bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4605: STK17A is a potential therapeutic target in glioblastoma
Authors: Mao Pingping , Jardine Mary P. , Rahme Gilbert J. , Yang Eric C. , Tam Janice , Kodali Anita , Biswal Bijesh , Fadul Camilo E. , Gaur Arti B. , Israel Mark A. , Pletnev Alexandre , Spinella Michael 
Published: May 2015

Abstract
Current targeted therapies for glioblastoma multiforme (GBM) fail to significantly improve clinical outcome. Identifying new molecular targets driving GBM tumorigenesis is imperative. Our previous study demonstrated that STK17A, a serine-threonine kinase in the death-associated protein family, is a bona fide p53 target gene. In silico analyses indicated that STK17A is highly overexpressed in GBM patients in a tumor grade-dependent manner. Furthermore, high STK17A expression correlated with poor clinical outcome and decreased survival of patients from multiple datasets. This correlation was independent of age, tumor subtype and known biomarkers such as EGFR, NF1, and IDH, suggesting STK17A may contribute to GBM development and progression.
In vitro experiments confirmed increased mRNA and protein expression of STK17A in GBM cells compared to immortalized normal human astrocytes and other cancer types. ShRNA mediated STK17A knockdown in GBM cells decreased cell survival and sensitized cells to genotoxic stress. In addition, STK17A knockdown led to reduced tumor cell proliferation and clonogenicity, suggesting a tumor-promoting role for STK17A in GBM. Interestingly, STK17A depletion resulted in a cell morphological change from a spindle-like phenotype to a phenotype with a flattened, enlarged and more rounded shape that was associated with induction of actin stress fibers. This cytoskeleton remodeling was associated with impaired cell migration and invasion. In contrast STK17A overexpressing cells displayed a pronounced needle-like elongated phenotype. In addition genome-wide expression analysis of STK17A knockdown GBM cells revealed regulation of genes involved in glycolysis including PKM2, PGAM1 and HK2, suggesting that STK17A may also promote tumor growth and survival through regulating metabolism. Small molecule inhibitors that block the kinase activity of STK17A decreased cell survival of GBM cells cultured under both serum and serum-free conditions. Further investigation is required to understand the precise role of STK17A in GBM.
Citation Format: Pingping Mao, Mary P. Jardine, Gilbert J. Rahme, Eric C. Yang, Janice Tam, Anita Kodali, Bijesh Biswal, Camilo E. Fadul, Arti B. Gaur, Mark A. Israel, Alexandre Pletnev, Michael Spinella. STK17A is a potential therapeutic target in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4605. doi:10.1158/1538-7445.AM2014-4605
Abstract 4608: Exploring anti-oncogenic properties of riluzole in breast cancer
Authors: Bukhsh Miriam A. , Speyer Cecilia L. , Hachem Ali A. , Nassar Mahdy , Assi Ali A. , Gorski David H. 
Published: May 2015

Abstract
Introduction: Triple negative breast cancer (TNBC) is a subtype of breast cancer that lacks the three receptors that current therapy targets (estrogen (ER), progesterone, HER2). Because of this, it is a very aggressive type of breast cancer with a high mortality rate. In a previous study, we discovered the drug, riluzole, to be an mGluR1 inhibitor and to reduce cell proliferation and tumor growth in triple negative breast cancer (TNBC), resulting in apoptosis. This was a significant finding because there are currently no major therapies available to successfully treat TNBC. It is now being thought that riluzole also has properties that may allow it to act as a therapy against ER-positive breast cancer (ER+).
Methods: The goal of this study was to learn more about how riluzole functions by analyzing the anti-oncogenic properties of riluzole. To do this, we conducted a series of transformation assays including cell proliferation (MTT), invasion, soft agar, adhesion, and in vivo metastasis using 4T1-12B cells (a luciferase-expressing clone of the 4T1 mouse mammary tumor cell line).
Results: The results of the assays completed thus far indicate that both TNBC and ER+ cells are sensitive to riluzole, with TNBC being more sensitive. Riluzole significantly inhibits invasion of TNBC cells but not ER+ cells. These findings are consistent with the previous study's results showing that riluzole targets mGluR1 pathways, since ER+ cells contain significantly smaller amounts of mGluR1 compared to TNBC cells. Additionally, riluzole inhibits both cell proliferation and anchorage independent growth of both cell types, suggesting both mGluR1 dependent and independent pathways are involved.
Conclusion: The results of this study suggest that riluzole can be developed as an anti-breast cancer therapy for both triple negative and ER-positive breast cancer patients. Further studies silencing mGluR1 in TNBC and overexpressing mGluR1 in ER+ cell lines will help to determine any significance of mGluR1 in mediating riluzole's mechanism of action.
Citation Format: Miriam A. Bukhsh, Cecilia L. Speyer, Ali A. Hachem, Mahdy Nassar, Ali A. Assi, David H. Gorski. Exploring anti-oncogenic properties of riluzole in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4608. doi:10.1158/1538-7445.AM2014-4608
Abstract 4609: MEF2 plays a critical role in RENCA macrobead-induced tumor cell growth inhibition
Authors: Martis Prithy C. , Dudley Atira , Laramore Melissa A. , Smith Barry H. , Gazda Lawrence S. 
Published: May 2015

