bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-B23: Medulloblastoma regulatory circuitries reveal subgroup-specific cellular origins
Authors: Lin Charles Y. , Erkek Serap , Tong Yiai , Yang Linlin , Federation Alexander J. , Zapatka Marc , Haldipur Parthiv , Kawauchi Daisuke , Risch Thomas , Warnatz Hans-Jörg , Worst Barbara , Ju Bensheng , Orr Brent A. , Zeid Rhamy , Polaski Donald R. , Segura-Wang Maia , Waszak Sebastian M. , Jones David TW , Kool Marcel , Hovestadt Volker , Buchhalter Ivo , Sieber Laura , Johann Pascal , Gröschel Stefan , Ryzhova Marina , Korshunov Andrey , Chen Wenbiao , Chizhikov Victor V. , Millen Kathleen J. , Amstislavskiy Vyacheslav , Lehrach Hans , Yaspo Marie-Laure , Eils Roland , Lichter Peter , Korbel Jan O. , Pfister Stefan , Bradner James E. , Northcott Paul A. 
Published: May 2016

Abstract
Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is currently lacking. Using H3K27ac and BRD4 ChIP-Seq, coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors responsible for subgroup divergence that validated by ChIP-Seq and implicated candidate cells-of-origin for Group 4. Our integrated analysis of cis-regulatory elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.
Citation Format: Charles Y. Lin, Serap Erkek, Yiai Tong, Linlin Yang, Alexander J. Federation, Marc Zapatka, Parthiv Haldipur, Daisuke Kawauchi, Thomas Risch, Hans-Jörg Warnatz, Barbara Worst, Bensheng Ju, Brent A. Orr, Rhamy Zeid, Donald R. Polaski, Maia Segura-Wang, Sebastian M. Waszak, David TW Jones, Marcel Kool, Volker Hovestadt, Ivo Buchhalter, Laura Sieber, Pascal Johann, Stefan Gröschel, Marina Ryzhova, Andrey Korshunov, Wenbiao Chen, Victor V. Chizhikov, Kathleen J. Millen, Vyacheslav Amstislavskiy, Hans Lehrach, Marie-Laure Yaspo, Roland Eils, Peter Lichter, Jan O. Korbel, Stefan Pfister, James E. Bradner, Paul A. Northcott. Medulloblastoma regulatory circuitries reveal subgroup-specific cellular origins. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B23.
Abstract LB-B25: Consensus tissue-independent epithelial tumour subtypes and their differing responses to therapy
Authors: Sadanandam Anguraj 
Published: May 2016

Abstract
Background: Epithelial cancers are highly heterogeneous, and each epithelial tumour is composed of a number of subtypes. It is becoming clear that the same dysregulated pathways are common to different tumours, regardless of their tissue of origin. Therefore, the goal of the current study was to identify intrinsic tissue-independent epithelial tumour subtypes by analysing a large cohort of different epithelial tumours.
Methodology: Different gene expression profiles from various epithelial tumours (n = ∼5000) and cell lines (n = ∼200) from 12 different organs were merged using distance weight discrimination analysis, followed by consensus clustering using non-negative matrix factorization (NMF). The association of subtypes with response to various therapeutic compounds was identified using publicly available cell line drug response data.
Results: Three to seven consensus gene expression subtypes were identified and validated in the epithelial tumours and cell lines, irrespective of the tissue of origin. Certain epithelial subtypes were not present in melanoma or haematological cancers. The consensus subtypes had gene expression and biological profiles similar to normal epithelial and stem cells, and could be readily compared to the transcriptomic subtypes previously reported for individual epithelial tumour types. Moreover, specific gene signatures were identified that would be suitable as clinical assays in future applications of this classification system. There were significant differential responses between subtypes to different therapeutic compounds.
Conclusion: Several consensus transcriptomic subtypes were identified that are applicable to different organ-specific tumours. This study provides new avenues for precision therapy irrespective of the tissue of origin.
Late-Breaking Poster Session C:[xx]Animal Models
Citation Format: Anguraj Sadanandam. Consensus tissue-independent epithelial tumour subtypes and their differing responses to therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B25.
Abstract LB-C13: Selective GPR55 antagonism attenuates EGFR-PKM2-β-catenin signaling and reduces chemoresistance in PANC-1 pancreatic cancer cells
Authors: Singh Nagendra , Bernier Michel , Wainer Irving W. 
Published: May 2016

