bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4332: Discovery of BAY 1163877 - A pan-FGFR inhibitor: De novo structure-based design and lead optimization of benzothiophenyl-pyrrolotriazines
Authors: Collin Marie-Pierre L. , Lobell Mario , Huebsch Walter , Brohm Dirk , Héroult Mélanie , Lustig Klemens , Gruenewald Sylvia , Boemer Ulf , Jautelat Rolf , Hess-Stump Holger , Jaroch Stefan , Brands Michael , Ziegelbauer Karl 
Published: July 2016

Abstract
Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFR1-4) and activating downstream signaling pathways. Alterations in FGFR encoding genes are frequently observed in a variety of solid tumors including lung, gastric, breast and urothelial cancer. Therefore, targeting FGFRs using selective FGFR inhibitors is an attractive therapeutic approach to treat cancer patients.
BAY 1163877 is an orally active, highly potent and selective small molecule FGFR-1, -2 and -3 kinase inhibitor. We disclose for the very first time its discovery and chemical structure. BAY 1163877 was derived from a de novo structure-based design approach and medicinal chemistry optimization. Data on the structure activity relationship and the pharmacokinetic profile of the benzothiophenyl-pyrrolotriazine structure class will be presented. Based on its favorable preclinical profile, BAY 1163877 is currently being investigated in a Phase 1 clinical trial (NCT01976741).
Citation Format: Marie-Pierre L. Collin, Mario Lobell, Walter Huebsch, Dirk Brohm, Mélanie Héroult, Klemens Lustig, Sylvia Gruenewald, Ulf Boemer, Rolf Jautelat, Holger Hess-Stump, Stefan Jaroch, Michael Brands, Karl Ziegelbauer. Discovery of BAY 1163877 - A pan-FGFR inhibitor: De novo structure-based design and lead optimization of benzothiophenyl-pyrrolotriazines. [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 4332.
Abstract 4351: A neighborhood-wide association study (NWAS) in prostate cancer: A new methodologic approach
Authors: Lynch Shannon , Mitra Nandita , Ross Michelle , Newcomb Craig , Daily Karl , Jackson Tara , Zeigler-Johnson Charnita , Riethman Harold , Branas Charles , Rebbeck Timothy 
Published: July 2016

Abstract
Background: Cancer results from complex interactions of multiple variables at biological, individual and social levels. However, comprehensive, empirical methods to assess social and neighborhood-level effects are limited. We propose a Neighborhood-Wide Association Study(NWAS), analogous to a genome-wide association study(GWAS), to comprehensively identify neighborhood signatures associated with disease. Methods: Pennsylvania State Cancer Registry data from 1995-2005 were linked to the 2000 U.S. Census data. In a successively more stringent multiphase approach, we evaluated the association between neighborhood exposures(n = 14,663, standard deviation adjusted census variables) and prostate cancer aggressiveness (n = 6,416 aggressive Stage&gt;3/Gleason grade &gt;7 cases vs. n = 70,670 non-aggressive Stage&lt;3/Gleason grade&lt;7 controls) in White men. Each phase accounted for age, year of diagnosis, spatial correlation, and multiple testing. We used generalized estimating equations in Phase 1 and Bayesian mixed effects models in Phase 2 to calculate odds ratios(OR) and credible intervals(CI). Variables meeting statistically significant thresholds after Bonferroni adjustment were identified and used in subsequent phases. In Phase 3, principal components analysis grouped correlated variables.
Results: From 14,663 census variables, 17 variables that were most significantly associated with prostate cancer aggressiveness were identified. The top two hits related to transportation (OR = 1.05;CI = 1.001-1.09) and poverty (OR = 1.07;CI = 1.01-1.12). Significant associations between prostate cancer and income, housing, employment, and immigration were also found.
Conclusions: This NWAS methodology addresses gaps in neighborhood and cancer research by proposing a standardized, agnostic evaluation of neighborhood using readily accessible data from the U.S. Census. This approach has implications for health disparities research and can be applied broadly to large-scale, public health data.
Citation Format: Shannon Lynch, Nandita Mitra, Michelle Ross, Craig Newcomb, Karl Daily, Tara Jackson, Charnita Zeigler-Johnson, Harold Riethman, Charles Branas, Timothy Rebbeck. A neighborhood-wide association study (NWAS) in prostate cancer: A new methodologic approach. [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 4351.
Abstract 4357: Harnessing system xCT- to target mutant p53 cancer cells
Authors: Liu David SH , Read Matthew , Wiman Klas G. , Haupt Sue , Duong Cuong P. , Abrahmsen Lars , Haupt Ygal , Clemons Nicholas J. , Phillips Wayne A. 
Published: July 2016

