependent tumor cell growth
Authors: Castell Alina , Yan Qinzi , Fawkner Karin , Hydbring Per , Zhang Fan , Verschut Vasiliki , Franco Marcela , Zinzalla Giovanna , Larsson Lars-Gunnar 
Published: August 2018

Abstract
The MYC family oncoproteins/transcription factors MYC, MYCN and MYCL (here referred to as MYC) are key players in tumor development and are particularly associated with aggressive disease and poor prognosis. Efficient and specific MYC-targeting drugs are therefore highly warranted, but no such drugs are available in the clinic at present. MYC is strictly dependent on heterodimerization with MAX for activation of transcription. In a cell-based Bimolecular Fluorescence Complementation protein-protein interaction screen for small molecule inhibitors we identified a molecule that exhibits strong selective inhibition of MYC-MAX interaction in cells as validated by Gaussia luciferase protein complementation assay, coimmunoprecipitation and in situ proximity ligation (isPLA) assay, reaching an IC50 at single-digit micromolar concentrations. The molecule was shown to inhibit MYC-MAX interactions in a biochemical FRET assay and binds selectively to the MYC bHLHZip domain with affinity in the single digit micromolar range as demonstrated by Microscale Thermophoresis and Surface Plasmon Resonance. Further, within the same concentration range, this molecule blocks MYC-driven transcription and efficiently inhibits tumor cell growth in a MYC-dependent manner, but spares normal cells. Moreover, the growth inhibitory responses to the molecule correlated significantly with MYC expression levels in a cohort of 60 human tumor cell lines. Importantly, utilizing a mouse tumor model of MYCN-amplified neuroblastoma, treatment with the molecule resulted in significant inhibition of the MYC-MAX interaction in tumor tissue, as shown by isPLA, and massive induction of apoptosis in the tumors. Since this molecule, unlike many experimental MYC inhibitors, is selective, has high affinity for MYC, has high efficacy in cells, reaches its target in vivo and does not affect MYC expression levels, it can be used as a chemical tool to specifically study the role of the MYC-MAX complex in MYC biology in normal and cancerous cells, and it has potential for drug development.
Citation Format: Alina Castell, Qinzi Yan, Karin Fawkner, Per Hydbring, Fan Zhang, Vasiliki Verschut, Marcela Franco, Giovanna Zinzalla, Lars-Gunnar Larsson. Selective high affinity MYC-binding compound inhibits MYC-MAX interaction and MYC-dependent tumor cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3952.
Abstract 3958: Inhibiting the inhibitor: Exploring the p53-Rbm38 loop as a potential cancer therapeutic target
Authors: Lucchesi Chris A. 
Published: August 2018

Abstract
Modulating Rbm38 negative regulation of p53 translation may be an effective therapeutic target in human cancers. As a focal regulatory component of RNA metabolism, RNA-binding proteins (RBPs) modulate all facets of RNA biogenesis. Given the fact that RBPs control RNA metabolism, defects in the function of RBPs can have far reaching implications including neurodegenerative disorders and cancer. Our group discovered that Rbm38 suppresses p53 mRNA translation by interacting with eukaryotic translation initiation factor 4E (eIF4E) on p53 mRNA. Conceptually, blocking the Rbm38 interaction with eIF4E employing synthetic peptides corresponding to their respective binding interface should relieve the translational repression caused by Rbm38. Indeed, treating cancer cells with synthetic peptides corresponding to the binding interface between Rbm38 and eIF4E resulted in robust p53 protein expression. Moreover, addition of peptide and low dose doxorubicin caused further accumulation of p53. Consequently, treatment of cancer cells with peptide alone or in combination with low dose doxorubicin leads to a decrease in colony formation as well as tumor sphere formation. Of significance, RKO xenografts with wild-type p53 were highly sensitive to treatment with a synthetic peptide comprising just 8 amino acids (Pep8) compared to the control group. Together, these data support that p53 expression can be modulated by using small peptides to inhibit Rbm38 from interacting with eIF4E, which may be used as a therapeutic approach in cancers carrying wild-type p53.
Citation Format: Chris A. Lucchesi. Inhibiting the inhibitor: Exploring the p53-Rbm38 loop as a potential cancer therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3958.
Abstract 3990: Clinicopathologic findings and in vitro efficacy of MYC-targeting agentsin NUT midline carcinoma
Authors: Kim Soyeon , Jung Minsun , Park Heae Surng , Yoon Sun Och , Hong Soon Won , Park Weon-Seo , Keam Bhumsuk , Kim Hyun Jik , Kim Dong-Wan , Kim Young Tae , Heo Dae Seong , Kim Tae Min , Jeon Yoon Kyung 
Published: August 2018