Abstract
G protein-coupled receptor GPR55 possesses pro-oncogenic activity, but the nature of GPR55 signaling pathways in mammalian tumor cells remain unclear. The effect of (R,R')-4'-methoxy-1-naphthylfenoterol (MNF), a potent GPR55 competitive inhibitor, on the expression of cancer biomarkers, such as EGFR, PKM2, β-catenin and HIF-1A, was investigated in human pancreatic cancer cell line, PANC-1. We also examined the modulation in expression of P-glycoprotein (Pgp) and other multidrug resistance drug exporters (MDR) in response to MNF. Incubation of PANC1 cells with MNF (1 μM) for 24h significantly decreased EGFR (∼2-fold), PKM2 (∼2.5-fold) and β-catenin (∼2-fold) protein levels and was accompanied by significant reduction in nuclear accumulation of HIF-1A(∼1.5-fold) and phospho-active forms of PKM2 (∼3-fold) and B-catenin (∼2-fold). MNF and the GPR55 antagonist CID16020046 consistently reduced the expression of Pgp (∼2-fold), BCRP (∼2-fold), MRP1 (∼1.5-fold) and MRP5 (∼1.5-fold) in total cellular extracts while diminishing the nuclear expression of Pgp (∼2.5-fold) and BCRP (∼4.5-fold). Further, a significant increase in the nuclear accumulation of doxorubicin was observed in MNF-treated PANC-1 cells using laser scanning confocal microscopy. Importantly, a 24-h preincubation with MNF increased the cytotoxicity of doxorubicin (IC50 reduced from 170nM to 24nM) and gemcitabine (IC50 reduced from 486nM to 157nM) in PANC-1 cells. In the mouse xenograft model, daily MNF treatment (10mg.kg-1, i.p.) for 21 days led to a ∼2-fold reduction in the expression of EGFR, PKM2, β-catenin and Pgp in PANC-1 tumor tissue relative to vehicle-treated controls (P &lt; 0.001). These data suggest that MNF exerts its antitumor effects by inhibiting GPR55-mediated activation of select cancer biomarkers, and suppressing multidrug resistance to chemotherapeutic agents in pancreatic cancer cells.
Citation Format: Nagendra Singh, Michel Bernier, Irving W. Wainer. Selective GPR55 antagonism attenuates EGFR-PKM2-β-catenin signaling and reduces chemoresistance in PANC-1 pancreatic cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C13.
Abstract LB-C16: Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): An ongoing Phase II trial
Authors: Bardia Aditya , Mayer Ingrid , Diamond Jennifer , Starodub Alexander , Moroose Rebecca , Isakoff Steven , Ocean Allyson , Guarino Michael , Kalinsky Kevin , O'Shaugnessy Joyce , Wilhelm Francois , Maliakal Pius , Sharkey Robert , Goldenberg David , Vahdat Linda 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 12:30 PM ET Sunday, November 8.
Citation Format: Aditya Bardia, Ingrid Mayer, Jennifer Diamond, Alexander Starodub, Rebecca Moroose, Steven Isakoff, Allyson Ocean, Michael Guarino, Kevin Kalinsky, Joyce O'Shaugnessy, Francois Wilhelm, Pius Maliakal, Robert Sharkey, David Goldenberg, Linda Vahdat. Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): An ongoing Phase II trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C16.
Abstract LB-C23: A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity
Authors: Heijink Anne Margriet , Blomen Vincent , Degener Fabian , Matsushita Felipe Yu , Foijer Floris , Van Vugt Marcel A. 
Published: May 2016