Abstract
p53, a critical tumour suppressor is mutated in over half of all human cancers. The loss of wild-type p53 activity together with oncogenic gain-of-function, secondary to aberrant accumulation of mutant p53 protein frequently results in aggressive tumour phenotype, resistance to conventional therapies and poor survival. Therefore, effective therapeutic strategies to target mutant p53 cancer cells remain an urgent and unmet medical need. Here we show that mutant p53 accumulation across multiple tumour types represses the transcription of SLC7A11, a key component of system xCT-, resulting in reduced cystine uptake, lowering endogenous glutathione stores and predisposing cells to oxidative damage. Notably, genetic knockdown or pharmacological inhibition (erastin and sulfasalazine) of system xCT- preferentially induces apoptosis in cancer cells with mutant p53 accumulation. Moreover, we found that APR-246 (PRIMA-1met), a first-in-class reactivator of mutant p53 currently in early clinical trials, depletes cellular glutathione and induces significantly higher amounts of reactive oxygen species in mutant p53 cancer cells compared with normal cells. This leads to lipid peroxidation of mitochondrial membranes and the release of matrix contents, culminating in apoptotic cell death. Conversely, APR-246-induced cytotoxicity could be rescued by cysteine or glutathione replacement, or with lipophilic antioxidants. In extension, we identified and functionally validated SLC7A11 expression as a specific predictive biomarker for APR-246. Importantly, we demonstrate that antagonising system xCT- activity in combination with APR-246 selectively and synergistically inhibit mutant p53 cancer cells. Together, our findings propose that accumulation of mutant p53 protein in cancer cells, through its repressive effects on SLC7A11 expression, creates an ‘Achilles heel’ that can be targeted by further perturbations of the glutathione pathway.
Citation Format: David SH Liu, Matthew Read, Klas G. Wiman, Sue Haupt, Cuong P. Duong, Lars Abrahmsen, Ygal Haupt, Nicholas J. Clemons, Wayne A. Phillips. Harnessing system xCT- to target mutant p53 cancer 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 4357.
Abstract 4359: Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent
Authors: Kamphorst Alice O. , Wieland Andreas , Yang Shu , Nasti Tahseen , Zhang Ruan , Barber Daniel L. , Konieczny Bogumila T. , Koenig Lydia , Yu Ke , Sica Gabriel , Owonikoko Taofeek K. , Pillai Rathi , Ramalingam Suresh S. , Sharpe Arlene H. , Freeman Gordon J. , Turka Laurence A. , Araki Koichi , Ahmed Rafi 
Published: July 2016