Abstract
Purpose: NUT midline carcinoma (NMC) is an aggressive and poorly differentiated carcinoma defined by chromosomal rearrangements of NUT gene, which is fused to the BET family genes (BRD3/4). Although NMC is extremely rare and mostly reported in a Western population, clinico-pathologic findings of Asian NMC patients are not well studied. Here, we performed the clinicopathologic analysis of Korean NMC cases and in vitro efficacy of MYC-targeting agents against patient-derived NMC cell lines.
Experimental Design: A total of 12 NMC patients (3 thoracic and 9 head and neck origins) were collected in Korean multi-centers by immunohistochemistry (IHC) and fluorescence in situ hybridization for NUT. IHC staining was performed for c-MYC, p53, EGFR, HER2, and PD-L1. NMC cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were exposed to MYC-targeting agents including BET (I-BET, OTX-015, and AZD5153) and HDAC (vorinostat, romidepsin, panobinostat, and CUDC-907) inhibitors. Cell viability assays were performed and IC50 values were determined.
Results: Primary sites of tumor included sinonasal area (n=7), salivary gland (n=2), and thorax/lung (n=3). The median age was 47.5 years (range, 8-73 years) with equal male-to-female ratio. NUT immunostaining showed diffuse positivity in all except for one who had focal NUT positivity. C-MYC and p53 were expressed in all evaluated cases. PD-L1 expression was observed only in a patient (8.3%). Seven of 12 patients died at 3-24 months (median, 9 months) after diagnosis. Long-term survivor was observed in one patient with stage IV NMC who received mass excision plus metastasectomy followed by 6 cycles of docetaxel plus cisplatin and radiotherapy (survival &gt; 27 months). Although BET and HDAC inhibitors showed limited in vitro efficacies against NMC cells, a dual HDAC/PI3K inhibitor, CDUC-907 exhibited the most potent efficacy with the IC50 of 6.2 to 9 pmol/L.
Conclusions: Korean NMC patients pursued grave prognosis like Western patients except one long-term survivor who received tri-modality treatments. Dual HDAC/PI3K inhibitor might be promising in NMC treatment.
Citation Format: Soyeon Kim, Minsun Jung, Heae Surng Park, Sun Och Yoon, Soon Won Hong, Weon-Seo Park, Bhumsuk Keam, Hyun Jik Kim, Dong-Wan Kim, Young Tae Kim, Dae Seong Heo, Tae Min Kim, Yoon Kyung Jeon. Clinicopathologic findings and in vitro efficacy of MYC-targeting agentsin NUT midline carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3990.
Abstract 4010: Identification of signaling pathways involved in colorectal adenoma-to-carcinoma progression using phosphoproteomics
Authors: Kemp Sanne Martens-de , Henneman Alex , Haas Richard de Goeij-de , Piersma Sander , Pham Thang , Meijer Gerrit , Carvalho Beatriz , Jimenez Connie 
Published: August 2018

Abstract
Background Colorectal cancer (CRC) develops in a multi-step-process from normal epithelium, through a pre-malignant lesion (adenoma), into a malignant lesion (adenocarcinoma). A minority of about 5% of adenomas will ultimately progress into cancer. To improve clinical practice it is important to identify the subgroup of colorectal adenomas that is at risk of progressing to cancer. By extensive genomic analysis we have shown that specific copy number alterations are associated with risk of progression. An example of such an alteration is the gain of chromosome arm 20q and we identified AURKA and TPX2 as major drivers of this amplicon. Yet, the activation status of these and other genes during colorectal carcinogenesis and the downstream signaling pathways affected with gene (in)activation are not fully known. In order to better understand the biology of adenoma to carcinoma transition, we performed a comprehensive analysis of phosphoproteomes at different stages of colorectal carcinogenesis.
Methods Phosphotyrosine containing peptides were immunoprecipitated from 5 mg of colorectal adenoma (n=81) and colorectal carcinoma tissues (n=50) using agarose bead-coupled phosphotyrosine antibody P-Tyr-1000. A Q Exactive HF mass spectrometer was used to perform NanoLC-MS/MS. Spectral counts of phosphoproteins and ion intensities of phosphopeptides were defined by MaxQuant for relative quantitation of protein phosphorylation.
Results Phosphotyrosine-based phosphoproteomics of the 131 colorectal tissue samples yielded 6056 phosphopeptides, corresponding to 2745 unique phosphoproteins including 183 phosphokinases. Data analysis to identify regulated phosphorylation states and inference of kinase activity is ongoing.
Conclusions and future plans This is the first large phosphoproteomics dataset of colorectal adenomas and carcinomas. Preliminary data analysis shows promising differences in kinase activities between adenomas and carcinomas. After further analysis, we will manipulate the activity of the driver kinases in adenoma-derived organoids and monitor tumor outgrowth in mice.
Citation Format: Sanne Martens-de Kemp, Alex Henneman, Richard de Goeij-de Haas, Sander Piersma, Thang Pham, Gerrit Meijer, Beatriz Carvalho, Connie Jimenez. Identification of signaling pathways involved in colorectal adenoma-to-carcinoma progression using phosphoproteomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4010.
Abstract 4012: SAG/RBX2/ROC2 regulates pancreatic cancer initiation, cystic formation in mice driven by KrasG12D
Authors: Tan Mingjia , Zhang Qiang , Sun Yi 
Published: August 2018

