bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2972: Development and characterization of synthetic antibodies with a human framework that directly link metabolism to immune system in cancer cells
Authors: Tomic Jelena , McLaughlin Megan , Geyer Ron , Sidhu Sachdev , Moffat Jason 
Published: July 2016

Abstract
Deregulated cellular energetics and evasion of immune system are two hallmark features of cancer cells. In fact, increased uptake of glucose and glutamine by cancer cells elevates flux of a minor glucose pathway known as the hexosamine biosynthetic pathway (HBP), resulting in alteration of glycosylation. Addition of sugar moieties to proteins plays an important role in sensing cellular metabolism, growth factors, signaling molecules, nutrient flux and stress. Since many of these processes are de-regulated in tumorigenesis, global alterations in glycosylation via HBP flux are likely to play an important role in cancer. We hypothesize that cancer cells can “sense” stress through the HBP pathway, and, consequently, reprogram the cell surface and adapt to tougher conditions. Neo-epitopes on the cell surface that emerge from tuning the HBP pathway activity may be prime candidates as readouts that reliably report the status of metabolic reprogramming.
In order to advance the understanding of metabolic reprogramming from the perspective of the cell surface, we combined genetics and advanced protein engineering using phage-displayed synthetic human antibody libraries to generate recombinant antibodies (rAbs) that respond to changes in the activity of the HBP. Our method for discovery of surface and nutrient-associated protein sensors (SNAPS) has allowed us to identify multiple human synthetic rAbs whose activity is potentiated under different metabolic states. More specifically, these rAbs recognize cell surface features that discriminate cancer cells with increased HBP flux and effectively recruit components of the immune system to initiate tumor cell lysis. Our findings suggest that the nutrient-dependent cell surface epitopes may have functional roles in defining cancer cell identity and may link multiple cancer hallmarks.
Citation Format: Jelena Tomic, Megan McLaughlin, Ron Geyer, Sachdev Sidhu, Jason Moffat. Development and characterization of synthetic antibodies with a human framework that directly link metabolism to immune system in 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 2972.
Abstract 2979: Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC
Authors: Khan Nayel , Davis Kara S. , Godse Neal , Kemp Carolyn , Kulkarni Sucheta , Alvarado Diego , LaVallee Theresa , Grandis Jennifer R. , Duvvuri Umamaheswar 
Published: July 2016

Abstract
Background: The phosphoinositide 3-kinase (PI3K) pathway is a frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC). This pathway is often further activated by dysregulation of receptor tyrosine kinases, such as the epidermal growth factor receptor family. HER3 has a direct phosphorylation site with the regulatory subunit of PIK3CA, and is being investigated as a potential co-target to increase anti-tumor effects of PI3K inhibition. In this study, we use the human monoclonal antibody KTN3379, which blocks HER3 in the autoinhibited configuration and thus inhibits ligand-independent and ligand, neuregulin β-1,-dependent HER3 activation, and an inhibitor of PIK3CA (BYL719) to determine if HER3 and PIK3CA can be inhibited in a synergistic fashion. KTN3379 and BYL719 are clinical stage compounds and are being evaluated in HNSCC clinical trials.
Methods and Results: Treatment with neuregulin β-1 significantly increased phosphorylation of HER3, AKT, and S6 across HNSCC cell lines, regardless of baseline level of HER3 expression. HER3 inhibition (KTN3379) consistently abrogated these effects and decreased baseline phosphorylation of HER3. Combined blockade of HER3 (KTN3379) and PI3K (BYL719) inhibited the growth of HNSCC cell lines in a synergistic fashion (CI range 0.1-0.5), in both cell proliferation and colony formation assays. This synergy appeared to be less pronounced in HPV-associated cancer cell lines. Combined treatment decreased tumor growth in xenograft models of HNSCC. Furthermore, treatment of some HNSCC cell lines with BYL719 led to upregulation of the HER3 protein in HNSCC cell lines by Western blotting analysis, suggesting a possible role of HER3 in PI3K pathway inhibitor resistance.
Conclusion: HER3 interacts with PI3KCA, and the PI3K pathway in multiple HNSCC cell lines, and combined blockade has synergistic effects in pre-clinical HNSCC models. These findings suggest that HER3 and PI3K dual inhibition may be more effective in tumors that are resistant to mono-therapy with either HER3 or PI3K inhibition alone.
Citation Format: Nayel Khan, Kara S. Davis, Neal Godse, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri. Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC. [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 2979.
Abstract 2983: Stat3 regulates supernumerary centrosome clustering in cancer cells via Stathmin/PLK1
Authors: Morris Edward J. , Kawamura Eiko , Gillespie Jordan , McDonald Paul , Muller William , Dedhar Shoukat 
Published: July 2016

