bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4422: Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation
Authors: Lee Yu Ran , Joo Hee Kyoung , Kim Ki Mo , Jeon Byeong Hwa , Choi Sunga 
Published: July 2016

Abstract
The present study evaluated the mechanism of apoptosis caused by posttranslational modification, hyperacetylation in triple-negative breast cancer (TNBC) cells. We previously showed that trichostatin A (TSA) induced secretion of acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that Ac-APE1/Ref-1 initiates apoptosis in TNBC cells by binding to the receptor for advanced glycation end products (RAGE). The functional significance of secreted Ac-APE1/Ref-1 was studied by induction of intracellular hyperacetylation through co-treatment with acetylsalicylic acid and TSA in MDA-MB-231 cells. In response to hyperacetylation, secretion of Ac-APE1/Ref-1 in vesicles was observed, resulting in significantly decreased cell viability and induction of apoptosis with increased expression of RAGE. The hyperacetylation-induced apoptosis was similar in two other TNBC cell lines: BT-459 and MDA-MB-468. Therefore, hyperacetylation may be a therapeutic target for treatment of TNBCs. This study introduces a novel paradigm whereby posttranslational modification induces apoptotic cell death in breast cancer cells resistant to standard chemotherapeutic agents through secretion of auto- or paracrine molecules such as Ac-APE1/Ref-1.
Citation Format: Yu Ran Lee, Hee Kyoung Joo, Ki Mo Kim, Byeong Hwa Jeon, Sunga Choi. Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation. [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 4422.
Abstract 4647: BET protein inhibition blocks growth of triple-negative breast cancer by inducing mitotic and cytokinetic dysfunction
Authors: Brancato Jennifer M. , Gayle Sylvia , Weber-Bonk Kristen , Summers Matthew , Bebek Gurkan , Keri Ruth 
Published: July 2016

Abstract
Bromodomain and Extra Terminal (BET) proteins are epigenetic “readers” that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer. It has been recently found to associate with super-enhancers, and elevated levels of BRD4 have been linked to increased expression of MYC as well as other oncogenes. BET protein inhibitors are currently being tested for their potential use in the treatment of HIV, heart failure, and cancer, all of which are diseases of aberrant transcription. However, little is known regarding their efficacy in triple-negative breast cancer (TNBC). We found JQ1, a prototypical BET inhibitor, impedes growth of seven TNBC cell lines in a dose-dependent manner within 72 hours of treatment. JQ1 also suppresses growth of three different TNBC xenografts, including a patient-derived model of basal-like breast cancer. Growth arrest, in vitro, is followed by either apoptosis or senescence. However, prior to the induction of these two terminal responses, prolonged treatment results in polyploidy in many of the cell lines, suggesting BETi disrupts mitosis/cytokinesis. Live-cell imaging revealed JQ1 significantly increased the duration of mitosis, and microarray analyses showed a significant JQ1-mediated downregulation of genes critical for cell cycle progression, mitosis, and cytokinesis. In all TNBC cell lines tested, Aurora kinases, proteins critical for proper progression through mitosis and cytokinesis, are suppressed in response to JQ1. Treatment with AZD1152, an Aurora kinase B inhibitor, elicits the same cellular responses as BET inhibition, indicating that the suppression of Aurora kinases plays a key role in the response of TNBC cells to BET inhibitors. These findings reveal that BET inhibitors block the growth of highly aggressive TNBC cells by inducing mitotic dysfunction and that these drugs are promising potential therapeutics for the treatment of TNBC.
Citation Format: Jennifer M. Brancato, Sylvia Gayle, Kristen Weber-Bonk, Matthew Summers, Gurkan Bebek, Ruth Keri. BET protein inhibition blocks growth of triple-negative breast cancer by inducing mitotic and cytokinetic dysfunction. [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 4647.
Abstract 4694: ABBV-075, a novel BET family inhibitor, disrupts critical transcription programs that drive prostate cancer growth to induce potent anti-tumor activity in vitro and in vivo
Authors: Faivre Emily J. , Wilcox Denise M. , Hessler Paul , Uziel Tamar , Tapang Paul , Magoc Terry , Albert Daniel H. , Fang Guowei , Rosenberg Saul , McDaniel Keith , McDaniel Keith , Kati Warren , Shen Yu 
Published: July 2016

