bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1227: New small molecules targeting MYC:MAX interactions that inhibits tumor cell growth in a MYC-dependent manner
Authors: Castell Alina , Ridderstråle Karin , Yan Qinzi , Zhang Fan , Hydbring Per , Franco Marcela , Goodwin Jacob , Müller Inga , Zakaria Siti Mariam , Johansson Lars , Larsson Lars-Gunnar 
Published: July 2016

Abstract
Deregulated expression of MYC family oncogenes MYC, MYCN and MYCL (here collectively referred to as MYC) occurs in many types of human tumors, and is often associated with aggressive tumor development and poor prognosis. In mouse tumor models, inactivation of MYC often leads to tumor regression with well-tolerated side effects, suggesting that MYC is a potential and suitable target for anti-cancer therapy. At present there are no drugs targeting MYC in the clinic, and transcription factors like MYC are considered difficult to target. However, MYC function is strictly dependent on interaction with cofactors, and targeting such interaction may be a plausible way to combat Myc. We have used cell-based screens utilizing Bimolecular Fluorescence Complementation (BiFC) and split Gaussia luciferase (G-Luc) to identify small molecule inhibitors of the interaction between MYC and its essential partner MAX. Several potent MYC:MAX interaction inhibitors have been identified in these screens and have been validated by other protein-protein interactions (PPI) assays such as in situ Proximity Ligation Assay (isPLA), Fluorescence Resonance Energy Transfer (FRET), Surface Plasmon Resonance (SPR) and coimmunoprecipitations. In general the identified molecules fall into two categories: those that inhibit MYC:MAX interactions not only in cells but also in vitro using purified MYC and MAX, and those that inhibit the interaction in cells but not in vitro, suggesting an indirect mode of action. Molecules of both categories inhibit cell growth and viability of a variety of tumor cells in culture with high efficacy in a MYC-dependent manner. So far, one of the molecules have been utilized for cancer treatment in mouse tumor models and found to significantly inhibit tumor growth and improve survival. These molecules have the potential to become important tools in the studies of MYC function in cells and in vivo as well as potentially basis for drug development for treatment of MYC-driven tumors. We have thus provided proof of principle that our screening systems are able to identify potent PPI inhibitors and we are at present setting up similar systems to screen for inhibitors of other MYC:cofactor interactions of relevance for specific tumor types.
Citation Format: Alina Castell, Karin Ridderstråle, Qinzi Yan, Fan Zhang, Per Hydbring, Marcela Franco, Jacob Goodwin, Inga Müller, Siti Mariam Zakaria, Lars Johansson, Lars-Gunnar Larsson. New small molecules targeting MYC:MAX interactions that inhibits tumor cell growth in a MYC-dependent manner. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1227.
Abstract 1230: BGB-283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models
Authors: Tang Zhiyu , Liu Yong , Jiang Beibei , Gao Yajuan , Gong Wenfeng , Wang Xing , Su Dan , Yu Fenglong , Liu Ye , Wei Min , Wang Lai 
Published: July 2016