Abstract
Regulation of cell proliferation and cell death is often dependent on the coupling of extracellular signals to the activation or repression of specific intracellular signaling pathways. We have previously demonstrated the capacity of mouse renal adenocarcinoma (RENCA) cells encapsulated in agarose macrobeads to form numerous small tumor colonies within the macrobeads over a period of several months. As the encapsulated tumor colonies mature and reach a maximum size, the macrobeads themselves, or conditioned media from cultured macrobeads, markedly inhibit the in vitro and in vivo growth of epithelial-derived tumor cells outside the macrobead microenvironment. Myocyte enhancer factor 2 (MEF2) is a family of four transcription factors that have been shown to play a central role in linking signaling pathways to the genes responsible for cell division, differentiation and death. In this study, we evaluated the expression and role of MEF2 in regulating cell proliferation in mouse (RENCA) and human cell lines (J82, MCF7) in response to RENCA macrobeads. Freely growing RENCA target cells transiently transfected with a MEF2 transcriptional response element and exposed to conditioned media from variously aged macrobeads demonstrated increased response element activation in parallel with the increasing age of the macrobeads. Similarly, growth inhibition of the freely growing RENCA cells increased with older macrobeads. Suppression of the expressed MEF2 isoforms in target RENCA cells, either individually (MEF2a, MEF2b, and MEF2d) or in combination (MEF2pool) using synthetic small interfering RNA (siRNA) markedly reduced the growth inhibitory effects of RENCA macrobeads. In J82 and MCF7 cell lines, MEF2D expression was responsive to replete media from RENCA macrobeads, increasing 2.0-fold and 2.7-fold respectively. Degradation of MEF2D mRNA transcripts in the human cell lines studied resulted in abatement of the growth inhibitory effect of the RENCA macrobeads. These findings reveal an essential role for MEF2 in RENCA macrobead-induced cancer cell growth inhibition and raise interesting questions about the molecular basis of this response.
Citation Format: Prithy C. Martis, Atira Dudley, Melissa A. Laramore, Barry H. Smith, Lawrence S. Gazda. MEF2 plays a critical role in RENCA macrobead-induced tumor cell growth inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4609. doi:10.1158/1538-7445.AM2014-4609
Abstract 4613: Identification of tumor necrosis factor receptor II as a regulatory T cell target for cancer immunotherapy using designed ankyrin repeat protein phenotypic selections
Authors: Williams Geoff , Anderton Judith , Bedian Vahe , Ulrichsen Jane Coates , Gonzalez-Munoz Andrea , Guillard Sandrine , Harris Olivia , Hair James , Leishman Andrew , Lewis Arthur , Moissan Jacques , Minter Ralph , Mistry Bina , Parmentier Julie , Poon Edmund , Popple Amy , Rust Steve , Sandercock Alan , Stewart Ross , Valge-Archer Viia , Wilkinson Robert W. 
Published: May 2015

