bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3956: Omomyc-based cell-penetrating peptides: From proof of concept to a clinically viable anti-Myc therapy
Authors: Beaulieu Marie-Eve , Jauset Toni , Massó-Vallés Daniel , Martínez-Martín Sandra , Rahl Peter , Maltais Löika , Zacarias-Fluck Mariano F. , Casacuberta-Serra Sílvia , Pozo Erika Serrano del , Fiore Christopher , Foradada Laia , Cano Virginia Castillo , Guenther Matthew , Sanza Eduardo Romero , Oteo Marta , Tremblay Cynthia Tremblay , Martín Génesis , Letourneau Danny , Montagne Martin , Alonso Miguel Ángel Morcillo , Whitfield Jonathan R. , Lavigne Pierre , Soucek Laura 
Published: August 2018

Abstract
Deregulation of the MYC oncoprotein drives tumorigenesis in most–if not all–cancers and generally correlates with poor prognosis, suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e., skin, lung, pancreatic cancer and glioma), without eliciting resistance to therapy, and causes only mild, well-tolerated and reversible side effects in normal tissues. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which is an effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene, as a successful proof of principle whose application was believed to be solely limited to gene therapy. Here, though, we show that the purified Omomyc polypeptide itself spontaneously transduces into cancer cells and effectively interferes with MYC transcription, abrogating cell cycle and promoting apoptosis in different cancer cells, independently of their mutational profile. Efficacy of the Omomyc polypeptide in two complementary murine models of non-small cell lung cancer (NSCLC) establishes its therapeutic potential through both direct tissue delivery (intranasal) and systemic intravenous administration, providing for the first time evidence that the Omomyc polypeptide is an effective MYC inhibitor worthy of clinical development.
Citation Format: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Sandra Martínez-Martín, Peter Rahl, Löika Maltais, Mariano F. Zacarias-Fluck, Sílvia Casacuberta-Serra, Erika Serrano del Pozo, Christopher Fiore, Laia Foradada, Virginia Castillo Cano, Matthew Guenther, Eduardo Romero Sanza, Marta Oteo, Cynthia Tremblay Tremblay, Génesis Martín, Danny Letourneau, Martin Montagne, Miguel Ángel Morcillo Alonso, Jonathan R. Whitfield, Pierre Lavigne, Laura Soucek. Omomyc-based cell-penetrating peptides: From proof of concept to a clinically viable anti-Myc therapy [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 3956.
Abstract 3984: Combination S6K and TAM tyrosine kinase targeting in PTEN-deficient glioma
Authors: Ennis Kelli N. , Sarma Pranjal , Behrmann Catherine A. , Wang Jie , Plas David R. 
Published: August 2018

Abstract
Loss of PTEN is one of the most frequent driver events in primary glioblastoma, conferring the ability to reconfigure metabolism and enhance apoptosis resistance to transformed glial cells. The ribosomal S6 protein kinases (S6Ks) are hyperactivated in PTEN-deficient settings, and genetic inactivation studies have shown that S6K1 deficiency can reduce the oncogenic growth of PTEN-deficient neoplasia. Investigating pharmacologic agents, we found that the S6K inhibitor LY-2584702 selectively elicits cytotoxic responses in PTEN-deficient cells when combined with the TAM kinase inactivating agent BMS-777607. Combined knockdown of TAM kinases sensitized cells to single agent treatment with LY-2584702. Conversely, expression of activated S6K1 or elevated AXL protected from combination treatment. These results indicate that both the TAMS and S6K1 are key regulators of survival in PTEN deficient cells.
Citation Format: Kelli N. Ennis, Pranjal Sarma, Catherine A. Behrmann, Jie Wang, David R. Plas. Combination S6K and TAM tyrosine kinase targeting in PTEN-deficient glioma [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 3984.
Abstract 3989: Dual targeting of ErbB2/ErbB3 for treatment of SCL3A2-NRG1-mediated lung cancer
Authors: Jo Jeong Yeon , Shin Dong Hoon , Han Ji-Youn 
Published: August 2018