Abstract
The novel bromodomain inhibitor, ABBV-075, is being tested in a Phase I study for the treatment of solid tumors. Here, we show that potent inhibition of the BET (bromodomain and extra-terminal) family with ABBV-075 is a highly efficacious therapy in pre-clinical models of prostate cancer. The single-digit to low nanomolar anti-proliferative IC50s and potent in vivo tumor growth inhibition of ABBV-075 is mediated in part via inhibition of androgen receptor (AR)-dependent transcription. Prostate tumor incidence and CRPC clinical progression are driven by aberrant activation of the AR transcription program. Gene expression profiling and qPCR results indicate that ABBV-075 inhibited DHT-stimulated transcription of AR target genes without significant effect on AR protein expression. Further, ABBV-075 disrupted DHT-stimulated recruitment of the BET family member BRD4 to gene regulatory regions co-occupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition led to the disassembly of AR occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and additionally downregulated enhancer RNA (eRNA) transcription. ABBV-075 displayed potent anti-proliferative activity in multiple models of resistance to the second generation anti-androgen Enzalutamide, including the F876L, L702H AR ligand binding domain mutations and the AR-V7 splicing variant. In addition to blocking the transcription activation downstream of AR, ABBV-075 is also a potent inhibitor of MYC and the TMPRSS2-ETS fusion proteins. Thus, we propose that ABBV-075 may provide a promising therapeutic option for CRPC patients who have developed resistance to second-generation anti-androgens.
Citation Format: Emily J. Faivre, Denise M. Wilcox, Paul Hessler, Tamar Uziel, Paul Tapang, Terry Magoc, Daniel H. Albert, Guowei Fang, Saul Rosenberg, Keith McDaniel, Keith McDaniel, Warren Kati, Yu Shen. ABBV-075, a novel BET family inhibitor, disrupts critical transcription programs that drive prostate cancer growth to induce potent anti-tumor activity in vitro and in vivo. [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 4694.
Abstract 4746: Pharmacological characterization of BAY-876, a novel highly selective inhibitor of glucose transporter (GLUT)-1 in vitro and in vivo
Authors: Kopitz Charlotte , Toschi Luisella , Algire Carolyn , Héroult Mélanie , Frisk Anna-Lena , Meyer Kirstin , Schmitz Arndt , Lagkadinou Eleni , Petrul Heike , Heisler Iring , Neuhaus Roland , Buchmann Bernd , Himmel Herbert , Bauser Marcus , Haegebarth Andrea , Ziegelbauer Karl 
Published: July 2016

Abstract
One hallmark of cancer is the accelerated metabolism, high energy requirements, and increased glucose uptake by the tumor cells, the latter being the first and rate-limiting step for glucose metabolism. Glucose transport into the tumor cell is mediated by facilitative high-affinity glucose transporter (GLUT) proteins. Among the 14 GLUT proteins, expression of GLUT1 in normal organs is nearly exclusively restricted to the blood brain barrier, while other GLUTs are also expressed in a wide variety of vital organs such as liver and heart. Interestingly, GLUT1 expression is highly regulated by hypoxia-inducible factor (HIF)-1α, a key driver of tumor progression. In line with this finding, GLUT1 over-expression was found to be associated with tumor progression and poor overall survival in various tumor indications. Consequently, GLUT1 represents a potential target for cancer treatment. Therefore, we have developed a highly-selective GLUT1 inhibitor, namely BAY-876, with selectivity over GLUT2, 3, and 4 of 4700-, 800-, and 135-fold, respectively. We here show for the first time the pharmacological characterization of BAY-876, comprising inhibition of glucose-uptake, anti-proliferative activity in vitro, and anti-tumor efficacy in vivo in models of different tumor indications in monotherapy as well as first results on the combinability of BAY-876. Furthermore, at the therapeutic dose, BAY-876 treatment did not show any relevant finding on the behavior of treated mice in the Irwin test, assuming no or only minor effects on brain function. In conclusion, BAY-876 is the first GLUT1-selective inhibitor which reduces glucose uptake and growth of tumor cells with sufficient tolerability at the efficacious dose in preclinical models.
Citation Format: Charlotte Kopitz, Luisella Toschi, Carolyn Algire, Mélanie Héroult, Anna-Lena Frisk, Kirstin Meyer, Arndt Schmitz, Eleni Lagkadinou, Heike Petrul, Iring Heisler, Roland Neuhaus, Bernd Buchmann, Herbert Himmel, Marcus Bauser, Andrea Haegebarth, Karl Ziegelbauer. Pharmacological characterization of BAY-876, a novel highly selective inhibitor of glucose transporter (GLUT)-1 in vitro and in vivo. [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 4746.
Abstract 4798: Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL
Authors: Balasubramanian Wesley Roy , Gummadi Venkateshwar Rao , Nellore Kavitha , Mukherjee Subhendu , Marappan Sivapriya , Basavaraju Aravind , Ainan Bharathi Raja , Daginakatte Girish , Gopinath Sreevalsam , Giri Sanjeev , Antony Thomas , Chelur Shekar , Samajdar Susanta , Pandit Chetan , Ramachandra Murali 
Published: July 2016