Abstract
Centrosome amplification and supernumerary centrosomal content are common features of cancer cells. Such cells must cluster their centrosomes to form a bipolar spindle and achieve productive mitosis. Targeting the mechanisms that allow cells to cluster extra centrosomes is considered a promising cancer therapeutic strategy. We have now identified Stat3, a protein that is frequently activated in many types of cancers and also regulates stem cell function, as a regulator of centrosome clustering in cancer cells. A high content chemical screen for the identification of inhibitors of centrosome clustering identified Stattic, a Stat3 inhibitor, as a centrosome clustering inhibitor. Stat3 depletion in cell lines as well as in tumors in vivo resulted in significant inhibition of centrosome clustering and in decreased tumor viability and growth. Interestingly, we identify a novel, transcription-independent mechanism for Stat3-mediated centrosome clustering that requires activities of Stathmin, a Stat3 interactor involved in microtubule depolymerisation, and polo-like kinase1 (PLK1). Furthermore, stem cell function in PLK4-driven centrosome amplified breast tumor cells is highly sensitive to Stat3 inhibitors, reflected in higher inhibitor sensitivity of tumors derived from these cells in vivo.
We have therefore identified a novel role of Stat3 in the regulation of centrosome clustering, and this role of Stat3 may be critical in identifying tumor types that are sensitive to Stat3 inhibitors.
Citation Format: Edward J. Morris, Eiko Kawamura, Jordan Gillespie, Paul McDonald, William Muller, Shoukat Dedhar. Stat3 regulates supernumerary centrosome clustering in cancer cells via Stathmin/PLK1. [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 2983.
Abstract 2984: Plumbagin induces p53-dependent apoptosis via generation of reactive oxygen species in human cancer cells
Authors: De Umasankar , Kundu Amit , Kim Eunbin , Kwack Jonghwan , Kim Hyungsik 
Published: July 2016

Abstract
Plumbagin [5-hydroxy-2-methyl-1,4-naphthaquinone], a major constituent derived from Drosera and Plumbago, displays antitumor activity both in vitro and animal models, but the molecular mechanisms of p53-mediated antitumor effects have not been clearly explored. The aim of this study is to determine the anticancer effects of plumbagin on MCF-7 (wild type p53) or Ishikawa (p53-mutant type) cells. We compared the cytotoxicity, cell cycle regulation, apoptotic cell death, and generation of intracellular reactive oxygen species (ROS) in these cancer cells. Plumbagin inhibits the growth of Ishikawa (endometrial cancer cells) and SKOV-3 cells, particularly MCF-7 cells. Plumbagin significantly increased the expression of p53 and reduced Murine Double Minute 2 (MDM2) in the MCF-7 cells. Plumbagin up-regulated the expression of p21(CIP1/WAF1) causing cell cycle arrest in the G2/M-phase by down-regulating cyclin B1 and Cdc2 in MCF-7 as well as Ishikawa cells. Plumbagin altered the ratio of Bax/Bcl-2 and cytochrome c released resulting apoptotic cell death in MCF-7 cells. Furthermore, plumbagin dramatically increased the intracellular ROS level, and pretreatment with the ROS scavenger, N-acetyl cysteine (NAC), protected against growth inhibition by plumbagin, suggesting that ROS play a pivotal role in the antitumor activity in MCF-7 cells. In mice bearing the MCF-7 cell xenografts, plumbagin significantly reduced the tumor growth and weight, without apparent side effects. In conclusion, plumbagin exerted anticancer activity in MCF-7 by generation of intracellular ROS that causes induction of apoptosis via Bcl-2/Bax pathways as well as cell cycle arrest.
KEYWORDS: Plumbagin; breast cancer; apoptosis; p53, reactive oxygen species
Citation Format: Umasankar De, Amit Kundu, Eunbin Kim, Jonghwan Kwack, Hyungsik Kim. Plumbagin induces p53-dependent apoptosis via generation of reactive oxygen species in human 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 2984.
Abstract 2987: Generation of a selectively cytotoxic fusion protein against p53 mutated cancers
Authors: Epenetos Agamemnon A. , Kousparou Christina , Filipovic Aleksandra 
Published: July 2016