Abstract
Regulatory T cells (Treg cells) are observed within multiple tumor types and contribute to immune evasion. Effective and specific targeting of Treg cells by antibodies is hampered by the lack of a unique surface marker. With the aim of identifying such a marker, human Treg cells were isolated from peripheral blood, expanded in vitro and used as a source of antigen in phage display selections with a diverse library of designed ankyrin repeat proteins (DARPins). The resulting DARPins were screened for binding to multiple cell-types, and approximately thirty with preferential binding to Treg cells were identified. All of these DARPins were determined to bind to the third and/or fourth cysteine-rich extracellular domains of tumor necrosis factor receptor II (TNFRII, also known as TNFRSF1B or CD120b). Expression of TNFRII has previously been demonstrated on Treg cells, and TNFRII is shown here also to be expressed on CD8+ T cells following exposure to cognate antigen and on the surface of tumor-infiltrating T cells in the 4T1 mouse tumor model. Furthermore, TNFRII mRNA was detected at increased levels in tumor-infiltrating leukocytes isolated from cancer patients. Functional characterisation of the anti-TNFRII DARPins and mAbs revealed an ability to enhance T-cell activation in response to polyclonal and antigen specific stimuli, and in Treg cell suppression assays. These studies demonstrate the utility of DARPins for phenotypic selections to identify drug targets using primary human lymphocytes and highlight TNFRII as a potential therapeutic target enriched on Treg cells.
Citation Format: Geoff Williams, Judith Anderton, Vahe Bedian, Jane Coates Ulrichsen, Andrea Gonzalez-Munoz, Sandrine Guillard, Olivia Harris, James Hair, Andrew Leishman, Arthur Lewis, Jacques Moissan, Ralph Minter, Bina Mistry, Julie Parmentier, Edmund Poon, Amy Popple, Steve Rust, Alan Sandercock, Ross Stewart, Viia Valge-Archer, Robert W. Wilkinson. Identification of tumor necrosis factor receptor II as a regulatory T cell target for cancer immunotherapy using designed ankyrin repeat protein phenotypic selections. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4613. doi:10.1158/1538-7445.AM2014-4613
Abstract 4621: Hedgehog acyltransferase as a novel target in breast cancer
Authors: Matevossian Armine , Resh Marilyn 
Published: May 2015

Abstract
Hedgehog acyltransferase (Hhat) catalyzes the transfer of a palmitoyl group onto Sonic Hedgehog (Shh), a modification that is essential for the signaling activity of Shh. Recent large scale genomics data show Hhat amplifications in a variety of tumor types including breast, liver, lung and uterine cancers. Breast invasive carcinomas have the highest percentage of Hhat amplification. To determine the functional significance of Hhat expression in breast cancers, we used a panel of estrogen receptor-α (ERα) positive and negative cell lines. Here, we show that Hhat is a novel target for inhibition of ERα positive breast cancer. Depletion of Hhat with lentivirally delivered shRNAs decreased both anchorage-dependent and anchorage-independent proliferation of ERα positive, but not ERα negative, breast cancer cells. Treatment with RU-SKI 43, a small molecule inhibitor of Hhat recently developed by our group, also reduced ERα positive cell proliferation, whereas a structurally related, inactive compound had no effect. To identify signaling pathways that mediate the growth defect in response to Hhat inhibition, we used a commercially available microarray which analyzes the phosphorylation of 18 different intracellular signaling components. Phosphorylation of Akt, S6 ribosomal protein, Bad, and PRAS40 were reduced after treatment of the ERα positive cell line MCF7 with RU-SKI 43. Of note, the Smoothened inhibitor erismodegib had no effect on ERα positive cell proliferation, indicating that cell growth is regulated by non-canonical signaling pathways. Overexpression of Hhat in ERα positive cells not only rescued the growth defect in the presence of RU-SKI 43, but also resulted in increased cell proliferation in the absence of drug treatment. Together, these data suggest that Hhat plays a critical role in ERα positive breast cancer and highlight the potential promise of Hhat inhibitors for therapeutic benefit.
Citation Format: Armine Matevossian, Marilyn Resh. Hedgehog acyltransferase as a novel target in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4621. doi:10.1158/1538-7445.AM2014-4621
Abstract 4622: Discovery of a novel target for monoclonal antibody therapy of breast and ovary cancers
Authors: Grandi Alberto , Campagnoli Susanna , Parri Matteo , Camilli Elisa D. , Jin Boquan , Sarmientos Paolo , Grandi Guido , Terracciano Luigi , Viale Giuseppe , Pileri Piero , Grifantini Renata Maria 
Published: May 2015