Abstract
Interleukin-1 receptor associated kinases (IRAKs) are serine/threonine protein kinases belonging to the tyrosine-like kinase (TLK) family. IRAKs function as mediators of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and play an important role in innate immune signaling. TLR/IL-1R stimulation leads to recruitment of MYD88, an adaptor molecule, to the activated receptor complex, which then complexes with IRAK4 and activates IRAK1. TRAF6 is then activated by IRAK1 leading to NFkB activation. Recent studies have reported the occurrence of gain of function oncogenic mutation (L265P) in MYD88 in ∼30% of activated B cell diffuse large B-cell lymphoma(ABC DLBCL) and ∼90% of Waldenstrom's macroglobulinemia (WM) leading to constitutive activation of IRAK4 and NFkB pathway. Among the DLBCL subtypes (GCB, ABC DLBCL and PMBL), ABC DLBCL is the most refractory. Inhibition of constitutive IRAK4 signalling can be used as a therapeutic strategy to treat ABC DLBCL
Small molecule inhibitors of IRAK4 were synthesized based on hits originating from Aurigene's compound library. Structure guided drug design approach was used to further improve the potency. Lead compounds demonstrated moderate to very high selectivity towardsIRAK4 (S35 score of 0.03) when screened against a large panel of 329 kinases. Aurigene's lead compounds have excellent PK profile and good oral bioavailability in mice, leading to good in-vivo activity in TLR4 induced cytokine release model. Selected lead compounds were tested in a OCI-Ly3 xenograft model, which has a MYD88(L265P) mutation leading to constitutive activation of IRAK4 signaling. An advanced lead compound has demonstrated excellent efficacy in OCI-Ly3 model, with tumor stasis at low doses and tumor regression at higher doses. The compound is well tolerated and has a good therapeutic window as determined in a 14 day rodent toxicity study. In summary, a selective IRAK4 inhibitor has been identified with excellent efficacy and good safety profile.
Citation Format: Wesley Roy Balasubramanian, Venkateshwar Rao Gummadi, Kavitha Nellore, Subhendu Mukherjee, Sivapriya Marappan, Aravind Basavaraju, Bharathi Raja Ainan, Girish Daginakatte, Sreevalsam Gopinath, Sanjeev Giri, Thomas Antony, Shekar Chelur, Susanta Samajdar, Chetan Pandit, Murali Ramachandra. Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL. [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 4798.
Abstract 4800: Covalent Flt3-Cys828 inhibition represents a novel therapeutic approach for the treatment of Flt3-ITD and Flt3-D835 mutant acute myeloid leukemia
Authors: Versele Matthias , Haefner Burkhard , Wroblowski Berthold , Stansfield Ian , Mevellec Laurence , Gilissen Ron , Neumann Lars , Augustin Martin , Jacobs Kris , Cools Jan , Barluenga S , Röthlingshöfer M , Karthikeyan G , Attar Ricardo , Meerpoel Lieven , Winssinger Nicolas 
Published: July 2016

