bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C151: Systematic discovery of cancer dependencies through deep coverage pshRNA screens
Authors: Schlabach Michael , Billy Eric , Mavrakis Konstantinos , Hoffman Greg , Schmelzle Tobias , Hofmann Francesco , Keen Nicholas , Stegmeier Frank , Sellers William 
Published: May 2016

Abstract
Large scale cancer genome sequencing efforts, such as TCGA, revealed the landscape of genomic alterations across many tumor types, but the functional relevance of these alterations and genetic interdependencies cannot be fully assessed from these datasets. Thus, functional genomic screens, such as pooled shRNA 9pshRNA) screens, hold great promise to systematically identify cancer dependencies. However, RNAi discovery screens have been plagued by off target effects causing false positive results and possibly masking on-target effects. In order to address the previous problems with RNAi screens for cancer target discovery, we conducted a large scale pshRNA screening campaign targeting 7500 genes at a depth of 20 shRNAs per gene, across more than 300 cell lines of the cancer cell line encyclopedia (CCLE). The substantial shRNA and cell line depth in this screen significantly increased the robustness of results relative to previous published screens, and allowed the more robust identification of cancer dependencies. Moreover, integration of those growth phenotypes with known features of the cancer cell line encyclopedia (CCLE) enabled the identification of biomarkers (genetic, epigenetic, or proteomic) that correlate with sensitivity, and thus permitted discovery of synthetic lethal relationships. The increased depth provides a robust data set that can be used to find and validate new drug targets as well as infer pathway membership of novel genes by simple phenotypic similarity. The findings of this screen will be presented here.
Citation Format: Michael Schlabach, Eric Billy, Konstantinos Mavrakis, Greg Hoffman, Tobias Schmelzle, Francesco Hofmann, Nicholas Keen, Frank Stegmeier, William Sellers. Systematic discovery of cancer dependencies through deep coverage pshRNA screens. [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 C151.
Abstract C156: GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts
Authors: Zhou Shu , Chang Sarah , McCann Thalia , French Randall , Lowy Andrew M. , Insel Paul A. 
Published: May 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts (PFs)/stellate cells (PSCs), immune/inflammatory cells and other cell types. This unique tumor microenvironment is increasingly recognized as a key mediator of PDAC progression and drug resistance. Targeting the tumor stroma may thus be a therapeutic approach for PDAC. Pancreatic cancer-associated fibroblasts (CAFs), myofibroblast-like cells that produce extracellular matrix proteins, are responsible for the desmoplasia in PDAC. PSCs and PFs are the key progenitors of CAFs. Blocking the activity of CAFs may be a means to improve the therapy and prognosis of PDAC. We hypothesized that G protein-coupled receptors (GPCRs) expressed by pancreatic CAFs are potential therapeutic targets for PDAC. To begin to test this hypothesis, we used an unbiased GPCRomic array approach to identify and quantify the GPCRs expressed by pancreatic CAFs. We discovered that 104 GPCRs have shared expression in CAFs from the primary tumors of five patients; 35 of those GPCRs had at least a 2-fold increased expression in CAFs compared to both PSCs and PFs. An orphan GPCR that we term Orphan 1 is one of the most highly up-regulated GPCRs in CAFs. We found that: 1) co-culture of PSCs with a PDAC cell line (ASPC-1) increases expression of fibrotic markers and Orphan 1 GPCR; 2) Transfection of Orphan 1 GPCR in PSCs increases the expression of fibrotic markers; 3) siRNA knockdown of Orphan 1 in CAFs decreases fibrotic marker expression and cytokine secretion. We conclude that GPCRomics can identify GPCRs that regulate pancreatic CAFs. One such GPCR, Orphan 1, contributes to pro-fibrotic activities in CAFs and is a potential therapeutic target to blunt the fibrosis associated with pancreatic cancer.
Citation Format: Shu Zhou, Sarah Chang, Thalia McCann, Randall French, Andrew M. Lowy, Paul A. Insel. GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts. [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 C156.