Abstract
BACKGROUND & AIMS: SAG, a small ring finger protein, a component of CRLs, might be involved in pancreatic tumorigenesis. SAG overexpression in human pancreatic ductal adenocarcinomas indicating that SAG could be promotes pancreatic tumorigenesis. We investigated how manipulated SAG (overexpression or disruption of SAG) cooperate KRAS to regulate pancreatic cancer progression in mice.
METHODS: We disrupted or overexpressed SAG specifically in pancreata of mice (Sagfl/fl;P48-Cre or SagTG;P48-Cre mice) and crossed them with LSL-KRASG12D mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Sagfl/fl;LSL-KRASG12D;P48-Cre or SagTG;LSL-KRASG12D;P48-Cre mice were monitored; Pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. Protein was isolated from mouse tissues and primary acinar cells were prepared and cultured in 3D condition. Human PDA TMA was analyzed by immunohistochemistry.
RESULTS: Overexpression of Sag with KRASG12D in pancreata of mice increased the proliferation of pancreatic epithelial cells, lead to formation of acinar to ductal metaplasia and pancreatic intraepithelial neoplasias (mPanINs) and shorten mice survival. Disruption of Sag in LSL-KRASG12D;P48-Cre mice accelerated the growth of pancreatic cystic lesions compared to LSL-KRASG12D;P48-Cre mice, but did not change mouse survival. In mechanism, Sag promotes pancreatic tumorigenesis by regulating Deptor/mTOR/S6K axis and EGFR signaling pathway.
CONCLUSION: Sag is an oncogenic cooperator of activated KRAS for pancreatic tumorigenesis. Targeting SAG E3 ligase may, therefore, have therapeutic value for the treatment of prostate cancer associated with mutant KRAS.
Citation Format: Mingjia Tan, Qiang Zhang, Yi Sun. SAG/RBX2/ROC2 regulates pancreatic cancer initiation, cystic formation in mice driven by KrasG12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4012.
Abstract 4019: The chronic intermittent hypoxia enhances cancer progression in lung cancer mouse model
Authors: Lee SangHaak , Kim In Kyoung , Kang Hyeon Hui , Kwon Hee Young , Kang Hye Sun , Yeo Chang Dong 
Published: August 2018

