bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2804: Disrupted integrity in IκB kinase alpha promotes lung adenocarcinoma progression via an oxidative stress-inflammation circuitry
Authors: Song Na-Young , Willette-Brown Jami , Dalta Mahesh , Hu Yinling 
Published: July 2016

Abstract
Recent advanced research has highlighted that multiple drivers and somatic aberrations drive intratumor heterogeneity. Multiple hits in different nucleotides of a single critical gene and diverse deregulatory mechanisms in one tumor have challenged to understand how these various forms of a single gene cooperate with other drivers in cancer development. IκB kinase alpha (IKKα) down-or-up-regulation and mutations have been detected in many human cancers; however, the function of IKKα in lung adenocarcinoma (ADC), a major type of human lung cancers, has not been explored. To study how the different mutant forms of IKKα regulate KrasG12D-induced lung ADC development, we crossed KrasG12D mice with Ikkα floxed mice and two Ikkα knock-in mice and found that a lung specific IKKα deletion (IkkαΔLung) and two different IKKα point mutants (IkkαKA/KA: K→A at amino acid 44 and IkkαAA/AA: S→A at amino acids 176 and 180) promote the progression of KrasG12D-induced lung ADCs. The IKKα mutants integrate into the KrasG12D-mediated diverse oncogenic pathways; additionally the mutants increase levels of pulmonary macrophage infiltration, ROS, and DNA damage compared to KrasG12D-induced lung ADCs. IKKα deficiency results in decreased levels of Nrf2, a transcription factor that regulates expression of genes encoding many anti-oxidants, and increased levels of NADPH oxidase 2 (Nox2), which form an oxidative stress-inflammation circuitry partially regulated by a new identified pathway of IKKα, aryl hydrocarbon receptor and Nox2. Treatment with a Nox inhibitor (apocynin) or a ROS scavenger (N-acetyl cysteine), and/or Nox2 null bone marrow transplant inhibits the pathogenesis of ADCs. Also, we observed various aberrations of IKKα in human lung ADCs. The study not only demonstrates that IKKα serves as a gatekeeper to suppress oncogenic oxidative stress in lung ADC development, but also provides an advanced model that explains how the different mutant forms of a signal gene integrate into distinct signalings to enhance the crucial driver KrasG12D-induced lung cancer development.
Citation Format: Na-Young Song, Jami Willette-Brown, Mahesh Dalta, Yinling Hu. Disrupted integrity in IκB kinase alpha promotes lung adenocarcinoma progression via an oxidative stress-inflammation circuitry. [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 2804.
Abstract 2806: Oxidative stress limits metastasis of human melanoma cells
Authors: Piskounova Elena , Agathocleous Michail , Murphy Malea , Hu Zeping , DeBerardinis Ralph , Morrison Sean 
Published: July 2016

Abstract
Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. We studied the complex and poorly understood process of metastasis by using a clinically relevant model of melanoma metastasis: patient-derived xenografts (PDX) that differ in their capacity to metastasize in NOD-SCID-Il2rg−/− (NSG) mice, mirroring their metastasis histories in the patients from which they were derived. We systematically dissected distinct steps of the metastatic cascade in vivo to show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Using Liquid Chromatography-Mass Spectrometry (LC-MS) and flow cytometry, we discovered that melanoma cells in the blood and visceral organs experienced high levels of oxidative stress not observed in subcutaneous tumours. This work demonstrates that successfully metastasizing melanomas undergo reversible functional and metabolic changes during metastasis that increases their capacity to withstand oxidative stress through an increased dependence on NADPH-generating enzymes in the folate pathway. Chronic antioxidant treatment promotes circulating melanoma cell survival and distant metastases in NSG mice. Folate pathway inhibition, using low-dose methotrexate or depletion of several NADPH-regenerating enzymes, inhibits distant metastases without significantly affecting the growth of subcutaneous tumours in the same mice. We are currently investigating the role of other NADPH-regenerating pathways such as the pentose phosphate pathway in metastasis of human melanoma cells. Finally, we hypothesize that other stress types may also play a role in limiting metastasis in vivo and we are looking for additional metabolic adaptations that may increase stress-resistance of metastasizing melanoma cells and represent novel therapeutic targets in metastatic disease.