Abstract
We previously identified an oncogenic fusion gene involving the 5′ region of SLC3A2 and the 3′ region of NRG1 in a patient with invasive mucinous adenocarcinoma (IMA) of the lung. Here, we characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the epidermal growth factor (EGF)-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3, which lacks tyrosine kinase activity, with ERBB2 using immunofluorescence staining, FACS analysis, and immunoprecipitation. Activation of the ERBB2-ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth in vivo in a xenograft model through the downstream signaling pathways of PI3K-AKT and MAP kinase. siRNA specific for ERBB2 and ERBB3, pertuzumab (a monoclonal antibody for ERBB2), lumretuzumab (a monoclonal antibody for ERBB3), and afatinib (an ERBB2 kinase inhibitor) all decreased ERBB2-ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or apatinib decreased tumor volume and weight, whereas combination treatment with these drugs and paclitaxel enhanced generation of cleaved-caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2-ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1-positive tumors.
Citation Format: Jeong Yeon Jo, Dong Hoon Shin, Ji-Youn Han. Dual targeting of ErbB2/ErbB3 for treatment of SCL3A2-NRG1-mediated lung cancer [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 3989.
Abstract 3992: Varlitinib demonstrates tumor regression and vessel normalization in ErbB-dependent and mutated beta-catenin hepatocellular carcinoma patient-derived xenograft model
Authors: Shuen Wai Ho , Ong Richard , Yeo Chloe , Banu Rebecca , Koh Lip Seng , Chee Chit Lai , Seet Qihui , Ooi Lisa , McHale Mark , Lindmark Bertil , Toh Han Chong , Hung Huynh 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and current therapies such as sorafenib, regorafenib and lenvatinib, prolong median overall survival by less than a year. Hence, there is an urgent need for additional HCC therapies. Varlitinib is a potent, reversible, small molecule pan – HER inhibitor that selectively binds to EGFR, HER2 and HER4. Varlitinib is currently being clinically tested across multiple indications including biliary tract cancer and gastric cancer. In HCC patient – derived xenograft (PDX) models, varlitinib has been shown to mediate potent anti – tumour activities (ASCO 2016). To understand the molecular profiles of HCC PDX sensitive to varlitinib, we studied the ErbB family signalling in 56 HCC PDX models and varlitinib was found to be efficacious in HCC PDX with activated ErbB2 / 3 as well as mutated beta – catenin. In HCC PDX models with activated ErbB2 / 3 , treatment with varlitinib inhibited multiple proliferation and anti – apoptosis pathways including AKT, PI3K and Survivin pathways. In addition, normalisation of blood vessels by varlitinib in the PDX models, as assessed by staining with biotinylated lectin and anti – CD31, also reduced hypoxia in the tumour microenvironment as well as enhanced the infiltration of immune cells. Activating mutations in the Wnt / beta – catenin pathway lead to tumour development in HCC and occur in a subset of HCC tumours. HCC PDX models with beta – catenin mutation were found to be sensitive to varlitinib. Varlitinib led to down – regulation of mutated beta – catenin signalling, and enhanced staining of beta – catenin at the membrane instead of in the nucleus. Since activating mutations in the Wnt / beta – catenin pathway are detected in 26 – 40 % of HCC samples, our data shows that varlitinib may represent an alternative treatment for a significant subset of HCC which are ErbB / beta – catenin – dependent.
Citation Format: Wai Ho Shuen, Richard Ong, Chloe Yeo, Rebecca Banu, Lip Seng Koh, Chit Lai Chee, Qihui Seet, Lisa Ooi, Mark McHale, Bertil Lindmark, Han Chong Toh, Huynh Hung. Varlitinib demonstrates tumor regression and vessel normalization in ErbB-dependent and mutated beta-catenin hepatocellular carcinoma patient-derived xenograft 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 3992.
Abstract 3994: Anti-metastatic drug MBQ-167 regulates cell polarity via Cdc42
Authors: Rivera-Robles Michael John , Medina-Velázquez Julia , Asencio-Torres Gabriela M. , González-Crespo Sahily , Rymond Brian C. , Rodríguez-Medina José , Dharmawardhane Suranganie 
Published: August 2018