Abstract
T cell exhaustion was first described in mice during chronic lymphocytic choriomeningitis virus (LCMV) infection and later shown to occur in humans during persistent infections and cancer. Sustained expression of the inhibitory receptor programmed cell death-1 (PD-1) is a hallmark of T cell exhaustion. Therapeutic blockade of PD-1 rescues proliferation, cytokine production and cytotoxicity of exhausted T cells. PD-1 targeted therapies have shown efficacy for multiple cancer types and changed the landscape of cancer treatment, but the requirements for T cell rescue by blockade of the PD-1 pathway remain elusive. T cell activation ensues when positive signals overcome negative signals. CD28 is the most prominent positive co-receptor for T cell activation, and human CD8 T cells become CD28neg upon continuous stimulation. We analyzed tumor specimens from non-small cell lung cancer (NSCLC) patients by flow cytometry and found heterogeneous CD28 expression on tumor-infiltrating CD8 T cells. In most NSCLC patients, CD28neg cells were prevalent among CD8 T cells co-expressing inhibitory receptors (such as PD-1 and Tim-3). To address the role of the CD28/B7 pathway on CD8 T cell rescue by PD-1 targeted therapies, we used the LCMV chronic infection model. When B7 signals were impeded by CTLA-4-Ig or B7 blocking antibodies, blockade of the PD-1 pathway failed to rescue virus-specific CD8 T cells. To investigate a cell intrinsic requirement of CD28 on exhausted CD8 T cells, we used an adoptive transfer strategy of cells genetically deficient in CD28. We found that CD28-deficient LCMV-specific CD8 T cells do not expand after blockade of the PD-1 pathway. Furthermore, to ensure appropriate development and differentiation of CD8 T cells, we used mice in which the CD28 gene can be conditionally deleted. We confirmed that CD28neg exhausted CD8 T cells failed to proliferate after blockade of the PD-1 pathway even when CD28 gene deletion was induced on already exhausted T cells. These data demonstrate that CD28 engagement is required for CD8 T cell rescue, and CD28 status may constitute a predictive biomarker for PD-1 targeted therapies.
Citation Format: Alice O. Kamphorst, Andreas Wieland, Shu Yang, Tahseen Nasti, Ruan Zhang, Daniel L. Barber, Bogumila T. Konieczny, Lydia Koenig, Ke Yu, Gabriel Sica, Taofeek K. Owonikoko, Rathi Pillai, Suresh S. Ramalingam, Arlene H. Sharpe, Gordon J. Freeman, Laurence A. Turka, Koichi Araki, Rafi Ahmed. Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent. [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 4359.
Abstract 4370: Genome-wide CRISPR-Cas9 screens reveal loss of redundancy between PKMYT1 and WEE1 in patient-derived glioblastoma stem-like cells
Authors: Toledo Chad , Yu Ding , Hoellerbauer Pia , Davis Ryan , Basom Ryan , Girard Emily , Corrin Philip , Bolouri Hamid , Davison Jerry , Zhang Qing , Nam Do-Hyun , Lee Jeongwu , Pollard Steven , Delrow Jeffery , Clurman Bruce , Olson James , Paddison Patrick 
Published: July 2016

Abstract
Glioblastoma multiforme (GBM) is the most aggressive and common form of brain cancer in adults. There are currently no effective therapies for GBM. Even with standard of care treatments, such as surgery, radiation, and chemotherapy, ∼90% of adult patients die within 2 years of diagnosis. To identify therapeutic targets for Glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 “knockout” (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, for genes required for their in vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered in GBM and GSCs (e.g., oncogenic drivers). In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1. Mechanistic studies demonstrated that PKMYT1 acts redundantly with WEE1 to inhibit Cyclin B-CDK1 activity via CDK1-Y15 phosphorylation and to promote timely completion of mitosis in NSCs. However, in GSCs, this redundancy is lost, likely as a result of oncogenic signaling, causing GBM-specific lethality. From a biological standpoint, our results help re-discover PKMYT1 function in human cells. From a cancer standpoint, these results suggest that targeting PKMYT1 is a glioma-lethal gene and that tandem or sequential use of PKMYT1 and WEE1 inhibitors may illicit therapeutic responses in GBM. In addition to these results we will also present retest data for other candidate glioma-lethal genes and networks in multiple patient samples.
Citation Format: Chad Toledo, Ding Yu, Pia Hoellerbauer, Ryan Davis, Ryan Basom, Emily Girard, Philip Corrin, Hamid Bolouri, Jerry Davison, Qing Zhang, Do-Hyun Nam, Jeongwu Lee, Steven Pollard, Jeffery Delrow, Bruce Clurman, James Olson, Patrick Paddison. Genome-wide CRISPR-Cas9 screens reveal loss of redundancy between PKMYT1 and WEE1 in patient-derived glioblastoma stem-like 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 4370.
Abstract 4386: CETSA as a new strategy to understand efficacy, adverse effects and resistance development of anticancer drugs
Authors: Nordlund Pär , Lööf Sara , Laursen Henritte , Öberg Anette , Lengqvist Johan , Jafari Rozbeh , Dai Lingyun , Go Ka DIam , Prabhu Nayana , Sobota Radoslaw , Larsson Andreas , Jansson Anna , Soon Chris Heng Tan , Sreekumar Lekshmy , Lim Yan Ting , Martines Molina Daniel 
Published: July 2016