Abstract
Liver cancer has the third highest mortality rate among all cancers in China and hepatocellular carcinoma (HCC) is the most common type of liver cancer. The mitogen-activated protein kinase (MAPK) signaling pathway is often constitutively active in HCC. The growth of HCC requires the formation of new blood vessels. and VEGF is critical in this process. Sorafenib, a multikinase inhibitor that targets both RAF and VEGF receptor, is to date the only approved drug to treat advanced stages of HCC. Despite sorafenib extended the survival in patients with HCC, its clinical benefits remain modest and drug resistance is common. BGB283 is a second generation RAF inhibitor with unique RAF dimer and VEGFR inhibition activity. Thus, there is good rationale to test BGB-283 in HCC. In this study, we compared the in vitro and in vivo activities of BGB-283 and sorafinib in human HCC cell lines and patient derived HCC xenograft models.
In the biochemical assays, BGB-283 demonstrated great potency for BRAF-V600E, BRAF-WT, CRAF(IC50 = 32, 69 and 6.5 nM, respectively) and for VEGFR family enzymes, VEGFR1, VEGFR2 and VEGFR3 (IC50 = 25, 14 and 58 nM, respectively). In the cellular assays, the anti-proliferative effect of BGB-283 and sorafinib was evaluated in several HCC cell lines. A head-to-head comparison of in vivo anti-tumor activities of BGB-283 and sorafinib were also evaluated in human primary HCC xenograft mouse models. The patient derived xenograft (PDX) HCC models were established in house using HCC patient surgical samples. Sorafinib was not active in 2 out of 7 models. Oral administration of BGB-283 resulted in significant tumor growth inhibition in all 7 models and was significantly more efficacious than sorafinib in 4 models and similar in the other 3 models.
In conclusion, BGB-283 is a unique RAF dimer inhibitor with VEGFR inhibition activity. BGB-283 has also demonstrated better anti-tumor activity than sorafinib in HCC PDX models, suggesting BGB-283 could be a promising drug candidate for treating HCC patients.
Citation Format: Zhiyu Tang, Yong Liu, Beibei Jiang, Yajuan Gao, Wenfeng Gong, Xing Wang, Dan Su, Fenglong Yu, Ye Liu, Min Wei, Lai Wang. BGB-283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1230.
Abstract 1238: A novel Ras inhibitor potently and selectively suppresses lung tumor cell growth by blocking Ras-Raf binding
Authors: Zhu Bing , Chen Xi , Ramirez-Alcantara Veronica , Lee Kevin , Valiyaveettil Jacob , Canzoneri Joshua , Sigler Sara , Berry Kristy , Lindsey Ashley , Keeton Adam , Boyd Michael R. , Piazza Gary A. 
Published: July 2016

Abstract
Mutations in ras genes that result in constitutive activation of Ras proteins are key drivers of oncogenesis, but no effective drugs have been developed that target these aberrant gene products. Screening using a phenotypic assay designed to select for Ras inhibitors and iterative chemical synthesis, identified a preclinical drug development candidate with attractive drug-like properties designated as DC070-547. Here we evaluated the sensitivity of non-small cell lung cancer (NSCLC) cell lines to DC070-547. The compound potently suppresses the growth of human A549, H460, HOP62, H1299, H1975 lung tumor cells having high levels of activated Ras with low nanomolar IC50 values. By contrast, normal human airway epithelial cells (NHAECs) and H322 lung tumor cells with low levels of activated Ras displayed IC50 values in the mid micromolar range. The Ras selectivity of DC070-547 was confirmed by ectopic expression of mutant H-Ras-G12V (H-Rasm) in H322 cells using a retroviral construct, in which the IC50 value of DC070-547 for growth inhibition was reduced approximately 2,500 fold compared with vector control cells. To study the mechanism of action, Ras activation status was measured by Ras-Raf pull-down assays using GTP-bound Ras from cell lysates with GST-Raf1-RBD/GSH sepharose and followed by western blotting with Ras antibodies. Direct binding to Ras was apparent by the ability of DC070-547 to inhibit Ras-Raf binding at concentrations that inhibit Ras-dependent tumor cell growth. Pull-down assays also showed a dose-dependent inhibition of Ras-GTP levels in intact H-Rasm-H322 cells treated with DC070-547 at the same concentration range. Western blot analysis of Ras-immunoprecipitated proteins revealed that DC070-547 also attenuated high levels of EGFR phosphorylation at Y1068 in H-Rasm-H322 cells but not in control cells. These results demonstrate novel Ras inhibitory activities of DC070-547 in NSCLC cell lines. DC070-547 and its pipeline analogs are being evaluated for antitumor efficacy in preclinical mouse models of lung cancers.
Citation Format: Bing Zhu, Xi Chen, Veronica Ramirez-Alcantara, Kevin Lee, Jacob Valiyaveettil, Joshua Canzoneri, Sara Sigler, Kristy Berry, Ashley Lindsey, Adam Keeton, Michael R. Boyd, Gary A. Piazza. A novel Ras inhibitor potently and selectively suppresses lung tumor cell growth by blocking Ras-Raf binding. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1238.
Abstract 1248: Ibrutinib inhibits platelet aggregation through inhibition of mitochondrial respiratory chain function and suppression of Syk activation
Authors: Huang Jie , Pelicano Helen , Li Feng , Keating Michael J. , Huang Peng 
Published: July 2016

