bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 836: Potent antitubulin and antitumor activities influenced by the 3-D conformational shape of bicyclic fused pyrimidines
Authors: Gangjee Aleem , Xiang Weiguo , Mooberry Susan L. , Hamel Ernest 
Published: May 2015

Abstract
Compounds that bind to the tubulin colchicine site cause microtubule depolymerization, inhibit the polymerization of purified tubulin and cause cancer cells to accumulate in mitosis. Some colchicine-site agents additionally have the ability to overcome multiple drug resistance mechanisms, including those mediated by the expression of P-glycoprotein (Pgp) or expression of the β-III isotype of tubulin. We have reported a series of aniline substituted pyrimidines and fused bicyclic and tricyclic pyrimidine compounds that bind to the colchicine site. These compounds are single to triple digit nanomolar inhibitors of cancer cell proliferation. We hypothesized that the conformational orientation of the 4-aniline and the fused pyrimidine scaffold plays an important role in the biological activity of these compounds. In this study, we utilized NMR (NOESY) and molecular modeling to compare the lowest energy conformation of different 4-substituted 2-methyl cyclopenta[d]pyrimidines and their microtubule depolymerizing, colchicine site binding and antiproliferative activities. Among the 4-position substituents were N-methyl-4’-methoxynaphthyl-1’-amino (1), N-methyl-6’-methoxynaphthyl-1’-amino (2) and N-methyl-5’-methoxy-2’-amino (3). The IC50 values towards the MDA-MB-435 tumor cell line were 250 nM for 1 and 10 nM for 3. NMR (NOESY) demonstrated that compound 2 lost the free rotation of the naphthyl ring attached to the cyclopenta[d]pyrimidine ring due to 5-H steric hindrance and did not cause microtubule depolymerization. Compounds 1 and 3 retain the ability to rotate the naphthyl ring even though they adopt slightly different stable conformers. The stable conformational differences of these three compounds afford different binding poses in docking to the colchicine site on tubulin (PDB: 1SA0, MOE 2012), which explains the significant differences in antiproliferative activity, microtubule depolymerizing and inhibition of colchicine binding. This study affords a lead compound that defines a 104o (orthogonal) orientation of the naphthyl ring to the cyclopenta[d]pyrimidine scaffold for the best biological activities.
Citation Format: Aleem Gangjee, Weiguo Xiang, Susan L. Mooberry, Ernest Hamel. Potent antitubulin and antitumor activities influenced by the 3-D conformational shape of bicyclic fused pyrimidines. [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 836. doi:10.1158/1538-7445.AM2014-836
Abstract 838: Establishment, identification and treatment data of TCGA glioblatoma xenograft subtypes
Authors: Keir Stephen T. , Rasheed B Ahmed , Hoadley Katherine A. , Roskoski Martin A. , Gasinski Danuta , Killela Patrick J. , Yan Hai , Kwatra Madan M. , Friedman Henry S. , Bigner Darell D. 
Published: May 2015

Abstract
The Cancer Genome Atlas (TCGA) Network recently catalogued recurrent genomic abnormalities in glioblastoma (GBM). This genomic profiling lead to the molecular classification of GBMs into four subtypes: Proneural, Neural, Classical and Mesenchymal. The importance of identifying these subtypes helps researchers and clinicians to better understand GBMs with the potential to personalize treatment options and explore different therapeutic approaches that each subtype may require. In addition, the TCGA identified possible mechanisms that can cause some GBM tumors to become resistant to therapy, including the standard of care alkylating agent temozolomide (TMZ).
For this project, we established xenografts using patient derived tissue and passaged these xenografts until reliable growth characteristics were obtained. Established GBM xenografts were classified into TCGA-defined subtypes first by obtaining global gene expression data using the GeneChip Human Genome U133A 2.0 array from Affymetrix. Microarray data was then quantile normalized and probes were summarized as gene expression levels using RMA. Then data was log2 transformed and genes median centered. Xenografts were subsequently classified into one of four previously defined subtypes as described using Classification to the Nearest Centroid (ClaNC) with the TCGA GBM data as the training dataset.
Using established xenografts from each subtype, a panel of standard of care treatment agents (including TMZ) was assessed by delay in tumor growth and by tumor regression. Statistical analysis was performed using a SAS statistical analysis program, the Wilcoxon rank order test for growth delay, and Fisher's exact test for tumor regression. Data regarding each xenografts BRAF, EGFR, EGFRvIII, IDH1, PIK3CA, PIK3R1, PTEN, RB1, TERT and TP53 status is reported within.
The identification of these valid xenograft models represents an important contribution toward the ability of studying GBM subtypes, in particular for modeling and predicting therapeutic response.
Citation Format: Stephen T. Keir, B Ahmed Rasheed, Katherine A. Hoadley, Martin A. Roskoski, Danuta Gasinski, Patrick J. Killela, Hai Yan, Madan M. Kwatra, Henry S. Friedman, Darell D. Bigner. Establishment, identification and treatment data of TCGA glioblatoma xenograft subtypes. [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 838. doi:10.1158/1538-7445.AM2014-838
Abstract 840: Enhancement of antitumor effect of platinum complexes by PXR antagonist
Authors: Kishimoto Shuichi , Bou Erika , Higashi Kaho , Suzuki Ryosuke , Fukushima Shoji 
Published: May 2015