Abstract
Background: Obstructive sleep apnoea (OSA) is a very prevalent disorder charaterized by chronic intermittent hypoxia (CIH) and some reports suggested that OSA is related to increased incidence of cancer as well as cancer progression. The purpose of this study was to evaluate whether intermittent hypoxia with a time course similar to that found in OSA influence lung cancer development and progression in metastatic lung cancer animal model.
Methods: C57/BL6 mice were divided into two groups; control condition (room air) or CIH. The mice of CIH group were exposed to IH for 2 weeks before and immediately for 2 weeks after tumour induction by tail vein injection of carcinoma cells. At day 14, the mice were sacrificed and measured cancer growth. Hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and metastasis related matrix metalloproteinases (MMP) were measured by ELISA and gelatin zymography in lung tissue and serum, respectively. The mRNA expressions of epithelial mesenchymal transition markers were measured by real-time PCR in lung tissue.
Results: The marked increase in tumor number and volume was found in CIH group (p &lt; 0.05). The accumulation of total cell and neutrophils in BAL fluids and the activation of MMP -2 and -9 in serum were also increased by CIH. The level of HIF-1α in the nuclear fraction of pneumocytes and the expression of VEGF were increased significantly in CIH group compared to the control (p &lt; 0.05). The mRNA expression of E-cadherin was decreased in CIH group compared to the control group while vimentin was increased.
Conclusions: Our data shows that CIH is associated with enhanced proliferative and migratory properties of cancer. These results suggest evidence for the causal link between OSA and lung cancer progression.
Key words: chronic intermittent hypoxia, obstructive sleep apnea, lung cancer
Citation Format: SangHaak Lee, In Kyoung Kim, Hyeon Hui Kang, Hee Young Kwon, Hye Sun Kang, Chang Dong Yeo. The chronic intermittent hypoxia enhances cancer progression in lung cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4019.
Abstract 4028: Molecular mechanisms of magnolin resistance in ovarian cancer cells
Authors: Yoo Sun-Mi , Lee Cheol-Jung , Kim Seung-Min , Cho Seon-Yeon , Park Juhee , Cho Yong-Yeon 
Published: August 2018

Abstract
Mitogen-activated protein kinase (MAPK) and PKB signaling pathways are highly activated in many human solid cancers and play a key role in carcinogenesis, tumor growth and cancer cell survival. Although regulation mechanisms of each signaling pathway are well-elucidated, interrelationship between both signaling pathways in cancer growth has not been understood. In this study, we found that magnolin, ERK1 and ERK2 inhibitor with 16 nM and 68 nM of IC50 value, suppressed cell proliferation and colony growth of ovarian cancer cells. In signaling pathway analysis, we found that TOV-112 and SKOV3 showed differential responsiveness by EGF stimulation. The differential responsiveness was caused by differential activation signaling through MAPK and PKB signaling pathway. Notably, TOV-112D sensitized by magnolin treatment in cell proliferation and colony growth in soft agar by alteration of cell cycle regulation, but not in SKOV3 cells. Notably, phosphorylation of ATF-1, a downstream target of RSK2, at Ser63 was inhibited in TOV-112 by magnolin treatment, resulted in cellular senescence. However, SKOV3 was vice versa. We further found that magnolin fraction suppressed TOV-112D cancer growth in xenograft animal model. Taken together, we concluded that signaling alteration might involve in magnolin resistance in SKOV3.
Keywords: MAP kinase, molecular targets, ovarian cancer, cancer growth
Citation Format: Sun-Mi Yoo, Cheol-Jung Lee, Seung-Min Kim, Seon-Yeon Cho, Juhee Park, Yong-Yeon Cho. Molecular mechanisms of magnolin resistance in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4028.
Abstract 4035: Cetuximab combined with dasatinib reduces drug resistance in KRAS/BRAF mutated colorectal carcinoma cells
Authors: Chiu Hsiang-Ling , Wu Yi-Che , Wei Wan-Chen , Kao Ling-Yi , Chao Wei-Ting 
Published: August 2018

Abstract
Colorectal carcinoma is the most common cancer worldwide. Cetuximab is the first-line target drug for late-stage metastatic colon cancer treatment; however, resistance to it was found in 45% patients having KRAS mutation. Therefore, the alternative signal axis to target mutated cancer cells is urgent and investigated. The role and the importance of Src has emerged in colon cancer; this study is to investigate the drug combined efficacy of cetuximab and dasatinib, the Src inhibitor and the underling molecular mechanism in KRAS/BRAF mutated cells. In this study, KRAS and BRAF mutated colon cancer cell lines SW480 and HT-29 were treated with cetuximab, dasatinib and fluorouracil (5-FU) solitary or combined. Cell viability and migration ability were monitored, and the molecular mechanisms were analyzed by Western blot for signal protein expressions. The in vivo study was carried with subcutaneous xenograft mouse model to evaluate the drug efficacy. The result showed that cetuximab treatment induced Src activation dose dependently, and induced matrix-dependent cell migration in SW480 cells. Cetuximab, dasatinib and 5-FU combined treatment compared to solitary treatment can reduce cell viability in either wild-type or KRAS/BRAF mutated colon cells. In the signal protein expressions, Src expression was suppressed sufficiently with dasatinib treatment; the phosphorylation of MAPK in SW480 cells and the phosphorylation of PI3K in HT-29 cells were downregulated after treated with cetuximab together with dasatinib and 5-FU. The drug combination was also demonstrated to suppress subcutaneous tumor growth as well. These findings demonstrate the combination of cetuximab, dasatinib and 5-FU can be the potential treating strategy for colon cancer cells with KRAS/BRAF mutation.
Citation Format: Hsiang-Ling Chiu, Yi-Che Wu, Wan-Chen Wei, Ling-Yi Kao, Wei-Ting Chao. Cetuximab combined with dasatinib reduces drug resistance in KRAS/BRAF mutated colorectal carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4035.
Abstract 4041: K-ras transformation leads to increased HS-degradation
Authors: Ju Donghong , Kosir Mary A. 
Published: August 2018