Abstract
The most common genetic alteration in human cancer involves the p53 tumor suppressor gene resulting in defective control of cell cycle arrest and death.
The p53 protein induces a cyclin-dependent kinase (cdk) inhibitor, p21 which occupies a central position in cell cycle regulation. Cdk inhibition by p21 results in a lack of progression from the G1 to the S-phase due to the prevention of retinoblastoma (Rb) phosphorylation and subsequent inhibition of transcription factors that regulate the genes involved in DNA replication and cell-cycle progression.
It is hypothesized that the re-introduction of p21 into tumor cells will regenerate the pathway to apoptosis (programmed cell death) and inhibit proliferation since it has been suggested that overexpression of p21 results in suppression of tumor growth in vitro and in vivo.Unfortunately, p21 protein alone is unable to be administered directly in vivo and progress to the cell nuclei of cancer cells since there is no active mechanism to transport the protein. However, a number of proteins are known which can translocate across the cytoplasmic membrane of mammalian cells and into the nuclei, carrying additional cargoes with them. One of these translocating proteins is a 60 amino acid peptide corresponding to the homeodomain of the Drosophilia protein Antennapedia [ANTP].
A fusion protein (TR1) has been developed where the full-length p21 protein is attached to the antennapedia protein with a view to delivering the p21 protein into cancer cells to restore cell cycle control.
TR1 penetrated and killed cancer cells that do not express wild type p53 or p21. This included cells that were matched to cogenic parental cell lines. Antp-p21 killed cancer cells selectively that were malignant as a result of mutations or nuclear exclusion of the p53 and p21 genes and over-expression of MDM2.Non-specific toxicity was excluded by showing that TR1 penetrated but did not kill p53- or p21- wild-type cells. TR1 was not immunogenic in normal New Zealand White rabbits. Recombinant Antp peptide alone was not cytotoxic, showing that killing was due to the transduction of the p21 component of TR1. TR1was shown to penetrate cancer cells engrafted in vivo and resulted in tumour eradication when administered with chemotherapy.
TR1 may represent a new and promising targeted therapy for patients with p53-associated cancers supporting the concept that rational design of therapies directed against specific cancer mutations will play a part in the future of cancer therapeutics.
Citation Format: Agamemnon A. Epenetos, Christina Kousparou, Aleksandra Filipovic. Generation of a selectively cytotoxic fusion protein against p53 mutated cancers. [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 2987.
Abstract 3032: A novel compound ARN-3236 inhibits SIK2 and sensitizes ovarian cancer to paclitaxel
Authors: Zhou Jinhua , Alfredi Albandri , Zhang Shu , Santiago-O’Farrill Janice M. , Ahmed Ahmed A. , Yang Hailing , Mao Weiqun , Wang Yan , Vankayalapati Hariprasad , Lu Zhen , Bast Robert C. 
Published: July 2016