Abstract
The goal of this study was to evaluate the enhancing ability of PXR antagonists for the antitumor effect of platinum complex. Cell lines used in this study were human hepatoma cell line HepG2, human ovarian cancer cell line 2008 and human colon cancer cell line HCT116. Changes in mRNA expression were assessed by real-time RT-PCR, and the ability of apoptosis induction was assessed as caspase-3 activity. Cytotoxicity of platinum complexes was assessed by SRB assay, and IC75 and IC90 values of them were determined. They did not induce apoptosis at IC75 but did it markedly at IC90. Previously, we reported that though apoptosis in HepG2 was induced by IC90 dose of CDDP, addition of a PXR agonist, rifampicin, from 24-hr before treatment and during treatment with CDDP was almost suppressed. Moreover, we found that apoptosis in 2008 and HCT116 induced by IC90 dose of CDDP or oxaliplatin was suppressed by rifampicin. That suggests a nuclear receptor PXR affects on the cytotoxicity of platinum complexes for cancer cells other than HepG2. Ketoconazole (KTZ) and phenethyl isothiocyanate (PEITC) were selected as PXR antagonists that were added with platinum complex. Both drugs at 30 μM induced cytostatic cell growth inhibition in HepG2, 2008 and HCT116 but did not affect on caspase-3 activity compared with control in those cells. When these PXR antagonists at 30 μM were added to cancer cell lines from 24-hr before treatment and during treatment with CDDP at IC75, caspase-3 activity was significantly increased compared with that in CDDP alone. Also, when cells were exposed to CDDP and a PXR antagonist without PXR antagonist pretreatment, caspase-3 activity was increased but the level was reduced compared with that in the combination with pretreatment. Similarly, oxaliplatin in combination with KTZ or PEITC markedly induced apoptosis in HCT116. In HepG2, KTZ reduced the level of MRP2 mRNA. That suggests that pretreatment with KTZ might increase the intracellular platinum content and enhance the cytotoxicity of platinum complex. We concluded that PXR antagonist can be an agent enhancing the antitumor activity of platinum complex, and one of the mechanism is to suppress the expression of the platinum efflux transporter.
Citation Format: Shuichi Kishimoto, Erika Bou, Kaho Higashi, Ryosuke Suzuki, Shoji Fukushima. Enhancement of antitumor effect of platinum complexes by PXR antagonist. [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 840. doi:10.1158/1538-7445.AM2014-840
Abstract 842: DNA opilymerase β participates in the repair of DNA damage from topoisomerase II
Authors: Sun Yilun , Bertram Sule , Nitiss John L. 
Published: May 2015