Abstract
INTRODUCTION: Degradation of glycosaminoglycans in the extracellular matrix impacts cell movement, angiogenesis and other cancer cell activities. The purpose of study was to detect and measure extracellular heparan sulfate (HS)-degrading enzyme in malignant ras-transformed cells where HS degradation occurred at attachment sites. METHODS: Serum free conditioned medium (CM) and lysate from subconfluent Balb/c3T3 and KiMSV (Ki-ras-transformed 3T3) cells were collected and protease inhibitors added. CM was concentrated by ultracentrifugal filters using 3K and 30K MWCO. Heparan degrading enzyme assay kit was use with lysate and CM for each cell line. Western blot analysis of lysate and CM used anti-HPSE, anti-NAP2, and anti-PPBP antibodies with actin control. mRNA for HPSE and PPBP was determined by RTPCR. RESULTS: The heparan degrading activity of CM from KiMSV cells was 12 fold higher than from Balb/c3T3 cells with 30K MWCO concentration. Further, HPSE was detected in the lysate, but not CM. Anti-NAP2 and anti-PPBP antibody detected protein greater than 30kD in CM and lysate for KiMSV cells. However, mRNA expression of PPBP/NAP2 was less in KiMSV than Balb/c3T3 cells. CONCLUSION: HS degradation in the CM of KiMSV cells is greater than for Balb/c3T3 cells from which they are derived after Ki-ras-transformation. The HPSE is not detected in the CM, but PPBP-like proteins at higher molecular weight are detected which may be responsible for the extracellular HS degradation.
Citation Format: Donghong Ju, Mary A. Kosir. K-ras transformation leads to increased HS-degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4041.
Abstract 4042: Metformin-induced caveolin-1 expression promotes T-DM1 drug efficacy in breast cancer cells
Authors: Wei Wan-Chen , Chung Yuan-Chiang , Kao Ling-Yi , Chiu Hsiang-Ling , Wu Yi-Che , Chao Wei-Ting 
Published: August 2018

Abstract
Trastuzumab emtansine (T-DM1, Kadcyla) is an antibody-drug conjugate (ADC) that was recently approved by the Federal Drug Administration (FDA) of the USA for the treatment of HER-2-positive metastatic breast cancer. The drug sensitivity of ADCs depends in the main on the internalization efficiency of the drug. Endocytic protein caveolin-1 was shown to promote T-DM1 internalization and enhance drug sensitivity. Whether caveolin-1 can be overexpressed to improve T-DM1 efficacy is interesting and has the potential for clinical application. In this study, the first-line diabetes drug metformin was investigated in terms of induction of caveolin-1 expression for increased efficacy of subsequent T-DM1 application. HER-2-positive BT-474 cells were pretreated with metformin, followed by combined therapy with metformin and T-DM1. The T-DM1 internalization and drug efficacy were determined, and the protein expressions for signal transduction were also monitored by Western blot to ascertain the molecular mechanism. Caveolin-1 shRNA was applied to suppress endogenous cellular caveolin-1 expression, and the ability of metformin to promote T-DM1 efficacy was investigated. The results showed that in BT-474 cells pretreated with metformin, cellular caveolin-1 overexpression was induced, which then promoted drug efficacy by enhancing T-DM1 internalization. As cellular caveolin-1 was suppressed by shRNA, the effect of metformin-enhanced T-DM1 cytotoxicity was decreased. This study demonstrated that metformin can be applied prior to T-DM1 treatment to improve the clinical efficacy of T-DM1 by enhancing caveolin-1-mediated endocytosis.
Citation Format: Wan-Chen Wei, Yuan-Chiang Chung, Ling-Yi Kao, Hsiang-Ling Chiu, Yi-Che Wu, Wei-Ting Chao. Metformin-induced caveolin-1 expression promotes T-DM1 drug efficacy in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4042.