Abstract
Inhibition of Flt3 kinase activity is a promising strategy for the treatment of Flt3 mutant acute myeloid leukemia (AML). However, clinical studies with Flt3 kinase inhibitors have shown that mutations of the gate keeper or an activation loop residue in the Flt3 catalytic domain limits the duration of response. Such mutations generally reduce kinase domain binding affinity and residence time of the kinase inhibitor, and consequently its efficacy. We therefore investigated whether covalent, irreversible binding to Flt3 could overcome some of the limitations of classic non-covalent Flt3 inhibitors. Here, we report for the first time on the high-affinity Cys828-covalent binding mode of a resorcylic acid lactone to the isolated Flt3 kinase domain using X-ray crystallography and kinetic binding assays. In a cellular context (Ba/F3-Flt3-ITD), mutation of Cys828 to Ala reduces potency (IC50) from low nM to microM, demonstrating all relevant Flt3 inhibition in cells critically depends on Cys828. Consistently, the molecule is a low nM inhibitor of both Flt3-ITD and Flt3D835Y in vitro and in BaF3 cells, translating to potent nM inhibition of Flt3-ITD driven AML cell line proliferation, with only microM antiproliferative activity in non-Flt3 driven AML and unrelated leukemia cell lines. Finally, in spite of its fast clearance when dosed to MV4-11 (Flt3-ITD AML) xenograft bearing mice, robust anti-tumor activity was observed using a once-daily treatment schedule. These data demonstrate the feasibility of covalent Flt3 inhibition, and suggest it represents an attractive novel therapeutic approach for the treatment of Flt3-driven AML.
Citation Format: Matthias Versele, Burkhard Haefner, Berthold Wroblowski, Ian Stansfield, Laurence Mevellec, Ron Gilissen, Lars Neumann, Martin Augustin, Kris Jacobs, Jan Cools, S Barluenga, M Röthlingshöfer, G Karthikeyan, Ricardo Attar, Lieven Meerpoel, Nicolas Winssinger. Covalent Flt3-Cys828 inhibition represents a novel therapeutic approach for the treatment of Flt3-ITD and Flt3-D835 mutant acute myeloid leukemia. [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 4800.
Abstract 4855: Discovery of NVP-HDM201 - First disclosure of a Next-Generation Mdm2 inhibitor with superior characteristics
Authors: Holzer Philipp , Chène Patrick , Ferretti Stéphane , Furet Pascal , Gabriel Tobias , Gruenenfelder Bjoern , Guagnano Vito , Hofmann Francesco , Kallen Joerg , Mah Robert , Masuya Keiichi , Ramos Rita , Ruetz Stephan , Rynn Caroline , Stachyra-Valat Thérèse , Stutz Stefan , Vaupel Andrea , Jeay. Sébastien 
Published: July 2016

Abstract
Activation of p53 by blocking the p53-Mdm2 interaction using non-peptidic small-molecule inhibitors has been pursued for many years as a promising cancer therapeutic strategy.
We disclose the identity of NVP-HDM201, a novel, highly optimized and selective inhibitor of the p53-Mdm2 interaction. NVP-HDM201 binds to human Mdm2 protein with a sub-nanomolar Ki value, activates p53 and induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. The activity and selectivity of NVP-HDM201 have been tested and confirmed across a panel of cancer cell lines and the molecule displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability. Application of NVP-HDM201 using various dosing schedules triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancers.
We report here how a promising lead series was discovered and how innovative medicinal chemistry efforts led to further optimization of the potency and physico-chemical properties, culminating in the discovery of NVP-HDM201. The superior characteristics of the compound allowed the fast progression of the compound into the clinic where NVP-HDM201 is currently in Phase 1 clinical trials both as a single agent and as a combination partner in patients pre-selected for p53 wild-type tumors.
Citation Format: Philipp Holzer, Patrick Chène, Stéphane Ferretti, Pascal Furet, Tobias Gabriel, Bjoern Gruenenfelder, Vito Guagnano, Francesco Hofmann, Joerg Kallen, Robert Mah, Keiichi Masuya, Rita Ramos, Stephan Ruetz, Caroline Rynn, Thérèse Stachyra-Valat, Stefan Stutz, Andrea Vaupel, Sébastien Jeay. Discovery of NVP-HDM201 - First disclosure of a Next-Generation Mdm2 inhibitor with superior characteristics. [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 4855.
Abstract 4908: Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells
Authors: Sánchez-Paulete Alfonso R. , Cueto Francisco J. , Martínez-López María , Labiano Sara , Morales-Kastresana Aizea , Rodríguez-Ruiz Maria E. , Jure-Kunkel Maria , Azpilikueta Arantza , Quetglas José I. , Sancho David , Melero Ignacio 
Published: July 2016

