bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2951: A comprehensive analysis of proteins involved in innate and acquired resistance to molecularly-targeted drugs in breast cancer cells
Authors: Montazeri Hamid 
Published: July 2016

Abstract
Cancer is the second leading cause of death among Americans, and despite advances in diagnosis, new technologies for early detection, and development of potent molecularly-targeted drugs, survival rates in advanced disease have not been improving at desired rates. Perseverance of cancer cells seem to rely both on their significant heterogeneity at the onset of treatment, and the inherent plasticity (genetic instability) to adopt to environmental conditions and exogenous agents. Cancer is known as a heterogeneous disease. In fact, extensive genetic diversity has been revealed not only between different types of cancer, but also within a single tumor (as diversity in the expression of protein biomarkers). This intra-tumor heterogeneity could be a major obstacle in cancer treatment due to a wide range of responsivity to any specific anticancer agent. This study aims to analyze the heterogeneity and plasticity among a small panel of breast cancer cell lines as a reaction to exposure to a variety of molecularly-targeted agents, which could lead us to identification of the proteins that play major roles in drug resistance in cancer cells.
After initial evaluation of the LC50, we exposed five different breast cancer cell lines to high doses of erlotinib (selective ErbB1/EGFR-inhibitor), vemurafenib (pan Raf inhibitor), everolimus (selective mTORC1 inhibitor), and ruxolitinib (pan JAK inhibitor), an collected the survivors. Using an in-house designed microarray and real-time PCR analysis, we analyzed the protein expression profile of the survivors compared to the untreated population, which revealed proteins involved in innate resistance and the heterogeneity among the population. In an alternative approach, we exposed the cells to gradually increasing doses of these selected agents, affording the cells the opportunity to adapt to the treatment. The resistant cells were then analyzed in a similar fashion to reveal proteins involved in acquired resistance.
Citation Format: Hamid Montazeri. A comprehensive analysis of proteins involved in innate and acquired resistance to molecularly-targeted drugs in breast 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 2951.
Abstract 2963: VB7-756: a Her2-specific diabody armed with deBouganin, a plant toxin with a distinct MOA
Authors: Chooniedass Shilpa , Dillon Rachelle L. , Premsukh Arjune , Entwistle Joycelyn , Adams Gregory P. , Hudson Peter J. , MacDonald Glen C. , Cizeau Jeannick 
Published: July 2016

Abstract
VB7-756 is Targeted Protein Therapeutic (TPT) comprised of a de-immunized form of bouganin (deBouganin), a potent, plant-derived, type I ribosome-inactivating protein (RIP), genetically linked to the C6.5 anti-Her2 diabody via a furin protease sensitive linker. To engineer the optimal diabody TPT format, several constructs were generated to assess the best diabody-deBouganin orientation. All constructs were expressed as a soluble protein in E. coli supernatant and compared with respect to expression level, stability and potency. The optimal configuration consisted of deBouganin genetically linked to the N-terminus of the VH-VL diabody via a furin protease-sensitive linker and was termed VB7-756. VB7-756 potency was analyzed against a panel of breast cancer cell lines with disparate levels of Her-2 expression and compared to that of Trastuzumab chemically linked to either DM1 (T-DM1) or MMAE (T-MMAE). Overall, VB7-756 was more potent than T-DM1 and T-MMAE with high Her-2 expressing tumor cell lines. In contrast to T-DM1, VB7-756 potency was unaffected by the Her2-Her3 dimerization mediated by heregulin. As opposed to T-DM1 and T-MMAE, which showed only minimal cytoxicity, VB7-756 was highly potent in vitro against tumor cells with cancer stem cell properties. To further differentiate the RIP mechanism of action of deBouganin from tubulin inhibitor reagents, tumor cells that escaped T-DM1 and T-MMAE treatment were incubated in the presence of VB7-756. Results revealed that, VB7-756 was cytotoxic against cancer cells surviving T-DM1 or T-MMAE treatment suggesting that deBouganin can overcome mechanisms of resistance developed by small molecule agents. Moreover, VB7-756 was also cytotoxic against tumor initiating cancer cells evading T-DM1 or T-MMAE toxicity by preventing tumorosphere formation. Overall these results demonstrate that deBouganin's distinct MOA could overcome mechanisms of resistance affecting the efficacy of small molecule drugs.