Abstract C157: Syndecan1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance
Authors: Yao Wantong , Ying Haoqiang , Draetta Giulio 
Published: May 2016

Abstract
Although the universal presence of KRAS mutations and their critical role in human pancreatic ductal adenocarcinoma (PDAC) designates it as an ideal therapeutic target, oncogenic KRAS (KRAS*) is still regarded as ‘undruggable’ to date. Therefore, to identify therapeutic points of intervention, it is critical to understand the impact of KRAS*-mediated pathways on in vivo tumor pathogenesis. We have recently generated an inducible KrasG12D-driven (iKRAS*) mouse PDAC model and established a critical role for sustained KRAS* activity in tumor maintenance, providing a model to characterize pathways required for KRAS*-dependent tumorigenicity. Cell surface proteins are relatively accessible and can not only provide candidates for biomarker discovery, but also be utilized as therapeutic targets. To characterize the KRAS*-specific organization of cell surface proteins for the development of possible diagnostic or therapeutic tools, we conducted an unbiased surfaceome analyses of tumor cells in the presence and absence of KRAS* signaling using the iKRAS* mouse PDAC model. Syndecans (SDC), a family of heparin sulfate proteoglycans, were identified as candidates whose membrane expression is correlated with KRAS* activity. SDC1 expression is increased in premalignant and malignant pancreatic lesions of primary human PDAC and various KRAS*-driven pancreatic cancer mouse models. In addition, SDC1 expression is specifically upregulated in response to KRAS* induction in acinar-ductal metaplasia (ADM) and early pancreatic intraepithelial neoplasia (PanIN), but not in cerulin-induced chromic pancretitis. Moreover, SDC1 membrane expression was abolished upon KRAS* extinction in PDAC cells and our data indicated that MAPK pathway, but not PI3K pathway, is important for KRAS*-mediated SDC1 surface localization. To further study the role of SDC1 in KRAS*-driven pancreatic cancers, SDC1 knockout mouse model was generated and crossed with LSL-KrasG12D-PDAC models. Our preliminary data indicated that genetic ablation of SDC1 expression effectively suppressed KRAS*-driven PDAC initiation and progression. The mechanisms of KRAS*-mediated SDC1 membrane localization and its impact on PDAC initiation and progression is being further explored. SDC1 might potentially be the drug target and diagnostic marker for PDAC.
Citation Format: Wantong Yao, Haoqiang Ying, Giulio Draetta. Syndecan1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance. [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 C157.
Abstract C168: A two stage prospective clinical trial with irofulven treatment targeting a selected subgroup of castration- and docetaxel resistant prostate cancer patients
Authors: Knudsen Steen , Jensen Thomas , Hansen Anker , Buhl Ulla , Rasmussen Annie , Pratt Bruce , Asaithambi Arun , Brünner Nils , Jensen Peter Buhl 
Published: May 2016

Abstract
Irofulven, a DNA damaging semi -synthetic analog of Illudin S (phytotoxin from Omphalotus illudins, jack-o'-lantern mushroom) which in the body is activated by prostaglandin reductase, has shown promising clinical activity in a range of cancer forms but the objective response rates were too low to justify further clinical development. Of particular interest is that irofulven may not be a substrate of the mdr-1 drug efflux pump and thereby potentially active in prostate cancer patients with acquired resistance to docetaxel. We have now developed an irofulven responsive predictor which is based on gene expression data by comparing associations between gene expression profiles and growth inhibition in a panel of cell lines treated with irofulven. A second step has included filtering the identified gene expression profile against mRNA expression from a collection of 3200 human tumors. Only genes being differentially expressed in the clinical tumor material were retained in the model. A total of 205 mRNA's were selected for the final irofulven responsive profile. The profile can be converted to a single score of predicted irofulven responsiveness. We are now initiating a prospective clinical trial (Simon's two stage design) in selected patients with castration - and docetaxel resistant prostate cancer and with a favorable irofulven responsive profile. We are screening 600 prostate cancer samples (FFPE tissue) in order to select the 10% of patients with the highest likelihood of benefit from irofulven treatment. Primary end-points are objective response rate and changes in serum PSA.