Abstract
Cdc42 (cell division control protein 42 homolog) is a Rho GTPase highly conserved among eukaryotes in structure and function. Mechanical or chemical cues in the microenvironment stimulate the localized activation of Cdc42, aiding cells to polarize and arrange their components accordingly. Its role in cell polarity was first described in budding yeast and subsequently in other eukaryotes, including animal cells determining the direction of motility. Accordingly, in cancer Cdc42 mediates migration, invasion, and spread of tumor cells. Therefore, we target Cdc42 as therapeutic strategy to treat metastatic breast cancer. Our group designed and characterized the small molecule MBQ-167 as a potent inhibitor against Cdc42 activation (IC50=0.1 µM), demonstrating its effectiveness in preventing tumor growth and cell migration in vitro and in vivo. Because in yeast S. cereviciae Cdc42 is well known for regulating the location of budding events, we used this well-characterized model of cell polarization to test our previous findings of MBQ-167 and its specificity for Cdc42. By using a tetracycline-controlled transcriptional inactivation (Tet-Off) system at the promoter region of the CDC42 gene of yeast, we knocked down Cdc42 supplementing the media with doxycycline (DOX; IC=10ug/uL). Next, we analyzed the growth, budding pattern, and Cdc42 activity of budding yeast exposed to DOX, MBQ-167 or in combination. The maximum growth, doubling time and budding polarity of recombinant yeast with the Tet-Off system were reduced when treated with DOX (EC50=10ug/mL), as expected. The same effect was seen in the group treated with MBQ-167 (ED50=100uM), both alone and in combination with DOX. Ultimately, pull-down assays of the active Cdc42-GTP complex confirmed our hypothesis that MBQ-167 disrupts cell polarity through impeding Cdc42 activation. Here we validated MBQ-167 as a Cdc42 inhibitor in another biologic context. and present a method for screening Cdc42 inhibitors and potential therapeutics against metastatic cancer.
Citation Format: Michael John Rivera-Robles, Julia Medina-Velázquez, Gabriela M. Asencio-Torres, Sahily González-Crespo, Brian C. Rymond, José Rodríguez-Medina, Suranganie Dharmawardhane. Anti-metastatic drug MBQ-167 regulates cell polarity via Cdc42 [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 3994.
Abstract 4000: Hepatitis B virus X gene accelerates the development of HBV-related hepatocellular carcinoma
Authors: ZHANG Yu , YAN Qian , YU Dandan , GUAN Xinyuan 
Published: August 2018

Abstract
Epidemic studies have shown hepatocellular carcinoma (HCC) is highly associated with chronic HBV infection. However, the underlying mechanism of how HBV integration leading to HCC remains elusive. We applied the ViralFusionSeq algorithm to aid our analysis of the raw whole-genome sequencing data from TCGA database and found HBX “re-integration” in tumor cells showed a relatively consistent pattern compared with the adjacent normal liver tissue. In order to further elucidate the oncogenic role of truncated HBX gene in HCC, full-length and two COOH-terminal truncated HBX (X120 and X134) genes were stably transfected into HCC cell lines to investigate its function. Results showed that both truncated forms (X120 and X134) overexpression increased HCC cell proliferation rate, the ability of foci formation and colony formation in soft agar, as well as migration and invasion, while full-length HBX showed the opposite effect, both in vitro and vivo. Furthermore, RNA-sequencing of HBX overexpression HCC cells revealed key cancer-related signaling pathways were altered compared with control cells. Here our findings give a novel insight into the HBV integration pattern in the host genome which contributes to HCC.
Citation Format: Yu ZHANG, Qian YAN, Dandan YU, Xinyuan GUAN. Hepatitis B virus X gene accelerates the development of HBV-related hepatocellular 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 4000.
Abstract 4009: Biotinylated estrogens a novel tool for early detection of adduct in ovarian cancer and their carcinogenic effects in cultured human cells
Authors: Tripathi Kaushlendra 
Published: August 2018

Abstract
In humans, endogenous estrogens such as Estrone (E1) and 17L-estradiol (E2) regulate many physiological processes including reproduction, primarily in females, and control the growth of certain responsive cells. However, unbalanced estrogen metabolism has been linked to development of several malignant diseases including breast, endometrial and ovarian cancer and has been identified as a risk factor for these cancers. Elevated estrogens exert their carcinogenic effects by at least three different mechanisms; they promote cell proliferation by transcriptional regulation of estrogen responsive genes, cause generation of reactive oxygen species and other free radicals, and directly react with DNA and form potentially mutagenic adducts. The metabolic breakdown of estogens is regulated by a series of reactions mediated by hepatic and peripheral enzymes that balances the induction and reduction of cellular stress. An imbalance in this enzymes and processes can lead to highly reactive catechol estrogen metabolites that can react with DNA, form carcinogenic DAN-adducts and lesions. Although several studies established a connection between estrogen-induced DNA damage and carcinogenesis, the underlying molecular mechanisms have been difficult to study because of the technical challenges in detecting and analyzing the variety of different DNA lesions that are formed by estrogen compounds. Moreover, detection and analysis of these adducts are important to directly monitor estrogen metabolites induced cellular responses in the cells. Towards this, we developed a novel method using biotinylated-estrogens that allows immunodetection of estrogen-induced DNA adducts by Slot-blot and single-cell molecular combing and proximity ligation assays. Using these modified estrogens we first time quantitatively detected these adducts on DNA by immune Slot-blot techniques and on DNA fibers. Furthermore, similar to other environmental carcinogens estrogens activates replication associated DNA damage responses and induces chromosomal instability. Thus, for the first time our studies demonstrate that biotin-labeled estrogens could be a powerful tool to detect estrogen adducts and to probe associated DNA damage responses and cellular responses.
Citation Format: Kaushlendra Tripathi. Biotinylated estrogens a novel tool for early detection of adduct in ovarian cancer and their carcinogenic effects in cultured human 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 4009.
Abstract 4023: Gap junctions contribute to anchorage-independent clustering of breast cancer cells
Authors: Gava Fabien , Rigal Lise , Mondesert Odile , Pesce Elise , Ducommun Bernard , Lobjois Valérie 
Published: August 2018