Citation Format: Shilpa Chooniedass, Rachelle L. Dillon, Arjune Premsukh, Joycelyn Entwistle, Gregory P. Adams, Peter J. Hudson, Glen C. MacDonald, Jeannick Cizeau. VB7-756: a Her2-specific diabody armed with deBouganin, a plant toxin with a distinct MOA. [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 2963.
Abstract 2985: Molecular mechanisms of dianhydrogalactitol (VAL-083) in cancer treatment
Authors: Zhai Beibei , Steino Anne , Bacha Jeffrey , Brown Dennis , Daugaard Mads 
Published: July 2016

Abstract
Dianhydrogalactitol (VAL-083) is a unique bi-functional alkylating agent causing methylation of N7-guanine and inter-strand DNA crosslinks. VAL-083 is a small water-soluble molecule that readily crosses the blood-brain-barrier. In China, VAL-083 is approved as a chemotherapeutic drug for the treatment of chronic myelogenous leukemia (CML) and lung cancer. In the United States, VAL-083 has been evaluated in more than 40 National Cancer Institute (NCI)-sponsored phase I and phase II clinical trials. Preclinical studies and clinical trial data suggested antineoplastic effects of VAL-083 in a variety of malignancies, including lung cancer, brain tumors, leukemia, cervical cancer, and ovarian cancer. Here we report new insight into VAL-083 mechanism of action by showing that VAL-083 leads to irreversible cell cycle arrest and cell death caused by replication-dependent DNA damage.
In lung (H2122, H1792, H23 and A549) and prostate (PC3 and LNCaP) cancer cell lines, VAL-083 treatment caused irreversible cell cycle arrest in late S and G2 phase as measured by propidium iodide (PI) and immunofluorescent (IF) staining in synchronized cultures. Importantly, VAL-083 was cytotoxic to all cell lines tested (IC50 range 3.06 - 25.7 μM). Western blot and IF analyses of DNA repair markers were employed to investigate the DNA damage response induced by VAL-083 in cancer cells. VAL-083 treatment led to phosphorylation of the proximal DNA double-strand break (DSB) sensor Ataxia Telangiectasia Mutated kinase (ATM), the single-strand DNA-binding Replication Protein A (RPA32), and the histone variant H2A.X (γH2A.X). Importantly, the DNA damage was specific to cells in S phase indicating that VAL-083-induced DNA cross-links translates into more severe DNA lesions during replication. Furthermore, S/G2 phase cell cycle arrest and increased phosphorylation of γH2A.X in cancer cells persisted after pulse-treatment with VAL-083, indicating irreversible DNA lesions.
Taken together, VAL-083 displayed broad anti-neoplastic activity in lung and prostate cancer cells through the induction of replication-dependent DNA damage. Elucidation of the molecular mechanisms underlying VAL-083 cytotoxicity in cancer cells will offer help in identifying and predicting efficacy of combination treatments.
Citation Format: Beibei Zhai, Anne Steino, Jeffrey Bacha, Dennis Brown, Mads Daugaard. Molecular mechanisms of dianhydrogalactitol (VAL-083) in cancer treatment. [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 2985.
Abstract 2993: Dichloroacetate inhibits cell proliferation and induces apoptosis in human endometrial cancer cell lines
Authors: Clark Leslie H. , Zhou Chunxiao , Bae-Jump Victoria 
Published: July 2016

Abstract
Objective: Dichloroacetate (DCA) is a well-tolerated, oral drug used in the treatment of hereditary lactic acidosis. DCA has been found to have anti-tumorigenic activity in various non-gynecologic cancers through its inhibition of pyruvate dehydrogenase, leading to profound mitochondrial defects in cancer cells. Thus, we sought to assess the effects of DCA on human endometrial cancer cell lines.
