bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1139: Translational control of MYC protein stability as a target of small molecules
Authors: Ikegaki Naohiko , Baloch Luqman , Chu Christopher , Lomahan Joshua , Harris Jamie , Chiu Bill 
Published: July 2016

Abstract
It is well established that MYC family proteins drive tumor growth and sustain the malignant phenotype. However, MYC family proteins have gained the reputation of being “un-druggable” by small molecule inhibitors. This is because MYC proteins lack intrinsic enzymatic activities or appropriate molecular grooves to which small molecules may bind and inhibit their function. Nonetheless, previous studies suggest that MYC family proteins (MYC, MYCN, MYCL) can be “targetable” indirectly by accelerating their turnover rate at different biochemical pathways that regulate the steady state level of the proteins. These include transcriptional-inhibition of the corresponding genes and acceleration of their proteasome-dependent degradation. The goal of this study is to gain a better understanding of how the MYC family protein turnover is regulated, which in turn might help develop future new drugs against “MYC family-driven” cancers. We have used neuroblastoma, a childhood cancer, as a disease model and identified several small molecules that rapidly destabilize MYC and MYCN proteins in MYC-driven neuroblastoma cells. The small molecules include FCCP, OSU-03012 and Salinomycin. Preliminary data suggest that the common target of these compounds is mitochondria. Recently, we have also found Halofuginone, an FDA approved orphan drug for Scleroderma treatment exhibits a similar MYC-destabilizing activity. At submicromolar concentrations and less than one hour of drug-treatment, Halofuginone rapidly causes significant down-regulation of MYC proteins in neuroblastoma cells. Halofuginone is known to activate the eIF2α pathway, which controls translation. Activation of the eIF2α pathway is initiated by the activation of eIF2a kinases (GCN2, HRI, PERK, PKR) via autophosphorylation by various stress-related stimuli such as reactive oxygen species and misfolded proteins. The activated eIF2α kinases then inactivates eIF2α by phosphorylation, which subsequently halts translation globally. Interestingly, FCCP, OSU-03012 and Salinomycin treatments also caused eIF2α phosphorylation. These observations suggest that activation of the eIF2α pathway results in translational block of the MYC family protein expression in tumor cells. Because half-lives of MYC family proteins are very short, a sudden attenuation in protein translation can cause rapid down-regulation of the proteins. Hence, activation of the eIF2α pathway by small molecules may prove effective for rapid down-regulation of MYC family proteins in MYC-driven cancer cells.
Citation Format: Naohiko Ikegaki, Luqman Baloch, Christopher Chu, Joshua Lomahan, Jamie Harris, Bill Chiu. Translational control of MYC protein stability as a target of small molecules. [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 1139.
Abstract 1153: Hand-1 overexpression inhibits medulloblastoma cell invasion and metastatic ability via Oct-3/4 / β-catenin interaction
Authors: Asuthkar Swapna , Guda Maheedhara R. , Tsung Andrew J. , Antony Reuben , Dinh Dzung H. , Velpula Kiran K. 
Published: July 2016

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. Treatment of medulloblastoma includes surgery, radiation and chemotherapy. Despite long-term survival for the majority of children, 50% of medulloblastomas recur. Recently, medulloblastomas are classified into four distinct molecular subgroups, viz., WNT, SHH, group 3, and group 4 based on constitutive activation of WNT/β-catenin, SHH, and NOTCH signaling pathways that regulate cancer stem cell pluripotency, tumor growth, progression and metastasis. Previously, we investigated the molecular machinery underlying uPAR and WNT/β-catenin interdependent signaling pathways in medulloblastoma stem cells. Further, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. Complementing to this we demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand-1. Here, we show that Hand-1 expression is observed to be downregulated in all the molecular subgroups of medulloblastoma. We also showed that the pluripotency marker, Oct-3/4 (encoded by the Pou5f1 gene) interacts with β-catenin and Hand-1 that ultimately regulated the uPAR expression. Our preliminary study demonstrated that Oct-3/4 preferentially cooperated with β-catenin in medulloblastoma to maintain tumor progression. Immunohistostaining of clinical specimens also confirmed our aforementioned results. Taken together, our studies show that overexpression of Hand-1 in medulloblastoma cells may effectively inhibit uPAR-induced invasion and metastatic ability, thereby regulating Oct-3/4/β-catenin balance.
Citation Format: Swapna Asuthkar, Maheedhara R. Guda, Andrew J. Tsung, Reuben Antony, Dzung H. Dinh, Kiran K. Velpula. Hand-1 overexpression inhibits medulloblastoma cell invasion and metastatic ability via Oct-3/4 / β-catenin interaction. [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 1153.
Abstract 1166: The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) invasion and migration
Authors: Hou Hsin-Han , Yu Chong-Jen 
Published: July 2016