Abstract
In our recent research activities, we identified a panel of novel candidate markers for prevalent cancers by a systematic immune-histochemical screening with a large collection of polyclonal antibodies (approximately 1600) raised against membrane-associated and secreted human proteins currently marginally characterized. Of utmost interest were those proteins over-expressed detected in one or more tumors showing surface exposure on cancer cells. Among them, here we describe the molecular characterization of a novel surface-associated protein (EXN36) belonging to the lectin-binding protein family for which very little is presently known. We found that the protein is mainly over-expressed in breast and ovary cancers (frequency of approximately 30-40% of tested cases, based on analysis of 50 patients) and it is involved in cell proliferation, migration and invasiveness, as demonstrated by gene silencing. With the intent of exploiting EXN36 as therapeutic target for monoclonal antibody (mAb) therapy, highly specific murine mAbs were generated and proved to recognize the protein on the surface of selected breast and ovary cell lines. Of particular interest are two mAbs, which, upon binding, are efficiently internalized by breast and ovary cancer cells. These two mAbs influence the viability of breast and ovary cells in vitro. One of them shows antibody-dependent cell-mediated cytotoxicity in vitro in breast cancer cells. An analysis of their biodistribution in normal human tissues showed that these mAbs have limited cytoplasmic reactivity in some tissues. Overall, the functional properties of the anti-EXN36 mAbs make them amenable for the generation of antibody-drug conjugates (ADCs). Moreover, they could be exploited for immune-nanoparticles targeted delivery systems. In vivo efficacy in breast and ovary xenograft cancer models are ongoing to evaluate their therapeutic activity either as naked antibodies or ADCs. Overall, data indicate that EXN36 and the specific mAbs represent innovative and promising tools for a targeted mAb therapy of breast and colon cancer, either alone or in combinatorial therapeutic strategies.
Citation Format: Alberto Grandi, Susanna Campagnoli, Matteo Parri, Elisa De Camilli, Boquan Jin, Paolo Sarmientos, Guido Grandi, Luigi Terracciano, Giuseppe Viale, Piero Pileri, Renata Maria Grifantini. Discovery of a novel target for monoclonal antibody therapy of breast and ovary cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4622. doi:10.1158/1538-7445.AM2014-4622
Abstract 4623: HDAC6 inhibition is a novel strategy to selectively impact inflammatory breast cancer cell survival
Authors: Putcha Preeti , Yu Jiyang , Califano Andrea , Silva Jose 
Published: May 2015

Abstract
Inflammatory breast cancer (IBC) is a lethal and understudied variant of breast cancer, presenting with a signature clinical phenotype of rapidly metastasizing diffuse tumor emboli and rapid resistance to traditional chemotherapeutics. In an unbiased, highthroughput search for novel genes and therapeutics which specifically impact IBC cell survival, we performed a genome wide shRNA screen on two IBC cell lines and identified Histone Deacetylase 6 (HDAC6) as vital for IBC vs non-IBC breast cancer cell line survival. In IBC vs non-IBC breast cancer cell lines, individual knockdown of HDAC6 decreases cell viability and causes apoptosis via cleaved PARP expression and annexin V assays. Importantly, HDAC6 is a therapeutically viable candidate. The orally bioavailable next generation HDAC6-selective inhibitor, Rocilinostat, also preferentially impacts IBC vs non-IBC cell survival. We transitioned these findings in vivo by treating a well-established mouse xenograft model of IBC with Rocilinostat and found significant slowing of tumor growth rates. Taken together, these data represent a new and tailored treatment option for IBC.
Note: This abstract was not presented at the meeting.
Citation Format: Preeti Putcha, Jiyang Yu, Andrea Califano, Jose Silva. HDAC6 inhibition is a novel strategy to selectively impact inflammatory breast cancer cell survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4623. doi:10.1158/1538-7445.AM2014-4623
Abstract 4624: Molecular target identification of quinolinone based anticancer compounds
Authors: Rylova Gabriela , Dzubak Petr , Janostakova Anna , Frydrych Ivo , Konecny Petr , Holub Dusan , Ozdian Tomas , Dolezal Dalibor , Soural Miroslav , Hlavac Jan , Hajduch Marian 
Published: May 2015