Citation Format: Steen Knudsen, Thomas Jensen, Anker Hansen, Ulla Buhl, Annie Rasmussen, Bruce Pratt, Arun Asaithambi, Nils Brünner, Peter Buhl Jensen. A two stage prospective clinical trial with irofulven treatment targeting a selected subgroup of castration- and docetaxel resistant prostate cancer patients. [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 C168.
Abstract C173: Anti-PD-L1 antibody-based IL-15 immunocytokine has enhanced antitumor immunity
Authors: Wu Yan , Zhong Zhaojing , Martomo Stella , Lu Dan , Polonskaya Zhanna , Luna Xenia , Zhang Haifan , Zhang Zhikai , Wang Zhun , Liu Leo , Patel Jeegar , Tonra James , Li Henry , Witte Larry , Waksal Sam , Zhu Zhenping 
Published: May 2016

Abstract
Immune checkpoint antagonists to PD-1/PD-L1 and immunostimulating cytokines such as IL-15 have shown success to some extent in certain clinical settings across multiple cancer types. However, the full potential of the checkpoint inhibitor is limited due to impaired overall antitumor immunity, and cytokine as single agent has insufficient half-life and systemic toxicities due to the lack of target specificity. To overcome these challenging hurdles, we developed a bifunctional fusion protein, KD-033, composed of an antibody specific for PD-L1 and complex of IL-15Rα sushi domain/IL-15 as a novel immunotherapeutic agent for achieving better antitumor efficacy. Previously, we presented the generation and characteristics of a prototype of bifunctional fusion protein and its potential of in vivo antitumor activity. Here, we report a genetically modified fusion protein that has enhanced immunological activity and capability to achieve stronger antitumor efficacy in tumor models in comparison with either single agent. Our data indicate that the improved bifunctional fusion protein has favorable thermal stability and can be efficiently expressed in mammalian cells. The bifunctional fusion protein has higher affinity to PD-L1, silenced binding activity to Fc receptors and better ability to increase the secretion of Th1 cytokine, i.e. gamma IFN and the cytotoxicity of CD8 T-cells and NK cells to tumor cells as assessed in immunological assays. In preclinical study, KD033 had stronger anti-tumor efficacy in controlling primary tumor growth and prolonging the survival of tumor bearing mice in a number of mouse tumor models including those aggressive tumor models. Furthermore, the PD-L1 targeted bifunctional protein had significantly less cytokine-related toxicity when compared to non-targeted full IgG/IL-15Rα sushi domain/IL-15 fusion protein in vivo. These results demonstrate that KD033 has the capacity of targeting IL-15-stimulated innate and adaptive immune effectors into local tumor sites, thereby effectively controlling tumor progression while having minimized potential adverse effect in vivo. The preclinical studies of the novel immunotherapeutics warrant further investigation towards the clinical development of the bifunctional immunotherapeutic agent for cancer treatment.
Citation Format: Yan Wu, Zhaojing Zhong, Stella Martomo, Dan Lu, Zhanna Polonskaya, Xenia Luna, Haifan Zhang, Zhikai Zhang, Zhun Wang, Leo Liu, Jeegar Patel, James Tonra, Henry Li, Larry Witte, Sam Waksal, Zhenping Zhu. Anti-PD-L1 antibody-based IL-15 immunocytokine has enhanced antitumor immunity. [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 C173.