Abstract
Ibrutinib represents a therapeutic improvement in hematologic cancers, but it is associated with bleeding-related adverse events. To minimize such adverse events and improve the therapeutic utility of this drug, it is important to understand the underlying mechanisms responsible for the adverse events. In this study, we observed that platelets isolate from the blood samples of chronic lymphocytic leukemia (CLL) treated with Ibrutinib exhibited deficiencies in collagen-mediated aggregation. Mechanistic studies identified the mitochondrial respiratory chain as a potential mediator of ibrutinib-induced impairment of platelet function. A short-term treatment of platelets isolated from human blood with ibrutinib for less than one hour led to reactive oxygen species (ROS) generation associated with inhibition of mitochondrial respiration, as evident by a reduction in oxygen consumption rate measured by a Seahorse metabolic analyser. Long-term incubation of megakaryocytes with ibrutinib markedly suppressed the expression of mitochondrial electron transport chain components in platelets and a reduction in mitochondrial respiration. Interference with the respiratory chain by rotenone also resulted in similar reduction in collagen-induced platelet aggregation. Interestingly, ROS generation upon collagen stimulation induced tyrosine phosphorylation of Syk (spleen tyrosine kinase) to activate platelet, while impairment of respiratory chain induced by ibrutinib diminished collagen-evoked activation of the Syk pathway. These data suggest that ibrutinib suppresses mitochondrial respiration, leading to defects in collagen-induced platelet aggregation, potentially through inhibiting the activation of the Syk pathway.
Citation Format: Jie Huang, Helen Pelicano, Feng Li, Michael J. Keating, Peng Huang. Ibrutinib inhibits platelet aggregation through inhibition of mitochondrial respiratory chain function and suppression of Syk activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1248.
Abstract 1257: A MYC-Aurka protein complex represents an actionable target in p53 altered liver cancer
Authors: Daniel Dauch , Rudalska Ramona , Cossa Giacomo , Nault Jean Charles , Imbeaud Sandrine , Malek Nisar P. , Longerich Thomas , Laufer Stefan , Poso Antti , Zucman-Rossi Jessica , Eilers Martin , Zender Lars 
Published: July 2016

Abstract
Myc oncoproteins are causally involved in the genesis of a large fraction of human tumors. Three closely related Myc proteins, c-myc, N-myc and L-myc, have been implicated in cancer, whereas c-myc was identified as an important oncogenic driver in frequent solid tumors.Applying transposon-based mosaic liver cancer mouse models and direct in vivo shRNA screening technology, we found that bypassing a latent p19Arf- and Aurka mediated G2/M cell cycle arrest is required for development of p53 altered liver carcinomas with activated Ras/MAPK signalling. The resulting tumors depend on high MYC levels for survival. A direct interaction of Aurka and MYC was identified in p53 altered liver cancer cells, which could be efficiently disrupted by conformation changing Aurka inhibitors, resulting in MYC degradation and cell death specifically of p53 altered human and murine hepatoma cells. Treatment studies in mouse models of p53 deficient therapy resistant liver cancer revealed marked therapeutic efficacy of conformation changing Aurka inhibitors, thus suggesting a new therapeutic strategy against this major lethal cancer.
Citation Format: Dauch Daniel, Ramona Rudalska, Giacomo Cossa, Jean Charles Nault, Sandrine Imbeaud, Nisar P. Malek, Thomas Longerich, Stefan Laufer, Antti Poso, Jessica Zucman-Rossi, Martin Eilers, Lars Zender. A MYC-Aurka protein complex represents an actionable target in p53 altered liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1257.
Abstract 1264: Targeting nuclear receptors and their coregulators in triple-negative breast cancer
Authors: Chang Ya-Fang , Wang Yuhao , Greene Geoffrey 
Published: July 2016