Abstract
Ovarian carcinomas account for 4% of total cancers in women in the United States. Improved outcomes might be attained if sensitivity to primary chemotherapy were enhanced. A recent study discovered that the salt inducible kinase 2 (SIK2) plays a key role in the initiation of mitosis and regulates paclitaxel sensitivity. Here we show that SIK2 is overexpressed in 30% ovarian cancer specimens, associated with a poor prognosis. ARN-3236, a selective, highly potent small molecule SIK2 inhibitor with function similar to SIK2 siRNA, blocks cell proliferation in a panel of ovarian cancer cell lines, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression. ARN-3236 also enhanced response to paclitaxel in ovarian cancer cells (OC316, SKOv3, A2780, HEY, ES2 and UPN251). Similar to the function of SIK2 siRNA, ARN-3236 effectively inhibits AKT phosphorylation at Ser473 and Tyr308, as well as the expression of the downstream effector survivin. ARN-3236 uncouples the centrosome from the nucleus in interphase, and blocks centrosome separation in mitosis, resulting in the accumulation of cells in prometaphase. In addition, ARN-3236 enhances tumor growth inhibition of paclitaxel in ovarian cancer xenograft models. Thus, functional inhibition of SIK2 with ARN-3236 had the same effects on ovarian cancer cell function as knockdown of SIK2 with siRNA. ARN-3236 deserves further study as a SIK2 inhibitor that significantly improves the sensitivity to paclitaxel for treatment of human ovarian cancer cells and xenografts.
Citation Format: Jinhua Zhou, Albandri Alfredi, Shu Zhang, Janice M. Santiago-O’Farrill, Ahmed A. Ahmed, Hailing Yang, Weiqun Mao, Yan Wang, Hariprasad Vankayalapati, Zhen Lu, Robert C. Bast Jr. A novel compound ARN-3236 inhibits SIK2 and sensitizes ovarian cancer to paclitaxel. [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 3032.
Abstract 3043: Survivin-mediated radio-sensitization response in p53 mutant tumor cells
Authors: Grdina David J. , Murley Jeffrey S. , Miller Richard C. , Weichselbaum Ralph R. , Rademaker Alfred W. , Woloschak Gayle E. , Li Jian Jian 
Published: July 2016

Abstract
Doses of ionizing radiation ≤100 mGy induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to doses as low as 5 mGy. Experiments were performed using two murine sarcomas, SA-NH and FSa,grown either in culture or as tumors, and two human cancer cell lines, Panc-1 (pancreatic epithelioid carcinoma) and MDA-MB-231 (breast adenocarcinoma). Doses of 5 mGy were used to induce changes in the response of these tumor cells to higher therapy doses using a multi-dosing paradigm. Effects on radiation sensitivity were associated with changes in both survivin concentration and its translocation to the cytoplasm (SA-NH, p53 wild type) or nucleus (FSa, Panc-1 and MDA-MB-231, p53 mutant). In vitro survival assays (2 Gy per fraction, two once daily fractions) and tumor growth delay (TGD) (5 Gy per fraction, five once daily fractions) studies were performed on SA-NH and FSa cells. Intracellular localization of survivin was determined by ELISA and correlated to survival response. 2 Gy alone had no effect on intracellular translocation of survivin. When preceded 15 min earlier by a 5 mGy exposure, survivin increased in the cytoplasm of SA-NH as compared to the nuclei of FSa, Panc-1 and MDA-MB-231 cells. SA-NH tumors were protected by 5 mGy exposures (1.9 day decrease in TGD, P = 0.032) while FSa tumors were sensitized (4.5 day increase in
TGD, P &lt; 0.001). Panc-1 and MDA-MB-231 tumor cells were also sensitized to ionizing radiation following 5 mGy exposures. Exposure of SA-NH to 4 mM of the free radical scavenger N-acetylcysteine inhibited the effect of 5 mGy on inducing this adaptive response. We have identified a very low radiation dose-induced survivin-mediated radio-sensitization response that could enhance therapeutic outcomes associated with the increased usage of imaging procedures in radiation therapy. This work was supported by NIH/NCI grant R01 CA132998 and DOE Low Dose Program/Project Grant DE-SC0001271 (D.J.G.)
Citation Format: David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Ralph R. Weichselbaum, Alfred W. Rademaker, Gayle E. Woloschak, Jian Jian Li. Survivin-mediated radio-sensitization response in p53 mutant tumor 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 3043.
Abstract 3056: Combined disulfiram and radiation therapy against atypical teratoid/rhabdoid tumor
Authors: Lee Yeoung Eun , Choi Seung Ah , Kwak Pil Ae , Wang Kyu-Chang , Phi Ji Hoon , Lee Ji Yeoun , Chong Sangjoon , Moon Youn Joo , Jangra Anshika , Joo Kyeung Min , Kim Seung-Ki 
Published: July 2016