Methods: Three endometrial cancer cell lines (KLE, Ishikawa, and ECC-1) were treated with varying concentrations of DCA from 0.1uM to 100 uM. Cell proliferation was measured using the MTT assay. Cell cycle progression was assessed by Cellometer. Apoptosis was evaluated by the Annexin V-FITC assay using Cellometer. Western immunoblotting was performed to assess effects of DCA on cell cycle and cellular stress proteins. In addition, cellular stress was measured using a reactive oxygen species assay. All experiments were performed in triplicate.
Results: DCA inhibited cell proliferation in a dose-dependent manner in all three endometrial cancer cell lines following 72 hours of exposure. The IC50 was 30 uM for KLE, 78 uM for Ishikawa, and 72 uM for ECC-1. Treatment with DCA resulted in G1 phase cell cycle arrest in all three cell lines. DCA induced apoptosis in all three cell lines. Western blotting analysis demonstrated that DCA increased cyclin D1 expression, decreased CDK4 expression, and increased PERK expression after 24 hours of DCA exposure. A dose dependent increase in reactive oxygen species was seen in all three cell lines. At a maximum dose of 100 uM DCA, ROS production compared to controls for KLE increased 3.2-fold (p = 0.002), Ishikawa increased 1.8-fold (p = 0.003), and ECC-1 increased 2.1-fold (p = 0.002).
Conclusions: DCA effectively inhibited cell proliferation via G1 cell cycle arrest and induced apoptosis in human endometrial cancer cell lines. DCA induced significant cellular stress as evidenced by a dose dependent increase in reactive oxygen species. Further evaluation of DCA as a targeted metabolic therapy in endometrial cancer is warranted.
Citation Format: Leslie H. Clark, Chunxiao Zhou, Victoria Bae-Jump. Dichloroacetate inhibits cell proliferation and induces apoptosis in human endometrial cancer cell lines. [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 2993.
Abstract 3027: Dual inhibition of PKC and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma
Authors: Carita Guillaume , Frisch Dit Leitz Estelle , Dahmani Ahmed , Raymondie Chloe , Cassoux Nathalie , Piperno-Neumann Sophie , Némati Fariba , Halilovic Ensar , Jeay Sebastien , Wylie Andrew , Emery Caroline , Roman-Roman Sergio , Schoumacher Marie , Decaudin Didier 
Published: July 2016

Abstract
Uveal melanoma (UM), although rare in incidence, is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified and therefore novel therapeutic approaches are urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway. This has led to the use of PKC inhibitors as a rational targeting strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models, several PKC inhibitor-based combination studies were performed using the PKC inhibitor AEB071 (Sotrastaurin). When combined with AEB071, the targeted agents CGM097 (p53-MDM2 inhibitor), RAD001 (Everolimus, mTORC1 inhibitor) and MEK162 (Binimetinib, a MEK inhibitor) demonstrated greater activity in the UM patient-derived xenograft models than their activity as single agents. Importantly, tumor regressions were observed in several UM models with AEB071 + RAD001 and AEB071 + CGM097 co-treatments. Follow-up in vitro studies in UM cell lines using AEB071 combined with either CGM097 or RAD001 provided a more detailed mechanistic understanding of their combination activity and confirmed their ability to induce cell death. Together, these preclinical studies reveal that combining PKC and p53-MDM2 inhibitors or PKC and mTORC1 inhibitors may provide significant clinical benefit for patients with UM.
