bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 998: OPeN: the oncology precision network data sharing consortium
Authors: Nadauld Lincoln , Haslem Derrick , Tittel Paul D. , Tameishi Mariko , Brown Thomas , Ford James 
Published: July 2017

Abstract
Background: The advent of Next-Generation Sequencing (NGS), and other molecular diagnostic technologies, has enabled the use of genomic information to guide targeted treatment in cancer patients. While this precision oncology approach can yield exciting clinical outcomes, the innumerable genomic variants identified in individual tumors effectively establishes each case as a unique N=1 clinical presentation. This scenario is contrary to a basic dogma of medical practice where historical cases and treatment outcomes guide future management and therapeutic decisions. Aggregation of large data sets, on a multi-institutional basis, has the potential to overcome the N=1 paradox and yield management insights in the implementation of precision oncology.
Methods: We have formed the Oncology Precision Network (OPeN), an oncology data sharing consortium, to aggregate big data sets consisting of clinical, genomic, pharmacological, and treatment response data from diverse patient cases. Data from Intermountain Healthcare, Stanford University, and Swedish Cancer Institute-Providence St. Joseph Health, as well as other institutions, comprises the database and is derived from 79 hospitals, over 800 physician clinics and more than 50,000 annual cases.
Results: The OPeN database can be interrogated by variant type, specific therapeutics, clinical outcomes, and by grouped variables, in a structured data format. The overarching IT platform is a cloud based, open source, triple store precision oncology solution, Syapse. These data are yielding valuable insights, including tumor mutational burden (TMB) scores and their correlation to immunotherapy response, clinical response in various drug-gene combinations, and therapy-specific adverse events.
Conclusions: We anticipate this resource will be used by the Molecular Tumor Boards of contributing institutions for clinical interpretation, and by treating providers to overcome the N=1 challenge associated with precision oncology.
Citation Format: Lincoln Nadauld, Derrick Haslem, Paul D. Tittel, Mariko Tameishi, Thomas Brown, James Ford. OPeN: the oncology precision network data sharing consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2017-998
Abstract CT137: Standard therapy versus active surveillance for low grade DCIS: the LORD trial
Authors: Wesseling Jelle , Duijnhoven Frederieke van , Tryfonidis Konstantinos , Peric Aleksandra , Leeuwen-Stok Elise van , Bijker Nina , Elshof Lotte , Rutgers Emiel 
Published: July 2017

Abstract
The introduction of population-based breast cancer screening and implementation of digital mammography have led to an increased incidence of ductal carcinoma in situ (DCIS) without a decrease in the incidence of advanced breast cancer. This suggests DCIS overdiagnosis exists.
We hypothesize that asymptomatic, low-grade DCIS can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be low-grade and hormone receptor positive with excellent survival rates. Also, breast-conserving treatment will still be an option, if no prior radiotherapy has been applied. It also may save many low-grade DCIS patients from intensive treatment.
We will compare active surveillance with conventional treatment, being either wide local excision (WLE) only, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy for primary low-grade DCIS, detected by calcifications only, in a phase III, open-label, non-inferiority, multi-center, randomized clinical trial legally supported by the Breast Cancer Group of the European Organisation for the Research and Treatment of Cancer (EORTC-1401-BCG). The Dutch Centers are coordinated by the BOOG Study Center (BOOG 2014-04).
Randomization will be 1:1 in to one of the following arms: active surveillance or standard treatment per local policy. In total, 1240 women (≥ 45 years) with asymptomatic, pure, low-grade DCIS, based on vacuum-assisted biopsies of calcifications as detected by population-based or opportunistic screening, without prior breast cancer, will be included. Assuming 25% of randomized women qualified to enroll in the study will drop out or will be excluded from per protocol population, at least 1,240 women need to be randomized to obtain the 930 patients required for the evaluation of the primary endpoint. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of 10 years. The primary end-point is ipsilateral invasive breast tumor-free rate at 10 years. Secondary end-points are among others: overall survival, breast cancer-specific survival, mastectomy rate and patient reported outcomes. Accrual has started in January 2017.
Acknowledgements: This trial is funded by Pink Ribbon Netherlands, the Dutch Cancer Society and Dutch Cancer Society/Alpe d’HuZes.
Citation Format: Jelle Wesseling, Frederieke van Duijnhoven, Konstantinos Tryfonidis, Aleksandra Peric, Elise van Leeuwen-Stok, Nina Bijker, Lotte Elshof, Emiel Rutgers. Standard therapy versus active surveillance for low grade DCIS: the LORD trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT137. doi:10.1158/1538-7445.AM2017-CT137
Abstract DDT02-01: Discovery of GDC-0077, a highly isoform selective inhibitor of PI3Kα that promotes selective loss of mutant-p110α
Authors: Staben Steven T. 
Published: July 2017