Abstract
Emerging evidence has indicated that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. One member of this family, ADAM15, has been shown to be upregulated in multiple cancers, including gastric, lung, breast, and prostate cancers, and the enzymatic activities of its extracellular metalloprotrease domain promote breast cancer proliferation and migration through mediating ErbB signaling pathway. The patients with ADAM15 high-expressing lung tumors have shorter survival time and enzymatic activity of ADAM15 extracellular domain activates MMP-9 and promotes NSCLC migration and invasion. We firstly demonstrated other than extracellular enzymetic activity, the longest isoform of ADAM15 (ADAM15 i6), which contains the most cytoplasmic Src homology 3 (SH3) binding motifs, significantly upregulated in primary lung cancer tissues and promoted NSCLC proliferation via growth factor receptor-bound protein 2 (Grb2) and Src homolog 2 domain containing (Shc) association. In this study, we further explore the roles of ADAM15 cytosolic domain in NSCLC invasion and migration. Overexpression of ADAM15 i6 promoted CL1-0 cell invasion and migration according to the transwell and wound healing assay. Ablation of Ras protein activator (RASA)1 and protein tyrosine kinase (PTK)6 attenuated the ADAM15 i6-promoted invasion and migration respectively. Thus, we identified a novel mechanism of the ADAM15 cytoplasmic domain in NSCLC tumor progression, which will shed light on the molecular mechanisms of ADAM proteins, and facilitate development of novel therapy in NSCLC.
Citation Format: Hsin-Han Hou, Chong-Jen Yu. The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) invasion and migration. [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 1166.
Abstract 1182: Heparin-binding epidermal growth factor-like growth factor is a pro-differentiating factor in neuroblastoma
Authors: Gaviglio Angela L. , Blobe Gerard C. 
Published: July 2016

Abstract
Neuroblastoma is the most common cancer in infancy. Current therapies are only modestly effective; patients with high-risk disease have less than a 50% chance of survival. High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low Schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble proteins, including heparan sulfate proteoglycans (HSPGs), which act to promote neuroblast differentiation.
Here we identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent pro-differentiating factor in neuroblastoma. Using microarray analysis, HBEGF mRNA expression is decreased in neuroblastoma compared to benign disease, correlating to an increase in mortality. HBEGF protein is expressed only in stromal compartments of tumor specimens, with tissue from high-stage disease having decreased stroma and HBEGF. Soluble HBEGF increased neuroblast differentiation and decreased proliferation, while HBEGF knockdown decreased neuroblast differentiation. In patient samples, HBEGF expression correlates with SOX10, a neural crest differentiation marker, and the cell cycle inhibitor, CDKN1A. Alternatively, HBEGF negatively correlates with ASCL1, a primitive neuroectodermal marker, and the cell cycle promoter CCND1. HSPGs, including TβRIII, GPC1, GPC3, and SDC3 further promote the differentiating effects of HBEGF treatment by forming a complex with the epidermal growth factor receptor (EGFR) via glycosaminoglycan modifications, leading to activation of the Erk1/2 pathway and upregulation of the inhibitor of DNA binding transcription factor, whose expression correlates with HBEGF in patient samples. Inhibition of EGFR with erlotinib, lapatinib, and gefitinib diminish HBEGF-induced differentiation.
These data identify a novel member of the pro-differentiating secretome and support the use of heparan sulfate mimetics in neuroblastoma, while cautioning against the use of EGFR inhibitors for neuroblastoma treatment.
Citation Format: Angela L. Gaviglio, Gerard C. Blobe. Heparin-binding epidermal growth factor-like growth factor is a pro-differentiating factor in neuroblastoma. [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 1182.
Abstract 1196: Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN
Authors: Ligon Gwenda F. , Lillquist Jay S. , Seibel Scott B. , Wallweber Jerry , Neumeister Veronique , Rimm David L. , LaVallee Theresa M. , Alvarado Diego 
Published: July 2016