Citation Format: Guillaume Carita, Estelle Frisch Dit Leitz, Ahmed Dahmani, Chloe Raymondie, Nathalie Cassoux, Sophie Piperno-Neumann, Fariba Némati, Ensar Halilovic, Sebastien Jeay, Andrew Wylie, Caroline Emery, Sergio Roman-Roman, Marie Schoumacher, Didier Decaudin. Dual inhibition of PKC and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. [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 3027.
Abstract 3034: Overcoming gefitinib resistance in non-small-cell lung cancer by inducing epidermal growth factor receptor (EGFR) degradation via methionine 790 oxidation
Authors: Leung Elaine Lai-Han , Fan Xing-Xing , Wong Maria Pik , Jiang Zhi-Hong , Liu Zhong-Qiu , Yao Xiao-Jun , Lu Lin-Lin , Zhou Yan-Ling , Yau Li-Fong , Tin Vicky Pui-Chi , Liu Liang 
Published: July 2016

Abstract
Personalized therapy is becoming a dominant cancer therapeutic strategy, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small-cell lung cancer (NSCLC) patients with EGFR mutation but they only inhibit EGFR phosphorylation, acquired-resistance still remains unavoidable without EGFRT790M removal. Here, we report a new treatment strategy to overcome such drug resistance by selectively inducing EGFRT790M degradation via specific stimulation of methionine 790 (M790) oxidation. The basal reactive oxygen species (ROS) levels in EGFRT790M containing gefitinib-resistant NSCLC cell lines were substantially high and 63 clinical lung tumors showed higher NADPH oxidase 2 (NOX2) expression than 61 normal lung tissues which may contribute to high basal ROS in cancer. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, resulted in EGFR over-oxidation and degradation as well as apoptosis. By contrast, such responses were lacking in EGFRWild-type (WT) cells, suggesting a new promising drug development strategy with wide therapeutic window between EGFRT790M and EGFRWT. Selective EGFRT790M degradation was manipulated by REDOX imbalance between NOX3 and methionine reductase (MsrA). When NOX3 was activated, NADPH, the key substrate of MsrA, was depleted to generate excessive ROS, resulting in inhibition of MsrA physiological reduction function on oxidized-methionine, thus localized methionine 790 oxidation
of EGFRT790M occurred. Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation and EGFR degradation were confirmed. These findings indicate that specific inducing EGFRT790M degradation via manipulating REDOX imbalance between NOX3 and MsrA would be promising strategy for treating gefitinib-resistant NSCLC.
Citation Format: Elaine Lai-Han Leung, Xing-Xing Fan, Maria Pik Wong, Zhi-Hong Jiang, Zhong-Qiu Liu, Xiao-Jun Yao, Lin-Lin Lu, Yan-Ling Zhou, Li-Fong Yau, Vicky Pui-Chi Tin, Liang Liu. Overcoming gefitinib resistance in non-small-cell lung cancer by inducing epidermal growth factor receptor (EGFR) degradation via methionine 790 oxidation. [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 3034.
Abstract 3040: A novel methoxyflavanone from a Chinese medicinal herb (Perilla frutescens) induces G2/M cell cycle arrest and apoptosis in A549 human lung adenocarcinoma cells
Authors: Mohamed Amer Ali Abd El Hafeez , Fujimura Takashi , Kamei Rikiya , Hirakawa Noriko , Baba Kenji , Nakano Miyako , Ono Kazuhisa , Kawamoto Seiji 
Published: July 2016

Abstract
Background: Perilla frutescens is a common traditional Chinese medicinal herb used for a variety of diseases, e.g. allergic asthma, cough and intestinal disorders. Flavonoids isolated from P. frutescens such as rosmarinic acid, caffeic acid and apigenin have been reported to inhibit proliferation of a variety of cancer cell lines. We recently identified a novel methoxyflavanone named PDMF (Perilla-derived methoxyflavanone) from P. frutescens as a candidate for anti-allergic drug. The objective of the study is to investigate antitumor potency of PDMF on A549 human lung adenocarcinoma and to elucidate its carcinostatic mechanisms.