Abstract C203: Cracking the (ultra)structural biology of Scribble to understand its role as a cell polarity regulator and tumor suppressor protein
Authors: Lim Krystle YB , Caria Sofia , House Colin M. , Godde Nathan J. , Ogden Allison J. , Humbert Patrick O. , Kvansakul Marc 
Published: May 2016

Abstract
Cell polarity or cell asymmetry is crucial for the normal biological function of all metazoan cells. Loss of cell polarity disrupts cellular organization that represents one of the hallmarks of cancer progression. Scribble, a member of the core polarity SCRIB module is deregulated in many cancers such as breast cancer, cervical cancer and prostate cancer. Scribble is a member of the LAP family that consists of 16 Leucine Rich Repeats and 4 PSD-95/Discs-large/ZO-1 (PDZ) domains. The PDZ domains (4PDZ) in particular are important in Scribble's interactions with molecules that are involved in many crucial signaling pathways. We hypothesized that Scribble acts as a scaffold protein to orchestrate these interactions. Our aim is to decipher Scribble's mechanism of action through characterization of Scribble interactions with βPIX (PAK-interacting exchange factor beta), which is well establish in exocytosis and neuronal transmission. Herein, we used pull down assay, isothermal titration calorimetry and small angle X-ray scattering to unravel the interaction profile of the region of Scribble encoding for all four PDZ domains. Our study proposes a working model to illustrate how PDZ domains modulate Scribble and βPIX interactions.
Citation Format: Krystle YB Lim, Sofia Caria, Colin M. House, Nathan J. Godde, Allison J. Ogden, Patrick O. Humbert, Marc Kvansakul. Cracking the (ultra)structural biology of Scribble to understand its role as a cell polarity regulator and tumor suppressor protein. [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 C203.
Abstract C27: Activation of PKA induces a mesenchymal-to-epithelial transition and epigenetic reprogramming-mediated loss of tumor initiating ability
Authors: Pattabiraman Diwakar R. , Weinberg Robert A. 
Published: May 2016

Abstract
Cancer stem cells (CSCs) have emerged in recent years as important targets for cancer therapy owing to their elevated resistance to conventional chemotherapy as well as to tumor-initiating ability that enables them to seed new tumors and thereby drive clinical relapse. The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that confers mesenchymal traits on both normal and neoplastic epithelial cells. By activating EMT programs, carcinoma cells acquire malignancy-associated traits and additionally may become converted into CSC-like cells, as has been shown in many cases. This association between the EMT program and the CSC state has presented an attractive opportunity for drug development and agents that preferentially target more mesenchymal carcinoma cells rather than their epithelial counterparts are highly sought. An alternative therapeutic approach is to convert CSCs to their non-stem cell counterparts through the induction of a mesenchymal-to-epithelial transition (MET). Here we observe that increases in intracellular levels of the second messenger 3'-5'-cyclic adenosine monophosphate (cAMP) and the subsequent activation of protein kinase A (PKA) induces an MET in mesenchymal human mammary epithelial cells and their neoplastic derivatives. The MET-induced differentiation is accompanied by a loss of stem-like properties and tumor-initiating ability, rendering the cells more sensitive to treatment with chemotherapeutic drugs such as doxorubicin and paclitaxel. Upon activation PKA phosphorylates and activates PHF2, a histone H3K9 demethylase, which relieves H3K9me2/3-mediated repression of epithelial genes. Genome-wide occupancy studies of PHF2 reveal that it interacts with numerous genomic loci, relieving their methylation-mediated silencing, enabling the access of epithelial loci to transcription machinery and ultimately, acquisition of an epithelial state. This works presents an attractive strategy to induce an MET through the activation of a histone demethylase that induces widespread epigenomic reprogramming and acquisition of an epithelial state that is more amenable to chemotherapeutic treatment.
Citation Format: Diwakar R. Pattabiraman, Robert A. Weinberg. Activation of PKA induces a mesenchymal-to-epithelial transition and epigenetic reprogramming-mediated loss of tumor initiating ability. [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 C27.