Abstract
ErbB3, the kinase-dead member of the EGFR/ErbB family, has been implicated as an oncogenic driver in a number of solid tumor types, including squamous cell carcinoma of the head and neck (SCCHN). However, clinical trials have demonstrated limited responses with certain single agent anti-ErbB3-directed therapies, suggesting that multiple ErbB inhibition and/or biomarker-directed patient selection may be beneficial. The anti-EGFR antibody cetuximab has demonstrated improved overall survival in SCCHN, but the overall response rate is relatively low. Several preclinical studies have suggested that pan-ErbB inhibition may result in improved clinical benefit and additionally, may overcome cetuximab resistance. Here we show that ErbB3 and its ligand neuregulin (NRG) are widely expressed in SCCHN, and that ErbB2, but not EGFR, drives ErbB3 activation in the presence of NRG. Although NRG is required for ErbB3 activation, it is not sufficient to fully predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN models. Metadata analysis of human SCCHN tumors revealed that NRG expression is significantly associated with expression of EGFR ligands amphiregulin (AREG) (P&lt;0.0001; R2 = 0.33) and transforming growth factor α (TGFα) (P&lt;0.0001; R2 = 0.25) but not other EGFR ligands. We demonstrate using NRG-positive cell lines that KTN3379 antitumor activity correlates with the level of secreted AREG and TGFα. Using a proximity-based assay for EGFR homodimerization as a surrogate assay for ligand (AREG or TGFα)-induced EGFR activation, we show that high EGFR homodimer levels correlate with KTN3379 antitumor activity in NRG-positive SCCHN cell lines and primary tumor models in vitro and in vivo. These preclinical studies provide the molecular rationale for combination treatment with KTN3379 and cetuximab in SCCHN patients. We propose that an enrichment strategy for NRG expression and EGFR activation signature may result in better clinical activity in response to treatment with KTN3379 and cetuximab in SCCHN patients.
Citation Format: Gwenda F. Ligon, Jay S. Lillquist, Scott B. Seibel, Jerry Wallweber, Veronique Neumeister, David L. Rimm, Theresa M. LaVallee, Diego Alvarado. Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN. [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 1196.
Abstract 1211: Killing cancer one cell at a time: Development and characterization of a novel antibody drug conjugate
Authors: Xiao Michael , Chu Roger , Pagaduan Jayson , Robison Richard A. , O’Neill Kim L. 
Published: July 2016