Citation Format: Elena Piskounova, Michail Agathocleous, Malea Murphy, Zeping Hu, Ralph DeBerardinis, Sean Morrison. Oxidative stress limits metastasis of human melanoma 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 2806.
Abstract 2808: Oxidative status of mouse azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer model and the effects of COX-2 inhibitor
Authors: Kismali Gorkem , Uner Aykut Gokturk , Meral Ogunc , Alpay Merve , Cakir Dilek Ulker , Kosova Funda , Sel Tevhide 
Published: July 2016

Abstract
Background: Colorectal cancer (CRC) is becoming increasingly common in Asian and European countries and still remains the second leading cause of cancer deaths in the United States. The prevention of carcinogenesis by anti-inflammatory agents including nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and natural products is an area of considerable interest and research. Numerous anti-inflammatory agents have been identified as potential CRC chemopreventive agents but vary in their mechanism of action.The objective of this study is to explore the oxidative status of the mouse model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer, and effects of COX-2 inhibitor in these animals.
Materials and Methods: Totally 40 mice were randomized divided to four groups All animals except control and Cox-2 inhibitor alone group received AOM/DSS to establish colitis-associated cancer model as reported elsewhere. Control group animals were fed with conventional mice diet. COX-2 preferential inhibitor meloxicam was used to minimize side effects such as gastrointestinal hemorrhage Meloxicam were used i.p. 5mg/kg tree times in a week for meloxicam alone and AOM/DSS + meloxicam group. Oxidative stress markers Superoxide dismutase (SOD), Glutation peroxidase (GPx), Malondialdehyde (MDA) and Advanced Oxidation Protein Products (AOPP) were measured by spectrophotometrically in sera.
Results: The combination treatment of Meloxicam and AOM/DSS significantly increased (p&lt;0,05) SOD activities. GPx activities were found significantly increased (p&lt;0,001) in mice treatment with Meloxicam and AOM/DSS combinations or alone. There were no differences between the control and treatment groups of MDA levels. Advanced Oxidation Protein Products levels of Meloxicam and AOM/DSS combination group were found higher than the other groups.
Conclusion: Meloxicam and /or AOM/DSS treatment not caused lipid peroxidation, but increased the antioxidant enzymes and Advanced Oxidation Protein Products levels.
Citation Format: Gorkem Kismali, Aykut Gokturk Uner, Ogunc Meral, Merve Alpay, Dilek Ulker Cakir, Funda Kosova, Tevhide Sel. Oxidative status of mouse azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer model and the effects of COX-2 inhibitor. [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 2808.
Abstract 2811: Antioxidant compounds and their effects on ECM-detached ovarian cancer cells
Authors: Davison-Versagli Calli A. 