Abstract
Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory monoclonal antibodies (mAbs) targeting PD-1 or CD137. Using Batf3-/- mice, which are defective for cross-presentation of cell-associated antigens, we show that Batf3-dependent dendritic cells (DCs) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3-/- mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFlt3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-OVA-derived melanomas, whereas this function was lost in Batf3-/- mice. These experiments show that cross-priming of tumor antigens by Flt3L- and Batf3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects.
Citation Format: Alfonso R. Sánchez-Paulete, Francisco J. Cueto, María Martínez-López, Sara Labiano, Aizea Morales-Kastresana, Maria E. Rodríguez-Ruiz, Maria Jure-Kunkel, Arantza Azpilikueta, José I. Quetglas, David Sancho, Ignacio Melero. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells. [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 4908.
Abstract 4914: Auristatin-based antibody drug conjugates activate multiple ER stress response pathways resulting in immunogenic cell death and amplified T-cell responses
Authors: Cao Anthony , Heiser Ryan , Law Che-Leung , Gardai Shyra J. 
Published: July 2016

Abstract
Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) directed against CD30. This ADC consists of monoclonal antibodies conjugated to the auristatin monomethyl auristatin E (MMAE) a microtubule-disrupting agent. ADC antitumor activity is thought to be primarily the result of intracellular payload release leading to mitotic arrest and apoptotic cell death. We have recently demonstrated that brentuximab vedotin induces surface expression of calreticulin and HSP70 as well as activation of the transcription factor ATF6 which are classical hallmarks of immunogenic cell death (ICD) associated with unfolded protein/ER stress response. In this study, we provide evidence that additional ER stress response pathways are activated.
Treatment of CD30+ Hodgkin lymphoma (HL) cells or xenografts with brentuximab vedotin resulted in the phosphorylation of the ER-associated, unfolded-protein response transmembrane protein inositol-requiring transmembrane kinase/endonuclease 1 (IRE1). Activation of IRE1 was confirmed by the increase in phosphorylation of the downstream effector Jun N-terminal kinase (JNK). Kinetics of tubulin disruption, ER stress induction, evidence of ICD, mitotic arrest, and apoptosis was assessed. Onset of ICD occurred concurrently with induction of ER stress response pathways including induction of pIRE1 and pJNK. Interestingly, induction of ER stress response and ICD preceded mitotic arrest and caspase activation. These results indicate that brentuximab vedotin-mediated disruption of the microtubule network contributes to ER stress, which maybe an apoptotic mechanism mediated by auristatin-ADCs in addition to mitotic arrest at G2/M phase of the cell cycle. Induction of ICD may also be a class effect of the auristatin-based ADCs, as the small molecule payload MMAE, was able to activate IRE1 and JNK and induced surface expression of calrecutilin on target cells.
Previously, brentuximab vedotin-killed HL cells were shown to induce innate immune cell activation in vitro and in vivo. Addition of ADC-killed tumor-like cells to autologous PBMCs results in the expansion of INFã-secreting cytotoxic T-cells. Via induction of ER stress, tumor cells killed by auristatin-based ADCs may initiate an antitumor immune response and provides a rationale for exploring therapeutic strategies that combine ADCs with other immune stimulatory regimens.
Citation Format: Anthony Cao, Ryan Heiser, Che-Leung Law, Shyra J. Gardai. Auristatin-based antibody drug conjugates activate multiple ER stress response pathways resulting in immunogenic cell death and amplified T-cell responses. [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 4914.