Abstract
Thymidine Kinase 1 (TK1) is a protein that we have established to be present on the surface of cancer cells and absent on the surface of normal cells. Various methods have been used to confirm the presence of TK1 using localization methods such as scanning electron microscopy gold labeling, fluorescence imaging, and flow cytometry analysis. In this project, we explored the potential of using the TK1 marker as a therapeutic target by conjugating an anti-TK1 antibody to the toxin saporin, a ribosome inhibiting protein derived from the seeds of Saponaria officinalis. The toxin is widely used in the biological and neurological fields due to its stability and adaptability. An additional benefit to using this particular toxin is the inability of saporin to transverse the cell membrane without an antibody or other agent mediating internalization into the cell. We expressed a cysteine mutated form of saporin in the BL21(DE3) E. coli strain. Saporin from the expressed protein was subsequently isolated with a cation exchange cellulose column before verification on a non-reducing SDS-PAGE gel. A single band was observed at approximately 30 kD, indicating purity of the protein. After thiolation of the amine groups in the anti-TK1 antibody, the cysteine residues on the mutated saporin toxin was linked to the antibody through the formation of disulfide bonds. Further purification of the conjugate was achieved by eliminating unconjugated saporin and antibody, and high molecular weight aggregates using a Sephacryl S-200 column. Over 90% cancer cell death was observed in the Burkitt's Lymphoma Raji cell line when exposed to conjugate concentrations of 10 nM. Complete cell death was observed with exposure to 100 nM concentrations. In addition, there was a significant difference between the saporin conjugated treated and untreated samples (p &lt; 0.001). Further tests are underway to determine the effectiveness of the conjugate in other cancer cell lines. These promising results suggest the use of saporin in an effective antibody drug conjugate therapeutic that could influence the way we treat cancer: a drug that will selectively target cancer cells.
Citation Format: Michael Xiao, Roger Chu, Jayson Pagaduan, Richard A. Robison, Kim L. O’Neill. Killing cancer one cell at a time: Development and characterization of a novel antibody drug conjugate. [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 1211.
Abstract 1218: A novel synergistic antibody pair targeting non-overlapping epitopes of MET effectively inhibits MET-driven cancer models
Authors: Grandal Michael M. , Poulsen Thomas T. , Koefoed Klaus , Eriksen Karsten W. , Dahlman Anna , Conrotto Paolo , Bouquin Thomas , Jacobsen Helle , Horak Ivan D. , Kragh Michael , Lantto Johan , Pedersen Mikkel W. 
Published: July 2016

Abstract
The receptor tyrosine kinase MET (Hepatocyte Growth Factor Receptor, HGFR) has been associated with development and progression of a range of human tumors due to its regulation of cell proliferation, migration, invasion, and angiogenesis. A subset of human tumors, particularly of lung or gastric origin, appear to have a primary dependency on MET, which is driven by alterations, such as MET-gene amplification, MET-exon 14 deletion, activating mutations, or autocrine HGF production. Furthermore, MET-amplification has been reported as a key mechanism of de novo resistance to EGFR targeting agents.
Sym015 is a mixture of two humanized monoclonal antibodies against non-overlapping epitopes on MET. The specific pair of antibodies was identified in a high-throughput cell based screen searching for antibody mixtures with superior growth inhibitory activity against four MET-dependent cell lines. Both antibodies bind the SEMA domain of MET with high affinity. Synergistic activity was confirmed by dose-response curves in several MET-dependent cell lines and cell line and patient-derived xenograft models. Mechanistically, Sym015 blocks HGF binding to MET, induces MET internalization and degradation effectively diminishing MET oncogenic signaling. Sym015 also induces higher levels of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro compared to individual mAbs.
In conclusion, Sym015, a novel monoclonal antibody mixture against MET, shows strong inhibitory activity against MET driven cell lines and xenografts due to a combined effect of MET degradation and secondary effector functions. These data support initiation of clinical trials.
Citation Format: Michael M. Grandal, Thomas T. Poulsen, Klaus Koefoed, Karsten W. Eriksen, Anna Dahlman, Paolo Conrotto, Thomas Bouquin, Helle Jacobsen, Ivan D. Horak, Michael Kragh, Johan Lantto, Mikkel W. Pedersen. A novel synergistic antibody pair targeting non-overlapping epitopes of MET effectively inhibits MET-driven cancer 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 1218.
Abstract 1231: Novel chromene analogs as small-molecule microtubule destabilizers for the treatment of chemo-resistant ovarian cancer
Authors: Kulshrestha Arpita , Ibrahim Safaa A. , Katara Gajendra K. , Patil Renukadevi , Patil Shivaputra , Beaman Kenneth D. 
Published: July 2016