Abstract
Disulfiram (DSF) has been studied as an anticancer drug and radiosensitizer. In our previous study, the therapeutic potential of DSF against atypical teratoid/rhabdoid tumor (AT/RT), one of the most aggressive forms of childhood cancer, had been confirmed using in vitro and in vivo studies. To develop more effective and safer therapy in AT/RT, we evaluated the sensitizing potential of DSF on radiation therapy (RT). The effect of DSF in low concentration alone and in combination with RT was investigated in vitro and vivo. Clonogenic assay, western blot analysis, autophagy assay and γ-H2AX foci staining were performed using several primary cultured AT/RT cells and cell lines. Also, in vivo study was performed using AT/RT orthotopic xenograft mouse model. Combination therapy with DSF and RT potently reduced clonogenicity and down-regulated protein expression of survivin and BCL2. The combination treatment strongly promoted the autophagic cell death and produced abundant γ-H2AX foci in all AT/RT cells. Moreover, the combination treatment significantly reduced the tumor growth and prolonged the survival rate compared to single treatment in AT/RT mouse model. Taken together, our results demonstrated that the combination therapy with DSF and RT has a synergistic therapeutic effect on AT/RT, suggesting a potential clinical application for AT/RT patients.
Citation Format: Yeoung Eun Lee, Seung Ah Choi, Pil Ae Kwak, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Youn Joo Moon, Anshika Jangra, Kyeung Min Joo, Seung-Ki Kim. Combined disulfiram and radiation therapy against atypical teratoid/rhabdoid tumor. [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 3056.
Abstract 3061: AS-10: a new small molecule with promising activity against pancreatic cancer
Authors: Karelia Deepkamal , Pandey Manoj K. , Plano Daniel , Amin Shantu , Sharma Arun K. 
Published: July 2016

Abstract
Patients with pancreatic cancer (PC) have a median survival of only 6 months and a five-year survival of less than 5%, hence making PC one of the deadliest cancer. Severity of PC is due to its identification at late stages, rapid local invasion, early metastases, and meager response to current chemotherapeutic agents. Current therapies result in minimal survival advantage and are linked with multiple adverse events and drug resistance. Hence, there is an urgent need for novel agents which are less toxic and offer greater benefits over conventional therapy. There is ample evidences in literature demonstrating that inflammation plays a critical role in PC growth and promotion. Nuclear factor κB (NF-κB) pathway, one of the major inflammatory pathway, is well known for its inflammatory response, cell proliferation, and resistance to apoptosis. It has been demonstrated that activation of NF-κB in PC is also responsible for resistance towards first line chemotherapeutic agent, gemcitabine, in PC. Through extensive structure-activity relationship studies, we have recently identified a novel small molecule, AS-10, which was lethal to PC cells. We sought to evaluate the mechanism of action of AS-10 responsible for inhibiting the growth of PC cells. In vitro, AS-10 reduced PC cell growth with an EC50, in the range of 2.5 to 5 μM. Growth arrest was confirmed by cell cycle studies, which showed that AS-10 induced G1 and G2 cell cycle arrest. The cell cycle arrest was associated with an increase of cell cycle inhibitory markers like p21 and p27. Effect of AS-10 on cell cycle was translated into activation of apoptosis, confirmed by caspase 3/7 activity, PARP cleavage and Annexin V staining. Due to its structural characteristics, we evaluated the effect of AS-10 on inflammatory NF-κB pathway. Our studies, in Panc-1 cells, showed that AS-10 inhibited NF-κB DNA binding activity as well as NF-κB translocation to the nuclei in the presence of inflammatory stimuli (tumor necrosis factor (TNFα)). Since, up regulation of NF-κB activity has been known to be responsible for gemcitabine resistance in PC, we evaluated the activity of our NF-κB inhibitor AS-10 in combination with gemcitabine, and showed that AS-10 synergistically potentiated gemcitabine activity in PC cells. Taken together, these results suggest that AS-10, may represent a potentially promising therapeutic agent for PC. Detailed investigations regarding the efficacy and mechanism of action of these compounds will be presented.
Citation Format: Deepkamal Karelia, Manoj K. Pandey, Daniel Plano, Shantu Amin, Arun K. Sharma. AS-10: a new small molecule with promising activity against pancreatic 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 3061.