Published: July 2016

Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynecological cancers. Approximately 70% of all EOC patients are diagnosed at advanced stages of the disease. In these patients, ovarian cancer cells shed from the primary tumor and accumulate in ascites in the peritoneal cavity. These shed cells have shown the ability to attach and form secondary tumors throughout the peritoneal cavity, making EOC more difficult to treat. A better understanding of the molecular mechanisms involved in the survival of ovarian cancer cells in ascites could lead to the development of improved chemotherapeutics aimed at eradicating this nonadhesive subset of cells and thus resulting in better survival rates of EOC patients. While non-tumorigenic epithelial cells require attachment to the extracellular matrix (ECM) for survival, ovarian cancer cells surviving in ascites gain the ability to survive in anchorage independence. Striking increases of reactive oxygen species (ROS) mediated by ECM-detachment has been shown to inhibit energy production and inhibit cell viability in non-tumorigenic mammary epithelial cells. Consequently, neutralization of ROS with antioxidant compounds enhance ATP production and promote survival in anchorage independence. Furthermore, previous publications from our laboratory suggest that antioxidant enzymes are critical for metabolic maintenance and survival of ECM-detached breast cancer cells. While these recent studies reveal a novel role for antioxidant activity in metastatic breast cancer, antioxidant activity and its effects on ECM-detached ovarian cancer cells has yet to be unveiled. Currently, we have found that neutralization of ROS through treatment with a variety of antioxidant compounds increases metabolic efficacy in ECM-detached ovarian cancer cells. More specifically, ECM-detached SKOV3 ovarian cancer cells treated with antioxidant compounds Trolox (a vitamin E analog), Vitamin C, and Epigallocatechin gallate (EGCG) results in large increases in ATP levels. Given these data, we are further working to understand the mechanisms involved in this metabolic increase. In addition, we are working to understand the relationship between this increase in metabolism and survival in anchorage independence. Future studies include looking at this phenomenon in other ovarian cancer cell lines as well as using mouse xenograft studies to examine the effects of antioxidant compounds on survival of metastatic ovarian cancer cells.
Citation Format: Calli A. Davison-Versagli. Antioxidant compounds and their effects on ECM-detached ovarian 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 2811.
Abstract 2815: Antitumor activity of CDK4/6 inhibition in combination with radiation therapy on glioblastoma stem cells
Authors: Nguyen Christopher , Piao Yuji , Martinez-Ledesma Juan Emmanuel , Dong Jianwen , Park Soon Yeung , Verhaak Roel , Sulman Erik , De Groot John F. 
Published: July 2016

Abstract
Almost 80% of glioblastoma tumors have alterations in the CNKN2A-CDK-Rb pathway. Cyclin dependent kinases 4 and 6 (CDK4/6) act as cell cycle regulators and have been recognized as therapeutic targets for glioblastoma (GBM). In the current study, we determined the antitumor activity of CDK4/6 inhibition (palbociclib and abemaciclib) alone and in combination with radiation on a panel of glioblastoma stem cells (GSCs). The GSCs were molecularly characterized using multiple ‘omimcs’ techniques and Western blots identified specific phospho- and total protein levels. Approximately 50% of cell lines have homozygous deletion of CDKN2A although CDK4 and CDK6 protein expression was significantly elevated in most of the GSCs. RB protein was constitutively phosphorylated in only a subset (45%): GSC11, GSC262, GSC231, GSC304 and GSC7-2. In our panel of GSCs, there were total of three cell lines with CDKN2A loss, RB phosphorylation and CDK4/6 overexpression (GSC262, GSC11 and GSC231). Our data showed that GSC262, GSC11, GSC231 (CDKN2A deletion, RB intact), GSC7-2 and GSC300 (CDKN2A WT, RB intact) were sensitive to CDK4/6 treatment (IC50 ≤ 1μM). CDK4/6 inhibitor treated GSCs showed G1 cell cycle arrest and decreased phospho-RB levels in GSC262 and GSC7-2 cells. We next determined whether CDK4/6 inhibition combined with radiation has additive or synergistic antitumor effect. A clonogenic assay demonstrated that neurosphere formation was significantly decreased by CDK4/6 inhibition in combination with radiation compared to either treatment in GSC262 (resistant to radiation treatment) or GSC7-2 (sensitive to radiation treatment) cell lines. The radiation resistant GSC (GSC262) treated with radiation and CDK4/6 inhibitor became sensitive to radiation therapy whereas radiation sensitive GSC (GSC7-2) had a significant decrease in colony formation compared to radiation alone. CDK4/6 combined with radiation increased γ-H2AX protein expression levels and decreased cyclin D1 protein expression in a time dependent manner compared to single drug treatment. These data indicate synergistic antitumor effects of CDK4/6 inhibition combined with radiation therapy in GSCs in vitro. Further investigation is ongoing to evaluate this combination therapy.