Abstract
Ovarian cancer is the most lethal gynecological malignancy with a 5-year survival rate of less than 40%, primarily because of treatment failure due to emergence of chemo-resistance to standard agents. This indicates a dire need for new treatments to improve survival rates. The tubulin dynamics is a promising target for new chemotherapeutic agents. In continuation of our efforts, using medicinal chemistry approach, we recently identified small molecular inhibitors of tubulin polymerization called chromenes, as new ovarian anti-cancer agents. A set of chromene compounds were screened for anti-cancer effect on cisplatin sensitive (A2780, SKOV-3, TOV112D) and cisplatin resistant (OVCAR-3, A2780-cisR, TOV112D-cisR) ovarian cancer cells. In vitro cell viability was assessed by fluorescence based Alamar Blue assay. Our preliminary studies identified SP-6-27 (IC50 range: 0.102± 0.006 - 2.24±0.056 μM) and SP-6-37 (IC50 range: 0.258± 0.159 - 3.61±0.049 μM) as most potent chromene analogs. Both compounds exhibited a potent anticancer activity towards both cisplatin sensitive (SP-6-27 IC50: 0.14± 0.03 μM; SP-6-37 IC50: 1.35± 0.88 μM) and cisplatin resistant (SP-6-27 IC50: 0.81± 1.2 μM; SP-6-37 IC50: 2.09± 1.7 μM) cell lines. The compounds exhibited least cytotoxicity towards normal ovarian epithelial cells (SP-6-27- IC50: 83.35 ± 9.47 μM; SP-6-37- IC50: 75.77 ± 5.37 μM). Additionally, the analysis of apoptotic changes as determined by Annexin-V assay revealed an enhanced apoptosis in both cisplatin sensitive and resistant cells upon treatment with compounds SP-6-27 or SP-6-37. Together, the data demonstrates that ovarian cancer cell lines respond sensitively to SP-6-27 and SP-6-37, demonstrating that the chromene scaffold is effective in suppressing ovarian cancer cell growth. The findings indicate that the novel chromene analogs are a new class of chemotherapeutic agents that will offer advantages for the treatment of ovarian cancer.
Citation Format: Arpita Kulshrestha, Safaa A. Ibrahim, Gajendra K. Katara, Renukadevi Patil, Shivaputra Patil, Kenneth D. Beaman. Novel chromene analogs as small-molecule microtubule destabilizers for the treatment of chemo-resistant ovarian 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 1231.
Abstract 1256: Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in cancer
Authors: Taylor Amanda , Adams Clare , Zhang Xiao-yong , Gennaro Victoria , Cotney Justin , Shadel Gerald , Cameron Craig , Eischen Christine , McMahon Steven 
Published: July 2016

Abstract
The MYC transcription factor is the most dramatically overexpressed gene product in human cancer. However, defining the MYC-driven transcriptome critical to malignant transformation has remained a challenge, in part because MYC controls several thousand genes. Consequently, little progress has been made in the identification of sensitive nodes downstream of MYC that might be targeted therapeutically in order to interrupt its oncogenic signaling. To overcome this impediment, we performed a screen for downstream MYC effector pathways that are selectively linked to MYC's functional properties. Via this strategy, we identified the mitochondrial RNA polymerase (POLRMT) as a direct downstream target of MYC. POLRMT induction by MYC regulates transcription of the mitochondrial genome, as well as mitochondrial DNA replication. Recent studies have shown that POLRMT also interacts with a mitochondrial ribosomal RNA methyltransferase TFB1M to regulate mitochondrial ribosome assembly. Notably, blocking induction of POLRMT (or TFB1M) by MYC converts the cellular response to MYC activation from enhanced cell cycle progression to apoptotic cell death. Of immediate clinical relevance, compounds blocking mitochondrial gene expression at any of several steps cause acute synthetic lethality with oncogenic levels of MYC. Among these compounds, the mitochondrial targeting antibiotic Tigecycline is FDA-approved and well-tolerated in patients. Tigecycline eliminates tumor formation and dramatically improves survival in our animal model of MYC-driven lymphoma. Evidence presented here demonstrates that uncoupling of MYC's nuclear and mitochondrial transcriptomes exposes a point of exquisite vulnerability in tumor cells. Although targeting MYC as a therapeutic strategy has proven to be challenging in the past, our identification of a new node of sensitivity in MYC-driven cancers offers a potential for broad therapeutic implications.
Citation Format: Amanda Taylor, Clare Adams, Xiao-yong Zhang, Victoria Gennaro, Justin Cotney, Gerald Shadel, Craig Cameron, Christine Eischen, Steven McMahon. Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in 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 1256.