Abstract
Metastasis and chemoresistance remain significant challenges in treating triple-negative breast cancer (TNBC). Nuclear receptors (NRs) are ligand-inducible transcriptional factors that play essential roles in key biological processes from embryonic development to differentiation, regulation of gene expression, and homeostasis, and their dysregulation has been implicated in many different pathologies including cancer. Using MDA-MB-231 cells as a model, we performed a siRNA screening to determine the importance of NRs and their co-regulators in cancer cell proliferation and death of TNBC. A total of 84 siRNA pools, each targeting a different gene, were evaluated. To further validate the candidate genes, we transfected MDA-MB-231 cells with each of the four individual siRNAs comprising each pool. The effect of candidate genes on the invasion and chemoresistance of TNBC cell lines was also assayed in vitro. Among 4 candidate genes, we focused in greater depth on steroid receptor coactivator-3 (NCOA3), which is a member of the p160 steroid receptor coactivators and found to be overexpressed in breast cancer. We found that although NCOA3 knockdown moderately inhibited the tumor growth of TNBC cells (MDA-MB-231, BT549, and HS578), the addition of siNCOA3 and paclitaxel significantly decreased cell proliferation and increased caspase-3/7 activity. In transwell invasion assays, NCOA3 knockdown also significantly decreased the invasion of TNBC cells. These results suggest that targeting NCOA3 is worth investigating for the treatment of TNBCs.
Citation Format: Ya-Fang Chang, Yuhao Wang, Geoffrey Greene. Targeting nuclear receptors and their coregulators in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1264.
Abstract 1274: Characterization of UROC1 protein as a novel prognostic biomarker and a therapeutic target for oral cancer
Authors: Phung Thang Manh , Takano Atsushi , Yoshitake Yoshihiro , Shinohara Masanori , Murakami Yohinori , Daigo Yataro 
Published: July 2016

Abstract
Oral cavity cancer (OCC) is the most common cause of cancer-related death worldwide and shows poor clinical outcome after standard therapies. Therefore, new prognostic biomarkers and therapeutic targets for OCC are urgently awaited. This study aims to identify novel prognostic biomarkers or therapeutic targets for OCC. To screen the new prognostic biomarkers and therapeutic targets for OCC, we selected from our original gene expression database up-regulated in oral cancer 1 (UROC1) that appeared to encode cytoplasmic protein as a candidate. Immunohistochemical analysis using tissue microarray covering 99 OCC tissues confirmed that UROC1 protein was expressed in 67 cases (68%) of 99 OCC tissues, but not in normal oral epithelia. High levels of UROC1 expression was significantly associated with poorer prognosis for OCC patients (P = 0.0299, log-rank test). In addition, knockdown of endogenous UROC1 expression by siRNAs significantly inhibited the growth and invasion of OCC cells, whereas the induction of exogenous UROC1 expression enhanced the growth and invasive ability of OCC cells. In addition, flow cytometric analysis and various apoptosis assays of these tumor cells transfected with siRNAs for UROC1 revealed a significant induction of apoptosis. Assays using phosphor-antibody array and lysates from cells transfected with siRNAs or plasmid for UROC1 and subsequent functional analyses revealed that UROC1 could regulate the growth, survival, and invasion of OCC cells probably through activation of insulin-like growth factor 1 receptor (IGF1R) pathway. These data suggest that UROC1 could be a novel prognostic biomarker and a therapeutic target for OCC.
Citation Format: Thang Manh Phung, Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yohinori Murakami, Yataro Daigo. Characterization of UROC1 protein as a novel prognostic biomarker and a therapeutic target for oral cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1274.
Abstract 1276: Pannexin 1 regulates rhabdomyosarcoma tumor growth: a potential novel therapeutic target
Authors: Xiang Xiao , Langlois Stephanie , St-Pierre Marie-Eve , Barre Jessica , Le Pham Tammy , Cowan Kyle N. 
Published: July 2016