Abstract
PIK3CA, the gene that encodes for the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3Kα), is frequently mutated in cancer, with activating and transforming mutations of PIK3CA occurring in approximately 17% of cancers diagnosed annually. The narrow therapeutic index of PI3K inhibitors evaluated in the clinic thus far may be due to insufficient selectivity for PI3K isoform or mutant oncogenic driver. We report the results of our efforts directed at improving efficacy and safety of a class of benzoxazepin inhibitors of PI3K. A structure-, property-, and phenotype-guided strategy directed at high PI3K-isoform and PIKK-family selectivity, as well as a distinct cellular mechanism of action, culminated in the discovery of GDC-0077. Differences in primary and tertiary structure among PI3K isoforms were leveraged to achieve &gt;300-fold selective inhibition of the PI3Kα isoform over the β, δ, and γ isoforms in biochemical assays. Very high selectivity over PIKK-family proteins such as mTOR, DNA-PK and VPS34 was also achieved through this process. In vitro and in vivo data indicate that GDC-0077 operates by a mechanism that promotes the selective degradation of “hotspot” p110α mutants (H1047R, E545K). Treatment of nude mice bearing PIK3CA-mutant breast tumor xenografts with oral GDC-0077 resulted in tumor regressions at well-tolerated doses. Together, the high degree of isoform selectivity, selective degradation of mutant-p110α, and in vivo PK/efficacy support the clinical evaluation of GDC-0077 as a treatment for patients with locally advanced or metastatic, PIK3CA-mutant cancer.
Citation Format: Steven T. Staben. Discovery of GDC-0077, a highly isoform selective inhibitor of PI3Kα that promotes selective loss of mutant-p110α [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-01. doi:10.1158/1538-7445.AM2017-DDT02-01
Abstract DDT02-02: SGN-2FF: A novel small molecule inhibitor of fucosylation with preclinical antitumor activity through multiple immune mechanisms
Authors: Alley Stephen C. , O'Meara Megan , Gardai Shyra J. , Okeley Nicole M. 
Published: July 2017