Methods: Effect of PDMF on cell proliferation and viability of A549 cells were assessed by BrdU incorporation assay and trypan blue dye exclusion test. Cell cycle and apoptosis analyses were carried out by flow cytometry. To elucidate antitumor mechanisms of PDMF, expression and activation status of cell cycle/apoptosis regulators (p53/p21/BAX/caspases) were thoroughly analyzed by immunoblotting.
Results: Stimulation with PDMF not only triggered G2/M cell cycle arrest but also induced apoptosis of A549 cells in a dose-dependent manner. Mechanistically, PDMF stimulation significantly induced protein levels of p53 and its phosphorylated active forms (pSer15) accompanied by induction of p21 and BAX. We also found that proapoptotic caspase molecules (caspase 3, 8, and 9) were all activated upon stimulation with PDMF.
Conclusion: These results suggest that this Perilla-derived methoxyflavanone represents a useful cancer-preventive phytochemical that triggers G2/M arrest, apoptosis, and activation of p53 pathway.
Citation Format: Amer Ali Abd El Hafeez Mohamed, Takashi Fujimura, Rikiya Kamei, Noriko Hirakawa, Kenji Baba, Miyako Nakano, Kazuhisa Ono, Seiji Kawamoto. A novel methoxyflavanone from a Chinese medicinal herb (Perilla frutescens) induces G2/M cell cycle arrest and apoptosis in A549 human lung adenocarcinoma 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 3040.
Abstract 3048: Drug repurposing: Validation of sulfasalazine as a radiosensitizer in melanoma by blocking system Xc−
Authors: Førde Hilde Elise , Sleire Linda , Espedal Heidi , Heggdal Jan Ingemann , Selheim Frode , Pedersen Paal-Henning , Enger Per Øyvind 
Published: July 2016

Abstract
Melanoma is a cancer that has become increasingly frequent over the last decades in the western world. Initial treatment for primary and locoregional melanoma is surgery. In metastatic disease, systematic treatment and recently immunotherapy has been the mainstay. At this stage however, the prognostic outlook is still bleak. Thus, new treatments are urgently needed.
Melanoma is considered to be a radioresistant cancer. The mechanisms underlying radioresistance are multiple and incompletely characterized. In some tumors, radioresistance is mediated by increased synthesis of anti-oxidants that scavenge reactive oxygen species (ROS), induced by radiotherapy. Glutathione (GSH) is an anti-oxidant synthesized from cystine and constitutes a major defense system against oxidative stress in mammalian cells. Cystine is taken up through system Xc− (SXC), an anti-port transmembrane protein with catalytic subunit xCT. Sulfasalazine, a drug approved in the 1950s for treatment of rheumatoid arthritis and inflammatory bowel disease, has been shown to block SXC. Based on previous reports by others, and our own recent findings, we hypothesize that: I) xCT represents a mechanism for radioresistance and is expressed in radioresistant melanoma cancer and II) xCT inhibitors can act as radiosensitizers to potentiate the efficacy of radiotherapy. Expression of the catalytic subunit of SXC, xCT, was found in tissue micro array of primary and secondary melanoma biopsies. In addition, SAS treatment dramatically reduced cystine-uptake and GSH levels in melanoma cells in vitro, and markedly increased the levels of reactive oxygen species (ROS). Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the anti-oxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and irradiation synergistically reduced subcutaneous melanoma tumor growth in vivo, compared to controls or either treatment alone. Thus, future experimental studies are warranted to validate SAS as a radiosensitizer in the treatment of metastatic melanoma. Future studies will also be aimed at assessing the effect on pulmonary melanoma metastasis.
Citation Format: Hilde Elise Førde, Linda Sleire, Heidi Espedal, Jan Ingemann Heggdal, Frode Selheim, Paal-Henning Pedersen, Per Øyvind Enger. Drug repurposing: Validation of sulfasalazine as a radiosensitizer in melanoma by blocking system Xc−. [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 3048.