Abstract
A key step of the action of most drugs is their binding (engagement) of the target protein(s). However, limitations in the available methods for directly accessing this critical step have added uncertainties in many stages of drug development.
We have developed a generic method for evaluating drug binding to target proteins in cells and tissues (Martinez Molina et al. Science, 341:84). The technique is based on the physical phenomenon of ligand-induced thermal stabilization of target proteins; the method is therefore called the cellular thermal shift assay (CETSA). The technique allows for the first time to directly measure the biophysical interactions between a drug and protein target in non- engineered cells and tissues. We show that using CETSA a range of critical factors for drug development can be addressed at the target engagement level, including drug transport and activation, off-target effects, drug resistance as well as drug distribution in cells, patient and animal tissues. Using quantitative mass-spectrometry, proteome-wide CETSA has been established which allows for off-target effects as well as downstream biochemistry to be discovered (Savitsk et al. Science, 346, 6205:1255784). Together the data supports that CETSA is likely to become a valuable tool for developing and understanding the action of cancer drugs in the future.
Citation Format: Pär Nordlund, Sara Lööf, Henritte Laursen, Anette Öberg, Johan Lengqvist, Rozbeh Jafari, Lingyun Dai, Ka DIam Go, Nayana Prabhu, Radoslaw Sobota, Andreas Larsson, Anna Jansson, Chris Heng Tan Soon, Lekshmy Sreekumar, Yan Ting Lim, Daniel Martines Molina. CETSA as a new strategy to understand efficacy, adverse effects and resistance development of anticancer drugs. [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 4386.
Abstract 4389: Therapeutic opportunities of RANK pathway in breast cancer
Authors: Perez Montoyo Hector , Gomez Miragaya Jorge , Trinidad Eva M. , Martinez-Aranda Antonio , Soler Monso Maria Teresa , Petit Anna , Sierra Angels , Gonzalez Suarez Eva 
Published: July 2016

Abstract
RANK pathway, key in bone remodeling and metastasis, is essential for mammary gland development. Using genetic mouse models we have previously shown that RANKL is the main mediator of the protumorigenic role of progesterone in the mouse mammary gland. RANK overexpression in non-transformed human mammary cell lines induces epithelial to mesenchymal transition and stemness, and promotes tumorigenesis and metastasis in breast cancer lines. RANK is expressed in a subset of basal and luminal human adenocarcinomas.
Our goal is to determine a putative association of RANK and RANKL expression in breast adenocarcinomas with clinical parameters and to evaluate the functional role of RANK signaling using patient derived orthoxenografts of breast cancer. We have analyzed RANK and RANKL expression levels in an extensive collection of human breast adenocarcinomas collected from multiple centers, enriched in metastatic tumor samples. From the 318 patients with breast adenocarcinomas 138 developed metastasis. RANK expression is found on tumor cells but also on stromal cells, including tumor associated macrophages. RANKL is strongly expressed in some tumors, although the frequency is low. Analyses of RANK and RANKL mRNA and protein expression has been performed in multiple models of patient derived breast orthoxenografts. Several models with variable levels of RANK as well as RANKL expression have been identified and established in the laboratory. Functionality of the pathway was corroborated analyzing NF-kB activation upon in vitro and in vivo treatments with RANKL, in order to activate RANK signaling, or with RANK-Fc to inhibit it. We found that RANKL treatment induced NF-kB activation even in tumor cells with low levels of RANK expression.
Citation Format: Hector Perez Montoyo, Jorge Gomez Miragaya, Eva M. Trinidad, Antonio Martinez-Aranda, Maria Teresa Soler Monso, Anna Petit, Angels Sierra, Eva Gonzalez Suarez. Therapeutic opportunities of RANK pathway in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4389.
Abstract 4400: Hematopoietic age at onset of breast cancer dictates disease aggressiveness and progression
Authors: Sceneay Jaclyn , Marsh Timothy , Wong Irene , Qin Yuanbo , Sjödin Andreas , Nilsson Björn , Stewart Sheila A. , McAllister Sandra S. 
Published: July 2016