Abstract
Increased fucosylation is associated with tumor progression and metastasis, and targeting fucosylation is a novel strategy in cancer therapy. 2-Fluorofucose (SGN-2FF) has been shown to inhibit cellular fucosylation by depletion of the fucosylation substrate GDP-fucose, as well as by direct inhibition of fucosyltransferases, leading to the production of afucosylated glycoproteins including antibodies. SGN-2FF has antitumor activity in multiple mouse tumor models, showing substantial tumor growth delay. SGN-2FF also enhanced the protective effect of a lymphoma vaccine in a syngeneic mouse model (1). This protection was determined to be immune dependent since depletion of CD4 and CD8 T cells reduced the SGN-2FF/vaccine activity. In vitro, SGN-2FF has been shown to activate human T cells in an antigen-dependent manner. Therefore, by inhibiting fucosylation SGN-2FF can potentially work through multiple mechanisms, including but not limited to effects on immune cells, tumor cells, and the tumor microenvironment. A first-in-human, phase 1, multicenter dose-escalation study of SGN-2FF is ongoing to investigate the safety, pharmacokinetics, and antitumor activity of SGN-2FF given orally to patients with advanced solid tumors (NCT# 02952989). Pharmacodynamic effects, including markers of fucosylation status, will also be evaluated to help determine the optimal biologic dose. This presentation reviews the preclinical activity data of SGN-2FF and describes the design of the phase 1 study, showing how demonstrated preclinical pharmacodynamic effects on fucosylation status informed how activity and pharmacodynamics will be monitored and evaluated in the phase 1 study.
Reference
&lt;BIBL&gt;
1. Okeley NM, Alley SC, Anderson ME, Boursalian TE, Burke PJ, Emmerton KM, et al. Development of orally active inhibitors of protein and cellular fucosylation. Proc Natl Acad Sci U S A 2013;110:5404-9.
Citation Format: Stephen C. Alley, Megan O'Meara, Shyra J. Gardai, Nicole M. Okeley. SGN-2FF: A novel small molecule inhibitor of fucosylation with preclinical antitumor activity through multiple immune mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2017-DDT02-02
Abstract LB-006: Oncology model fidelity scores
Authors: Datta Debajyoti , Goldstein Theodore , Gu Zhiping , Butte Atul 
Published: July 2017

Abstract
Animal models remain a cornerstone of research efforts in Oncology to model the complexity of cancer progression and to discover new therapeutic approaches to disease management. With the advent of new genomic manipulation techniques such as CRISPR, and advances in mouse modeling with genetically engineered mice (GEM) and patient-derived xenografts (PDX), we can expect the development of novel and powerful animal models in the near future. These techniques are expanding our capability for pre-clinical testing of novel therapeutic agents or for n-of-1 patient-specific disease modeling. However, the reliability of animal models to faithfully recapitulate human disease, especially cancer, remains controversial, as evidenced by numerous therapeutic agents that show promise in animal models but fail in clinical trials. We propose a new scoring system called the Oncology Model Fidelity Scores, which allow researchers and clinicians to compare animal models and select those most suited for the question at hand, whether in basic science, for translational research, or within clinical applications. The formalism and tools we are developing for the analysis of mouse models and other model organisms are based on the Hallmarks of Cancer and therapeutic pathways as well as The Cancer Genome Atlas (TCGA) and other comprehensive systems. The scoring system begins with RNASEQ expression data and DNA variation analysis, and is designed for use in mapping animal models both to individual patients and to a TCGA cohort. We are applying this scoring system to mouse models available through NCI’s Oncology Model Forum and we are analyzing how these animal models compare to human cancers based on TCGA data. Ultimately, the development of an Oncology Model Fidelity Score will help to advance patient care through efficient identification and validation of animal models for a variety of applications, from pre-clinical testing of novel therapeutics to the use of patient-specific animal models.
Citation Format: Debajyoti Datta, Theodore Goldstein, Zhiping Gu, Atul Butte. Oncology model fidelity scores [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-006. doi:10.1158/1538-7445.AM2017-LB-006
Abstract LB-007: Leveraging spatial heterogeneity in tumor purity for improved somatic variant calling of archival tumor-only samples
Authors: Halperin Rebecca F. , Liang Winnie S. , Tassone Erica , Adkins Jonathan , Russell Megan , Tran Nhan , Hank Nicole , Newell James , Gupta Sandeep , Berens Michael , Korn Ronald , Craig David W. , Byron Sara A. 
Published: July 2017