Citation Format: Christopher Nguyen, Yuji Piao, Juan Emmanuel Martinez-Ledesma, Jianwen Dong, Soon Yeung Park, Roel Verhaak, Erik Sulman, John F. De Groot. Antitumor activity of CDK4/6 inhibition in combination with radiation therapy on glioblastoma stem 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 2815.
Abstract 2816: Evaluation of Cdk5 inhibitors in neural crest tumors
Authors: Norris Robin E. , Pink John J. , Pareek Tej , Letterio John L. 
Published: July 2016

Abstract
Cyclin-dependent kinase 5 (Cdk5) is a ubiquitously expressed proline-directed serine threonine kinase active mainly in post-mitotic neurons due to abundant expression of its obligate activating partners p35 and/or p39. Cdk5 has been viewed narrowly as a neuron-specific kinase and as an essential regulator of neuronal function and migration.
Recently, Cdk5 activity has been implicated in mediating tumor invasion, progression, and metastasis. We have found invariably high expression and activity of Cdk5/p35 in a series of pediatric tumor cell lines including neuroblastoma.
To evaluate the potential role of Cdk5 inhibitors in the treatment of neural crest tumors, we evaluated the in vitro kinase activity and growth inhibition of 4 Cdk5 inhibitors (AT7519, dinaciclib, flavopiridol, and seliciclib). We compared the in vitro activity against Cdk2/cyclin E, Cdk5/p25, Cdk5/p35, Cdk7/cyclin H, and Cdk9/cyclin K. Using a DNA-based proliferation assay, we assessed the in vitro growth inhibition in a panel of 10 neural crest-derived tumors (melanoma, neuroblastoma, Ewing sarcoma).
All Cdk5 inhibitors demonstrated enzyme and growth inhibition at clinically achievable concentrations. Dinaciclib was the most potent inhibitor of Cdk5/p35 with an enzyme IC50 of 0.0002 μM, compared to 0.003 μM for AT7519, 0.021 μM for flavopiridol, and 0.097 μM for seliciclib. Dinaciclib was also the most potent inhibitor of Cdk2. However, flavopiridol and AT7519 were the most potent inhibitors of Cdk7 and Cdk9, respectively.
Across all cell lines, dinaciclib was the most potent inhibitor of growth. The median (range) growth inhibition IC50 for dinaciclib was 0.006 μM (0.004 - 0.14), compared to 0.079 μM (0.045-0.16) for flavopiridol, 0.52 μM (0.14 - &gt;15) for AT7519, and 13.2 μM (7.8 - 22.1) for seliciclib. Interestingly, within the Ewing sarcoma cell lines, there was disparate sensitivity to the 2 most potent Cdk5 inhibitors, dinaciclib and AT7519. Based on the activity of these Cdk inhibitors in neural-crest tumors, we expanded our evaluation of AT7519 in 6 pediatric tumor cell lines (medulloblastoma, rhabdomyosarcoma, osteosarcoma) and found similar in vitro potency with a median (range) IC50 of 0.43 μM (0.20 - 1.26).
AT7519, dinaciclib, flavopiridol, and seliciclib demonstrated in vitro growth inhibition in a panel of neural crest and pediatric solid tumor cell lines at clinically achievable concentrations. Further in vivo evaluations and in vitro combination studies including this novel class of agents in models of neural crest and select pediatric cancers are warranted.
Citation Format: Robin E. Norris, John J. Pink, Tej Pareek, John L. Letterio. Evaluation of Cdk5 inhibitors in neural crest tumors. [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 2816.