Abstract
Rhabdomyosarcoma (RMS) is a skeletal muscle-derived soft tissue sarcoma for which a novel therapeutic strategy is greatly needed. RMS cells have lost the ability to terminally differentiate thus proliferating indefinitely. Promoting their redifferentiation to skeletal muscle tissue is thus a promising therapeutic approach. We have recently shown that levels of Pannexin 1 (Panx1) are below detectable limits in undifferentiated myoblasts, but become highly upregulated during their differentiation and indeed promote this process. We thus hypothesize that the levels of Panx1 are deregulated in RMS and that restoration of Panx1 levels may induce differentiation of RMS cells thereby alleviating their malignant properties. Briefly, our results demonstrate that both Panx1 transcript and protein are at very low levels in, both embryonal and alveolar RMS tumor specimens and patient-derived cell lines similar to that seen in fetal skeletal muscle tissue and undifferentiated myoblasts, respectively. In vitro functional analyses have revealed that while re-introduction of Panx1 in RMS cell lines led to their partial differentiation, it significantly inhibited their rate of proliferation and migration. Moreover, re-expression of Panx1 in RMS cell lines prevented both spheroid formation and growth, and induced RMS cell apoptosis. Based on this in vitro data, pre-clinical orthotopic xenograft studies are currently underway to assess the ability of Panx1 to inhibit tumor onset and growth, and induce tumor regression in vivo. Our preliminary results thus far have shown that Panx1 over-expression significantly suppresses RMS xenograft tumor growth. Taken together, these results indicate that restoration of Panx1 levels in RMS reduces its malignant properties. This, together with further investigation into the tumor-suppressive mechanism by which Panx1 mediates its effects, will establish Panx1 as a novel therapeutic target for RMS.
Citation Format: Xiao Xiang, Stephanie Langlois, Marie-Eve St-Pierre, Jessica Barre, Tammy Le Pham, Kyle N. Cowan. Pannexin 1 regulates rhabdomyosarcoma tumor growth: a potential novel therapeutic target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1276.
Abstract 1278: Popdc proteins: novel targets in inhibiting breast cancer cell migration and proliferation
Authors: Amunjela Johanna N. , Tucker Steven J. 
Published: July 2016

Abstract
Tumour growth and metastasis are major challenges in cancer treatment and metastasis is the primary cause of death in more than 90% of cancer patients with solid tumours (Gupta & Massagué 2006). This necessitates identification and validation of clinically relevant anticancer therapeutic targets that result in maximum clinical efficacy with minimal side-effects when manipulated by drugs. Our research project has identified Popeye domain containing (Popdc) proteins as promising potential therapeutic targets in the treatment of breast cancer.
Popdc proteins are a class of membrane-tethered proteins encoded by the three members of the Popdc gene family Popdc1, Popdc2 and Popdc3. Their suppression has been correlated with disease progression and poor clinical outcomes in various cancers including breast cancer, gastric cancer, lung cancer, hepatocellular carcinoma and colorectal cancer (Kim et al., 2010, Luo et al., 2012, Williams et al., 2011, Wang et al., 2011). Loss of Popdc protein expression has been correlated with increased cancer cell migration, invasion, metastasis, drug-resistance and poor patient survival (Luo et al., 2012, Williams et al., 2011, Han et al., 2014). In breast cancer, Popdc1 suppression has been reported in breast carcinoma cells while upregulation of Popdc2 has been linked to the mechanism by which arsenic trioxide mediates breast cancer cell death (Williams et al., 2011, Wang et al., 2011).
Our use of various assays including single-cell migration assays, cell population migration assays, cell proliferation assays and fluorescent imaging strongly implicate Popdc proteins as drivers of cancer cell migration and proliferation. Expression patterns of Popdc proteins revealed high expression levels in non-malignant (HMepC) breast cells and low expression in breast cancer (MCF7) cells. This suggests that loss of Popdc protein expression correlates with an increasingly malignant phenotype. Furthermore, knocking down Popdc1, Popdc2 and Popdc3 in MCF7 breast cancer cells significantly promoted cell migration both at single cell and at cell population level while Popdc2 knockdown significantly promoted unstimulated MCF7 cell division. Taken together, this strong data set suggests that Popdc proteins play significant roles in the migration and proliferation of different cancer cell lines and that they indeed represent promising potential therapeutic targets in reducing breast cancer cell division and migration.
Citation Format: Johanna N. Amunjela, Steven J. Tucker. Popdc proteins: novel targets in inhibiting breast cancer cell migration and proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1278.