Abstract
Archival tumor samples present a rich resource of annotated specimens for genomics research. However, standard variant calling approaches require a matched normal sample from the same individual, which is often not available with archival tissue. Without a matched normal sample, it is very difficult to distinguish between true somatic variants and germline variants that are private to the individual. Archival FFPE sections often contain adjacent normal tissue, but this normal tissue is often contaminated with infiltrating tumor cells. Comparative somatic variant callers are designed to exclude variants present in the normal sample, so a novel approach is required to leverage sequencing of adjacent normal tissue. Here we present LumosVar 2.0, a software package designed to jointly analyze multiple samples from the same patient. The approach is based on the concept that the allelic fraction of somatic variants, but not germline variants, would be diluted by the presence of normal tissue. Given the allele specific copy number state and expected tumor fraction of each sample, one can model the expected allelic fractions of somatic and germline variants. LumosVar estimates allele specific copy number and tumor sample fractions from the data, and uses the model to call somatic and germline variants. LumosVar is also able to detect sub clonal events and spatial heterogeneity between samples. To evaluate this approach, we used a glioblastoma dataset, where enhancing (high tumor content) and non-enhancing (low tumor content) samples were available for each patient, as well as the matched normal sample to define the true somatic variants. We show that both sensitivity and positive predictive value are improved by analyzing the high tumor and low tumor jointly compared to analyzing the samples individually or in silico pooling of the two samples. Finally, we apply this approach to a set of breast and prostate archival FFPE tumor samples where normal samples were not available for germline sequencing.
Citation Format: Rebecca F. Halperin, Winnie S. Liang, Erica Tassone, Jonathan Adkins, Megan Russell, Nhan Tran, Nicole Hank, James Newell, Sandeep Gupta, Michael Berens, Ronald Korn, David W. Craig, Sara A. Byron. Leveraging spatial heterogeneity in tumor purity for improved somatic variant calling of archival tumor-only samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-007. doi:10.1158/1538-7445.AM2017-LB-007
Abstract LB-017: HSP110 sustains aberrant NFkB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization
Authors: Boudesco Christophe , Causse Sebastien , Hammann Arlette , Verhoeyen Els , Martin Laurent , Fest Thierry , Wolz Oliver , Weber Alexander , Garrido Carmen , Jego Gaetan 
Published: July 2017

Abstract
Diffuse large B cell lymphoma (DLBCL) is an aggressive lymphoproliferative disorder of B lymphocytes accounting for 30 % of adult Non Hodgkin Lymphoma (NHL). Among DLBCL, Activated B Cell - DLBCL (ABC-DLBCL) is the most aggressive form and has a poor prognosis. Heat-shock proteins (HSPs) are molecular chaperons highly expressed in cancer cells and implicated in resistance to radio- and chemotherapy. Therefore, HSPs are envisioned as therapeutic targets in many cancers. Among the different HSPs, HSP110 has been recently identified as a pro-survival factor in germinal center-derived DLBCL (GC-DLBCL), through stabilization of the GC-DLBCL oncogene Bcl-6. Here, we have explored if HSP110 could also be involved in the survival of the most aggressive form of DLBCL. We observed a high HSP110 expression in all ABC-DLBCL patient samples, compared to normal reactive lymph nodes by using IHC staining of ABC-DLBCL tumor sections and transcriptional analysis of ABC-DLBCL patient tumors. Furthermore, shRNA silencing of HSP110 decreases the survival of several ABC-DLBCL cell lines, and downregulates the expression of pro-survival factors such as BcL2 and BcL-XL. SiRNA silencing of HSP110 abrogates NF-kB signaling, which is the major oncogenic pathway in ABC-DLBCL cell lines. In accord with these results, over-expression of HSP110 in DLBCL and non-DLBCL cell lines increases NF-kB signaling, indicating a tight interplay between HSP110 and the NF-kB pathway. Using immune-precipitation and DuolinkTM assays, we identified an in vitro and in cellulo interaction between HSP110 and Myd88, a critical protein of the NF-kB pathway that bears an activated mutation in many ABC-DLBC patients and that is responsible for lymphoma aggressiveness. Finally, we demonstrate that HSP110 stabilizes the wild type as well as the mutated form of Myd88, therefore facilitating the chronic NF-kB pathway activation in those cells. In conclusion, we identified HSP110 as a regulator of NF-kB signaling through MyD88 stabilization in ABC-DLBCL. This finding highlights HSP110 as a new potential therapeutic target in DLBCL.
Citation Format: Christophe Boudesco, Sebastien Causse, Arlette Hammann, Els Verhoeyen, Laurent Martin, Thierry Fest, Oliver Wolz, Alexander Weber, Carmen Garrido, Gaetan Jego. HSP110 sustains aberrant NFkB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-017. doi:10.1158/1538-7445.AM2017-LB-017
Abstract LB-019: Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase
Authors: Shrestha Hridaya , Ryu Taeyong , Seo Young-woo , Park So-yeon , He Yongfeng , Dai Weiye , Park Eunsook , Simkhada Shishli , Kim Hangun , Lee Keesook , Kim Kwonseop 
Published: July 2017