Abstract
The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anti-cancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibitor treatment and undercover potential resistance mechanisms, identification of these currently unknown genes and underappreciated functions of Wee1 is necessary. The aim of this study was to identify gene mutations that determine Wee1 inhibitor sensitivity.
We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G1/S regulatory genes, including SKP2, CUL1 and CDK2. Stable depletion of SKP2, CUL1 and CDK2 or chemical Cdk2 inhibition rescued the γ-H2AX induction and abrogation of G2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1 and CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patient. Conversely, loss of the identified S-phase genes could serve as a resistance mechanism and coincides with development of severe genomic instability.
Citation Format: Anne Margriet Heijink, Vincent Blomen, Fabian Degener, Felipe Yu Matsushita, Floris Foijer, Marcel A. Van Vugt. A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C23.
Abstract PL02-03: Combination with/of immunotherapies
Authors: Blank Christian 
Published: May 2016

Abstract
Systemic treatment of melanoma has faced a revolution the last decade. After 30 years of disappointments and no clinical benefit for patients, targeted agents, like the BRAF inhibitors vemurafenib or dabrafenib, and checkpoint inhibitors of CTLA-4 or PD-1/PD-L1, like ipilimumab, pembrolizumab or nivolumab, have improved for the first time the overall survival of late stage melanoma patients in phase 3 trials. Addition of MEK inhibitors to the BRAF inhibitors and combination of CTLA-4 and PD-1 blockade were able to improve the response rate and progression free survival further.
However, despite these promising data, a considerable percentage of patients will not benefit long-term from these treatments.
This raises questions in two directions: 1) how can we identify the patients that benefit long-term from current treatment options, and 2) what are future therapies, that should be tested in patients that do not benefit from current standards.
Based on recent analyses from mainly expanded access programs and safety trials we propose to characterize patients (‘ tumors) according to:
a) Tumor foreignness, e.g. mutational load,
b) General immune status, e.g. lymphocyte count,
c) Infiltration capacity, e.g. intratumoral CD8 infiltration,
d) Absence of locally expressed inhibitory factors, e.g. PD-L1,
e) Absence of local soluble inhibitory factors, e.g. IL-6, as measured by surrogate markers like C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR),
f) Absence of inhibitory tumor metabolism, e.g. as measured by LDH or glucose uptake, and
g) Sensitivity to effector mechanisms, like MHC expression.
Most these markers have already been identified to be clinical relevant for the patient's outcome upon T cell checkpoint blockade, and been shown to be crucial mechanisms for anti-tumor immune response in preclinical models. They often have a prognostic and a predictive relevance for patients treated with checkpoint modulators. This often raised critic cannot be solved, particularly for immune modulatory therapies, as the immune system, as effector compartment of any of these therapies is upfront any intervention present in the cancer patients, and thus will have always also prognostic relevance. Nevertheless, these clinical markers are important tools to understand requirements for an effective anti-tumor immune response in any cancer, and can be used to develop a cancer immunogram for individual patients or malignancies.
Based on this immunogram personalized immunotherapy can be applied using current/future combinations of immunotherapeutic approaches and agents used in targeted therapy. I will discuss several of such combination therapy options currently tested in early phase trials that address the different levels of the cancer immunogram.
Citation Format: Christian Blank. Combination with/of immunotherapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL02-03.
Abstract PL04-03: Basket studies: Lessons learned and future directions
Authors: Hyman David 
Published: May 2016

Abstract
Dramatic improvements in the ability to test for all classes of potentially actionable alterations in hundreds or even thousands of genes simultaneously, along with the rapidly expanding portfolio of therapeutic agents targeting a variety of cell signaling networks, have converged to create an unparalleled opportunity to pursue precision medicine in oncology. One obstacle to realizing the full potential of precision medicine in the clinic is the low prevalence of many potentially actionable genomic alterations as well as the diverse range of cancer types potentially implicated. To address this emerging challenge, multi-histology, genomically selected, basket studies have been developed. These studies represent a potentially transformative approach to genomically targeted drug development. In basket studies, patients with tumors known to harbor a qualifying genomic alteration are enrolled irrespective of tumor histology. Tumor types most likely to harbor the genomic biomarker are enrolled to their own cohort. Notably, in these tumor types that enroll to sufficient quantities, efficacy assessments are independently undertaken, therefore accounting for the possibility that tumor lineage may influence drug sensitivity. While the first generation of basket studies were designed mainly to detect early signals of activity across multiple tumor types simultaneously, newer basket studies are now being designed to collect the data required to seek health authority approval. Here we review the current landscape of precision medicine basket studies, with a focus on how to maximize their potential for advancing the standard of care.
Citation Format: David Hyman. Basket studies: Lessons learned and future directions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL04-03.
Abstract PL05-02: Synthetic Lethal Interaction between Homologous Recombination Repair and POLQ-mediated Alternative End-Joining
Authors: D'Andrea Alan D. 
Published: May 2016