Abstract
Purpose: Cancer cell cluster formation is a key process involved during primary tumor growth, metastatic cells dissemination and secondary tumor evolution. We previously reported that cell-cell adhesion proteins such as E-Cadherin and desmosomal proteins are involved in cell aggregation independently of cell migration or matrix adhesion (Saias et al. 2015). Here we investigate the involvement of gap junction intercellular communication (GJIC) during anchorage-independent clustering of MCF7 breast adenocarcinoma cells.
Experimental Design: Live cell imaging and image processing was used to evaluate MCF7 clustering in the presence of pharmacological inhibitors and to perform a LOPAC® small bioactive compound library screening. Flow cytometry was performed to monitor calcein transfer assay and to evaluate GJIC.
Results: We first demonstrate that functional GJIC are established in the early phase of aggregation. We next show that pharmacological inhibition of GJIC using Tonabersat and Meclofenamate both reduces calcein transfer and delays clustering of MCF7 cells. We found that treatment with Latrunculin A, an actin cytoskeleton-disrupting agent, inhibits MCF7 clustering and impairs calcein transfer. In a screen for inhibitors of cell aggregation using a small-compound chemical library we identified Brefeldin A, an inhibitor of vesicular trafficking, and showed that it also impairs calcein transfer.
Conclusion: Our results demonstrate that GJIC are involved at the earliest stages of the anchorage-independent clustering process. They shed new light on the regulatory mechanisms that could modulate the formation of clusters of circulating tumor cells.
References:
Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H et al: Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 2014, 158(5):1110-1122.
Saias L, Gomes A, Cazales M, Ducommun B, Lobjois V: Cell-Cell adhesion and cytoskeleton tension are key but opposing regulators of tumor cell aggregation. Cancer Research 2015, 75(12):1-8.
Gava, F., Rigal, L ., Mondesert, O., Pesce, E., Ducommun, B. and Lobjois, V. Gap junctions contribute to anchorage-independent clustering of breast cancer cells (Submitted).
Citation Format: Fabien Gava, Lise Rigal, Odile Mondesert, Elise Pesce, Bernard Ducommun, Valérie Lobjois. Gap junctions contribute to anchorage-independent clustering of 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 4023.
Abstract 4024: TRAF2 Ser-11 phosphorylation confers resistance to AKT inhibitors in breast cancer cells
Authors: Habelhah Hasem , Zhang Laiqun 
Published: August 2018

Abstract
The PI3K-AKT pathway is the most frequently aberrantly activated pathway in breast cancer (BC), with alterations in genes encoding the pathway components (e.g. RTKs, HER2, PTEN, PIK3C and AKT) occurring in ~80% of cases. However, inhibition of this pathway is either not effective or often results in development of resistance in BC. TRAF2 is a key effector protein downstream of the TNF receptor superfamily, and activates NF-κB to promote BC cell survival. We mapped two phosphorylation sites (Ser-11 and Ser-274) in TRAF2, and identified TBK1/IKKϵ and AKT as the kinases that directly phosphorylate TRAF2 at Ser-11 and Ser-274, respectively. TBK1 and IKKϵ are serine/threonine kinases activated by inflammatory stimuli and the oncogenic RTK-Ras-RALB pathway, and play a critical role in BC transformation and survival. IKKϵ and TRAF2 are overexpressed in a significant portion of BC, and their overexpression is associated with poor prognosis in patients with invasive breast carcinoma. We found that inhibition of AKT leads to increased TBK1 activation and TRAF2 Ser-11 phosphorylation in triple negative BC (TNBC) cells. Importantly, combination of AKT and TBK1/IKKϵ inhibitors synergistically induced apoptosis in all TNBC cell lines tested in vitro, suggesting that inhibition of PI3K-AKT derepresses the pro-survival TBK1-TRAF2 pathway, which in turn confers resistance to AKT inhibition in TNBC. We believe that any positive outcomes from our ongoing xenograft experiments will have an immediate translational impact in TNBC treatment.
Citation Format: Hasem Habelhah, Laiqun Zhang. TRAF2 Ser-11 phosphorylation confers resistance to AKT inhibitors 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 4024.