Abstract 282: Pan-RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4 and 6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1
Authors: Chen Shih-Hsun , Zhang Youyan , Van Horn Robert D. , Yin Tinggui , Huber Lysiane , Burke Teresa F. , Gong Xueqian , Wu Wenjuan , Bhagwat Shripad , Buchanan Sean , Beckmann Richard P. , Tiu Ramon V. , Peng Sheng-Bin 
Published: July 2016

Abstract
KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, including melanoma, lung, colorectal, and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor currently in phase I clinical trial, has been shown to inhibit cell proliferation of RAS- or BRAF-mutant tumor cells in vitro and xenograft tumor growth in vivo. An unbiased screen for compounds that synergize with LY3009120 in RAS/BRAF mutant cancers identified inhibitors of CDK4 among the top hits. In this study, we found that combined inhibition of RAF and CDK4 and 6 by LY3009120 and abemaciclib cooperatively reduced viability of tumor cells with KRAS, NRAS or BRAF mutation in vitro. In animal models, the LY3009120 and abemaciclib combination exhibited synergistic regression of tumor growth in multiple xenograft models with KRAS, NRAS, or BRAF mutation. Molecular mechanistic analysis revealed that pan-RAF inhibitor treatment suppressed the cyclin D1 upregulation which was mediated through CDK4 and CDK6 inhibition by abemaciclib, and the combination treatment cooperatively demonstrated more complete inhibition of RB phosphorylation. These results were further verified by CDK4 and CDK6 siRNA knockdown and another CDK4 and CDK6 selective inhibitor palbociclib. Importantly, the more complete phospho-RB inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combinational treatment led to more significant cell cycle G0/G1 arrest and apoptosis of tumor cells. These preclinical findings suggest that the combinational inhibition of RAF and CDK4 and CDK6 signaling by LY3009120 and abemaciclib is synergistic and should be further studied compared to single agents in the treatment of cancer in patients with KRAS, NRAS or BRAF mutations.
Citation Format: Shih-Hsun Chen, Youyan Zhang, Robert D. Van Horn, Tinggui Yin, Lysiane Huber, Teresa F. Burke, Xueqian Gong, Wenjuan Wu, Shripad Bhagwat, Sean Buchanan, Richard P. Beckmann, Ramon V. Tiu, Sheng-Bin Peng. Pan-RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4 and 6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1. [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 282.
Abstract 2822: TPX2 overexpression is essential for the survival of MYC-driven triple negative breast cancer
Authors: Rohrberg Julia , Corella Alexandra , Balakrishnan Sanjeev , Goga Andrei 
Published: July 2016

Abstract
Triple-negative breast cancer (TNBC) presents the most challenging subtype with the poorest clinical outcome and no targeted therapy. Our lab previously showed that oncogenic MYC pathways are deregulated in human TNBC tumors and predict patients’ poor prognosis. However, clinical development of small molecule inhibitors for MYC has not been successful yet. We identified a synthetic-lethal interaction in which inhibition of cyclin-dependent kinase 1 (CDK1) resulted in the selective killing of MYC overexpressing cancer cells. CDK1 is a mitotic kinase that regulates a large number of substrates and its inhibition causes proliferation arrest in all cells, which may be associated with toxicity. We hypothesize that the MYC-CDK1 synthetic lethality can be attributed to the loss of function of only one or a handful of CDK1 substrates. To identify those substrates, we combined bioinformatics analysis of gene expression data from patient samples and cell based screening approaches. We identified TPX2 depletion to efficiently kill MYC overexpressing cells, while sparing normal cells. Using analog-sensitive CDK1 we confirmed that TPX2 is a direct substrate of CDK1. TPX2 is highly overexpressed in TNBC and predicts patients’ poor prognosis. Its loss of function efficiently kills TNBC cells in a MYC dependent manner.
We hypothesize that TPX2 is a novel synthetic lethal interaction partner of MYC. Our studies will help elucidate the biology of MYC-driven cancer such as TNBC, which will eventually lead to the development of less toxic and more efficacious targeted therapies.
Citation Format: Julia Rohrberg, Alexandra Corella, Sanjeev Balakrishnan, Andrei Goga. TPX2 overexpression is essential for the survival of MYC-driven triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2822.