Abstract
Hakai ubiquitinates and induces endocytosis of the E-cadherin complex; thus, modulating cell adhesion and regulating the epithelial-mesenchymal transition in development of metastasis. Our previous published data show that δ-catenin promotes E-cadherin processing and thereby activates β-catenin-mediated oncogenic signals in prostate cancer. Although several published data show the interactions between δ-catenin and E-cadherin; and Hakai and E-cadherin separately, we found no published report on the relationship between δ-catenin and Hakai. In this study, we show Hakai stabilizes δ-catenin regardless of its E3-ligase activity. We found that Hakai and Src increase the stability of δ-catenin synergistically. Furthermore, we show that Hakai stabilizes Src, which in turn inhibits binding between glycogen synthase kinase-3β and δ-catenin, resulting in less glycogen synthase kinase-3β mediated phosphorylation and proteosomal degradation of δ-catenin. Taken together, these results suggest that stabilization of δ-catenin by Hakai is dependent on Src. Our novel findings on the Hakai mediated δ-catenin stabilization in an ubiquitination independent manner will add a new perspective to provide further insight into E3-ligase activity independent role of Hakai in cancer pathogenesis.
Citation Format: Hridaya Shrestha, Taeyong Ryu, Young-woo Seo, So-yeon Park, Yongfeng He, Weiye Dai, Eunsook Park, Shishli Simkhada, Hangun Kim, Keesook Lee, Kwonseop Kim. Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-019. doi:10.1158/1538-7445.AM2017-LB-019
Abstract LB-028: Mdm4 regulates mutant p53 stability in vivo
Authors: Plehaty Molly , Srinivas Tara , Stevens Wanida , Sobhani Nema , Iwakuma Tomoo , Podell Brendan , Arbab Farinaz , Terzian Tamara 
Published: July 2017

Abstract
The p53 tumor suppressor is maintained mainly at low physiological levels in normal cells by its two major inhibitors, Mdm2 and Mdm4. Mdm2 is an E3 ubiquitin ligase while Mdm4 lacks this activity. Deletion of either inhibitor results in p53-dependent embryonic lethality in mice. We have shown that Mdm2 binds and inhibits mutant p53R172H in a mouse model of Li-Fraumeni syndrome. We recently established that Mdm4, like Mdm2, regulates p53R172H stability in vivo, and that endogenous Mdm2 cannot compensate for this stabilization. Thus, mice that lack Mdm4 and are homozygous for the p53R172H allele have stabilized p53R172H and display accelerated tumor development and an increased range of tumor types, compared to p53R172H/R172H mice. Furthermore, we compared mutant mice with the loss of two different alleles of Mdm4 and observed a threshold for metastasis associated with higher p53R172H levels. These data support the gain-of-function hypothesis: high levels of mutant p53 increase the frequency of metastasis. We are currently analyzing mutant p53 target genes expression differences between the two Mdm4 alleles and Mdm2 to assess mutant p53 mode of regulation of these alleles.
Citation Format: Molly Plehaty, Tara Srinivas, Wanida Stevens, Nema Sobhani, Tomoo Iwakuma, Brendan Podell, Farinaz Arbab, Tamara Terzian. Mdm4 regulates mutant p53 stability in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-028. doi:10.1158/1538-7445.AM2017-LB-028