Abstract
Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair. Loss of HR accounts for the genomic instability and replicative stress of EOCs and for their cellular hyperdependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms. Previous studies have implicated the DNA polymerase POLQ in an error-prone pathway required for the repair of DNA double-strand breaks, referred to as alternative endjoining (alt-EJ). In Drosophila melanogaster and Caenorhabditis elegans, POLQ functions in alt-EJ and in the maintenance of genome stability at sites of G-quadruplex structures. Whether POLQ interacts with canonical DNA repair pathways to prevent genomic instability at stalled replication forks remains unknown. We have recently demonstrated an inverse correlation between HR activity and POLQ expression in EOCs (Ceccaldi R. et al, Nature, 518: 258-262, 2015). While knockdown of POLQ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, knockdown of POLQ in HR-deficient EOCs results in enhanced cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, POLQ contains a repeat of RAD51 binding motifs, and it blocks D-loop formation and recombination. Taken together, these results reveal a synthetic lethal relationship between the HR pathway and POLQ-mediated alternative end-joining in EOCs, and identify POLQ as a novel druggable target for ovarian cancer therapy.
Citation Format: Alan D. D'Andrea. Synthetic Lethal Interaction between Homologous Recombination Repair and POLQ-mediated Alternative End-Joining. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL05-02.
Abstract A19: Role of NF-κB and gene targets of NF-κB in glioma cell plasticity
Authors: Friedmann-Morvinski Dinorah , Narasimamurthy Rajesh , Xia Yifeng , Myskiw Chad , Soda Yasushi , Verma Inder M. 
Published: May 2016

Abstract
Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. In the last century we have accumulated tremendous amounts of data on this type of cancer, but despite extensive study, few therapeutic targets have been identified for GBM. We have established a lentiviral-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signatures of human GBM. RNAseq analysis of these tumors revealed high NFκB activation showing enrichment of known NFκB target genes. Depletion of IKK2 in tumor derived cell lines attenuated tumor proliferation and prolonged mouse survival. We have previously shown that gliomas can originate by reprograming/dedifferentiation of terminally differentiated astrocytes and neurons following oncogenic insult. This tumor cell plasticity seems to be impaired when either cortical astrocytes or neurons derived from floxed-IKK2 mice are infected with a lentivirus expressing HRAS-iresCREerT2-shp53. The addition of tamoxifen to the infected cells induces IKK2 depletion and blocks the reprogramming process, manifested by inhibition of tumorspheres formation and retention of differentiation makers. When these cells are transplanted into mice, the control group (vehicle treated) succumbs to the disease, while induction of IKK2 depletion in the tamoxifen treated group (20 days post-transplantation) significantly prolonged the mice survival. Activation of NFκB requires the activity of IκB kinase (IKK) complex containing IKKα and IKKβ, and the regulatory protein NFκB essential modifier (NEMO). We tested a peptide corresponding to the NEMO-binding domain (NBD) of IKKα(IKK1) or IKKβ(IKK2), to specifically inhibit the induction of NFκB activation, and the mice treated with NBDwt peptide showed long-term survival compared to NBDmut control. We propose targeting the NFκB pathway as an attractive therapeutic strategy to treat GBM.
Citation Format: Dinorah Friedmann-Morvinski, Rajesh Narasimamurthy, Yifeng Xia, Chad Myskiw, Yasushi Soda, Inder M. Verma. Role of NF-κB and gene targets of NF-κB in glioma cell plasticity. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A19.