Abstract C30: The 1,2-diaminocyclohexane carrier ligand in oxaliplatin induces p53-dependent transcriptional repression of factors involved in thymidylate biosynthesis
Authors: Kitao Hiroyuki , Kiyonari Shinichi , Iimori Makoto , Matsuoka Kazuaki , Morikawa-Ichinose Tomomi , Miura Daisuke , Niimi Shinichiro , Saeki Hiroshi , Oki Eiji , Maehara Yoshihiko 
Published: May 2016

Abstract
Platinum-based chemotherapeutic drugs are widely used as components of combination chemotherapy in the treatment of cancer. One such drug, oxaliplatin, exerts a synergistic effect against advanced colorectal cancer in combination with 5-FU and leucovorin. In the p53-proficient colorectal cancer cell line HCT116, oxaliplatin represses the expression of deoxyuridine triphosphatase (dUTPase), a ubiquitous pyrophosphatase that catalyzes the hydrolysis of dUTP to dUMP and inhibits dUTP-mediated cytotoxicity. However, the underlying mechanism of this activity has not been completely elucidated, and it remains unclear whether factors other than downregulation of dUTPase contribute to the synergistic effect of 5-FU and oxaliplatin. In this study, we found that oxaliplatin and dachplatin, platinum-based drugs containing the 1,2-diaminocyclohexane (DACH) carrier ligand, repressed the expression of nuclear isoform of dUTPase (DUT-N), whereas cisplatin and carboplatin did not. Oxaliplatin induced early p53 accumulation, upregulation of primary miR-34a transcript expression, and subsequent downregulation of E2F3 and E2F1. Nutlin-3a, which activates p53 non-genotoxically, had similar effects. Introduction of miR-34a mimic also repressed E2F1 and DUT-N expression, indicating that this miRNA plays a causative role. In addition to DUT-N, oxaliplatin repressed, in a p53-dependent manner, the expression of genes encoding enzymes involved in thymidylate biosynthesis. Consequently, oxaliplatin significantly decreased the level of dTTP in the dNTP pool in a p53-dependent manner. These data indicate that the DACH carrier ligand in oxaliplatin triggers signaling via the p53-miR-34a-E2F axis, leading to transcriptional regulation that ultimately results in accumulation of dUTP and reduced dTTP biosynthesis, potentially enhancing 5-FU cytotoxicity.
Citation Format: Hiroyuki Kitao, Shinichi Kiyonari, Makoto Iimori, Kazuaki Matsuoka, Tomomi Morikawa-Ichinose, Daisuke Miura, Shinichiro Niimi, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara. The 1,2-diaminocyclohexane carrier ligand in oxaliplatin induces p53-dependent transcriptional repression of factors involved in thymidylate biosynthesis. [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 C30.
Abstract C58: Small molecule inhibitors targeting the interaction of xeroderma pigmentosum group A protein with cisplatin-damaged DNA
Authors: VanderVere-Carozza Pamela S. , Gavande Navnath , Mishra Akaash , Turchi John J. 
Published: May 2016

Abstract
Targeting DNA repair and the DNA damage response for cancer therapy has recently gained increasing attention with inhibitors of the PI3-K-like kinases in early stage clinical trials. The utility of DNA repair inhibitors can be expanded by their use in combination treatment with DNA damaging chemotherapeutics including cisplatin. We have focused on directly targeting the DNA repair pathway responsible for repairing platinum-induced DNA damage, nucleotide excision repair (NER). We have selected the molecular target XPA, whose role is in the identification and verification of the sites of DNA damage. Clinical validation of XPA has been obtained where high XPA expression in lung, ovarian and lung cancer results in decreased efficacy of platinum therapy. We report the continued development of the X80 class of XPA small molecule inhibitors. In a two-step, iterative process we have identified critical structure activity relationships that have resulted in a 100-fold increase in potency with in vitro IC50 values below 1μM. Analyses of the SARs define the chemical and structural features that impact the interaction with XPA, cellular permeability and contribute to selectivity. Data demonstrate that the X80 class of inhibitors do not interact with DNA but directly bind the XPA protein. Recent production of a sub-fragment of the XPA protein will allow the identification of the direct binding domain to enable continued structure-based design of more potent XPA inhibitors.
Supported by NIH grants R01CA180710 and R41CA162648 to JJT.
Citation Format: Pamela S. VanderVere-Carozza, Navnath Gavande, Akaash Mishra, John J. Turchi. Small molecule inhibitors targeting the interaction of xeroderma pigmentosum group A protein with cisplatin-damaged DNA. [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 C58.