Abstract
Aging is strongly associated with increased risk of developing breast cancer. Young age at diagnosis is typically associated with more aggressive disease, while breast cancer is generally more indolent in older women. Among the different breast cancer subtypes, triple negative breast cancer (TNBC) accounts for ∼15% of invasive breast cancer cases and TNBC patients have a poor prognosis due to lack of targeted therapies and limited sensitivity to chemotherapy. Emerging studies indicate that older women with TNBC have a better outcome than younger women for reasons that are unclear. Nevertheless, older patients tend to suffer co-morbidities associated with chemotherapy and often forego treatment, resulting in disease recurrence and a poor outcome for these patients. Treatment of TNBC therefore presents age-specific challenges.
Here, we investigated how age affects the composition and function of pro-tumorigenic bone marrow cells using TNBC models that enable us to interrogate the impact of bone marrow derived cells on both tumor cells and the tumor microenvironment. Consistent with clinical observations, we found that disease progression was significantly more aggressive in young mice relative to aged mice. We identified age- and tumor-dependent molecular and functional changes to bone marrow derived hematopoietic cells that impact TNBC progression. A specific population of Sca1+/cKit- bone marrow cells that expresses CSF1R and secretes the growth factor granulin to support stromal activation and robust tumor growth in young mice, fails to promote tumor outgrowth in aged mice, resulting in maintenance of disease indolence. Importantly, bone marrow cells from young mice are sufficient to activate a tumor-supportive microenvironment and rescue tumor progression in aged mice.
The results presented here indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent activation of tumor-promoting bone marrow cells.
Citation Format: Jaclyn Sceneay, Timothy Marsh, Irene Wong, Yuanbo Qin, Andreas Sjödin, Björn Nilsson, Sheila A. Stewart, Sandra S. McAllister. Hematopoietic age at onset of breast cancer dictates disease aggressiveness and progression. [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 4400.
Abstract 4405: Over-expression of PARP is associated with an aggressive phenotype and can be synergistically targeted using combination of PARP and XIAP inhibitors in breast cancer
Authors: Ahmed Maqbool , Hussain Azhar R. , Beg Shaham , Thangavel Saravanan , Begum Rafia , Ajarim Dahish , Al-Dayel Fouad , Siraj Abdul Khalid Siraj K. , Al-kuraya Khawla S. 
Published: July 2016

Abstract
Breast cancer is the most common cancer in females and despite improvement in treatment modality with the introduction of hormonal targeted therapy, these cancers still remains a major cause of morbidity and mortality in females. Poly ADP ribose polymerase (PARP) is an enzyme which plays a critical role for repairing single-strand breaks. The main function of PARP1 is dependent upon cellular stress responses and directs cells towards DNA repair based on the strength of the stress stimulus. PARP has been found to be over-expressed in various tumors including ovarian cancer; breast cancer and lung cancer, however, its role in the pathogenesis of breast cancer of Middle Eastern origin have not been completely elucidated. Therefore, we examined the expression of PARP in a large cohort of more than 1000 breast cancer by IHC in a tissue microarray format and found PARP was over expressed in 44.7% (451/1008) and was found to be significantly associated with aggressive markers such as Triple negative phenotype, high grade tumors, large tumor size, stage 4 disease and had a poor 5 year overall survival of 72.6 months as compared to 85.4 months (p = 0.0005). Interestingly PARP expression was also found to be significantly associated with aggressive molecular markers such as activated AKT, XIAP and proliferative marker; ki67. Next, in vitro effect of inactivation of PARP was evaluated using a PARP inhibitor; olaparib on a panel of BC cell lines. Olaparib treatment alone did not affect the cell viability and apoptosis at doses up to 10μM concentration. However, when BC cells were treated with sub-optimal dose of Olaparib (1μM) and Embelin (XIAP inhibitor)(5μM) in combination for 48 hours, there was appreciable inhibition of cell viability via induction of apoptosis. Combination of Olaparib and Embelin induced apoptosis via activation and cleavage of caspases-9, -3 and PARP in BC cells. These studies highlight the importance of targeting PARP in combination with either small molecular inhibitors or chemotherapeutic agents in BC can improve the management and survival of this aggressive disease.
Citation Format: Maqbool Ahmed, Azhar R. Hussain, Shaham Beg, Saravanan Thangavel, Rafia Begum, Dahish Ajarim, Fouad Al-Dayel, Abdul Khalid Siraj K. Siraj, Khawla S. Al-kuraya. Over-expression of PARP is associated with an aggressive phenotype and can be synergistically targeted using combination of PARP and XIAP inhibitors in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4405.