Abstract
Quinolinones, compounds derived from quinolone antibiotics, are well known for their antibacterial, antiprotozoal, cytotoxic and immunosuppressive effects. Screening of collection of small molecules revealed 2-phenyl-3-hydroxy-4(1H)-quinolinones as molecules with highly selective cytotoxic activity against tumor cell lines. Moreover, in vivo activity assessment of the most active compounds against mouse tumor hollow fibre model of CCRF-CEM cells, showed anticancer activity comparable to doxorubicin. Furthermore, cell biology tests revealed that DNA/RNA synthesis was inhibited together with block of tumor cells in G1 phase within the cell cycle.
With these promising results, we decided to continue to identify molecular target and mechanism of action of these compounds and based on such understanding to further improve its biological activity and pharmacological properties.
As a first step, the biotinylated molecules of original derivatives were synthesized, which were used for immunoafinity pull down target identification. By mass spectrometry analysis we have reproducibily identified complex of proteins, which are involved in glucose metabolism, translational regulation and are building blocks of cytoskeleton. Involvement of these pathways was further supported by metabolomics, proteomics profiling and by microarray expressional analysis. Identified molecular targets were further validated by western blots, in reporter cell lines and in the cell-free system by measurement of enzymatic activity and monitoring of complex interaction of identified partners, suggesting new mechanisms of regulation. Currently, we are working on the state-of-art proof by structural analysis of target and chinolinone ligand. Acknowledgement: This work was supported by internal grant of Palacky University (LF_2013_016) and BIOMEDREG (CZ.1.05/2.1.00/ 01.0030).
Citation Format: Gabriela Rylova, Petr Dzubak, Anna Janostakova, Ivo Frydrych, Petr Konecny, Dusan Holub, Tomas Ozdian, Dalibor Dolezal, Miroslav Soural, Jan Hlavac, Marian Hajduch. Molecular target identification of quinolinone based anticancer compounds. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4624. doi:10.1158/1538-7445.AM2014-4624
Abstract 4650: Pharmacokinetic and pharmacodynamic study of adjuvant gemcitabine therapy of biliary tract cancer following major hepatectomy (KHBO1101)
Authors: Fujiwara Yutaka , Kobayashi Shogo , Nagano Hiroaki , Kanai Masashi , Hatano Etsuo , Toyoda Masanori , Ajiki Tetsuo , Takashima Yuki , Hamada Akinobu , Minami Hironobu , Ioka Tatsuya 
Published: May 2015

Abstract
Background: Gemcitabine at a standard dose of 1000 mg/m2 on Day 1, 8 and 15 every 4 weeks is not tolerated in biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy determined that the recommended dose is 1000 mg/m2 on Day 1 and 15 every 4 weeks. Here, we evaluated the pharmacokinetics and pharmacodynamics of gemcitabine at this recommended dose. Methods: This study evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by postoperative gemcitabine therapy. Pharmacokinetic evaluation of gemcitabine and 2′,2′-difluorodeoxyuridine (dFdU) was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800 to 1000 mg/m2. Physical examination and adverse events were assessed for two weeks. Results: Thirteen patients were enrolled from August 2011 to January 2013, with 12 completing the study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had distal extrahepatic cholangiocarcinoma. Median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43-83 days). In the twelve patients, the following disorders at all grades of severity were observed: leukopenia (83.3%), neutropenia (66.7%), and thrombocytopenia (50.0%). Further, Grade 3 of neutropenia was observed in 16.7% of these patients. The dose-normalized AUC of gemcitabine and dFdU in patients with major hepatectomy was 10.22 ± 2.54 and 94.38 ± 45.38 mg/L/hr, respectively. These values were generally similar to those of patients with pancreatic cancer who did not undergo hepatectomy in a previous study. Conclusion: This study demonstrated that major hepatectomy did not affect the pharmacokinetics of gemcitabine and dFdU, despite an increase in hematological toxicity.
Citation Format: Yutaka Fujiwara, Shogo Kobayashi, Hiroaki Nagano, Masashi Kanai, Etsuo Hatano, Masanori Toyoda, Tetsuo Ajiki, Yuki Takashima, Akinobu Hamada, Hironobu Minami, Tatsuya Ioka. Pharmacokinetic and pharmacodynamic study of adjuvant gemcitabine therapy of biliary tract cancer following major hepatectomy (KHBO1101). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4650. doi:10.1158/1538-7445.AM2014-4650