Abstract
DNA topoisomerase II (Top2) is the target of several important anti-cancer agents, including doxorubicin and etoposide. Clinically active Top2 agents, termed Top2 poisons, act by blocking the enzyme reaction at a step where the protein is covalently bound to DNA. This leads to the accumulation of Top2/DNA complexes that act as DNA damaging agents that interfere with DNA metabolism and trigger cell death. The mechanisms leading to tumor specific killing by Top2 poisons remain poorly understood, and have been hypothesized to result in part from DNA repair defects that arise during tumorigenesis. If this hypothesis is correct, then targeting repair pathways important for topoisomerase mediated cell killing could be used to enhance the activity of Top2 poisons. Similar reasoning has led to extensive trials of agents such as PARP inhibitors, and other DNA repair inhibitors. The DNA repair pathways that have been examined for sensitization to Top2 poisons include homologous recombination, non-homologous end-joining, proteasome mediated degradation, and nucleolytic activities that may participate in the removal of protein/DNA adducts (such as Tdp1 and Tdp2). We have been studying the repair of damage from Top2 poisons, and have optimized a quantitative assay for Top2/DNA covalent complexes in cultured mammalian cells. This assay, termed the ICE assay, detects Top2 covalent complexes by DNA purification followed by antibody detection of protein adducts. Using this assay, we have demonstrated a role of the MRN complex in processing Top2/DNA adducts, using both MRN knockdowns and small molecule inhibitors of the Mre11 nuclease activities. We also confirmed the importance of proteolytic pathways in repairing Top2 damage. A surprising candidate protein for participation in repair of damage from Top2 poisons is DNA polymerase β (pol β), an “X” family polymerase critical for base excision repair. Recent results have implicated pol β in processing of protein/DNA adducts (1). We found that the pol β inhibitor pamoic acid (4-[(3-Carboxy-2-hydroxynaphthalen-1-yl)methyl]-3-hydroxynaphthalene-2-carboxylic acid) and etoposide led to a large increase in Top2/DNA covalent complexes compared to etoposide alone. We are currently validating these results using other pol β inhibitors and gene knockdown approaches. We speculate that the dRP lyase activity may play a role in processing DNA damage arising from Top2 poisons.
Literature cited:
1. Lawson, M.H., et al. (2011) Two Novel Determinants of Etoposide Resistance in Small Cell Lung Cancer. Cancer Res, 71, 4877-4887.
Citation Format: Yilun Sun, Sule Bertram, John L. Nitiss. DNA opilymerase β participates in the repair of DNA damage from topoisomerase II. [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 842. doi:10.1158/1538-7445.AM2014-842
Abstract 848: Galectin-1 mediates radiation-related lymphopenia in non-small cell lung cancer and attenuates tumor radiation response
Authors: Kuo Peiwen , Bratman Scott , Shultz David , Eyben Rie von , Chan Cato , Wang Ziwei , Say Carmen , Gupta Aparna , Loo Bill W. , Giaccia Amato , Koong Albert , Diehn Maximilian , Le Quynh-Thu 
Published: May 2015

Abstract
Decreased circulating lymphocytes after tumor irradiation has been linked to worse outcomes in several cancers treated with fractionated radiotherapy. The mechanism underlying radiation (RT)-induced lymphopenia is not well understood. Here, we show that lymphopenia also occurs after stereotactic ablative radiotherapy for early stage non-small cell lung cancer, and that it is associated with reduced survival. We provide evidence that RT-induced secretion of Galectin-1 (Gal-1), a b-galactoside binding protein, can potentially explain for this phenomenon. Using matched Gal-1 wild type and null mice together with Lewis lung carcinoma cells stably knocked-down of Gal-1 or scramble control, we show that irradiation of Gal-1 expressing tumor increases Gal-1 secretion in the blood and that it is linked to decreased circulating T-lymphocytes. This was ablated by either genetic down regulation of Gal-1 in the tumor or inhibition of Gal-1 activity by TDG. Moreover, Gal-1 down regulation resulted in enhanced radiation sensitivity in vitro as well as less intratumoral T cell apoptosis and angiogenesis in vivo, resulting in marked tumor growth delay and reduced spontaneous lung metastases when combined with radiotherapy. Similar results were noted when Gal-1 function was inhibited with TDG in vivo. Together, our data identify Gal-1 as an important mediator of RT-related lymphopenia and its proangiogenic and T cell proapototic effect may explain for the poorer outcome associated with RT-related lymphopenia. Gal-1 is therefore a new potential therapeutic target to combine with radiotherapy.
Citation Format: Peiwen Kuo, Scott Bratman, David Shultz, Rie von Eyben, Cato Chan, Ziwei Wang, Carmen Say, Aparna Gupta, Bill W. Loo, Amato Giaccia, Albert Koong, Maximilian Diehn, Quynh-Thu Le. Galectin-1 mediates radiation-related lymphopenia in non-small cell lung cancer and attenuates tumor radiation response. [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 848. doi:10.1158/1538-7445.AM2014-848
Abstract 856: Combination of crizotinib and radiation in the treatment of ALK-positive and cetuximab-resistant lung cancer
Authors: Li Chunrong , Huang Shyhmin , Walters Noah , Armstrong Eric A. , Harari Paul M. 
Published: May 2015

Abstract
Approximately 4% of patients with non-small cell lung carcinoma (NSCLC) carry the EML4-ALK chromosomal rearrangement. Crizotinib, a c-MET and ALK inhibitor, has shown significant therapeutic benefit as a single agent with FDA approval for the treatment of patients with ALK-positive NSCLC. Since radiation commonly plays a key role in lung cancer treatment, we sought to evaluate the potential of crizotinib as a radiation sensitizer and the role of ALK in cellular radiation sensitivity. We examined the effect of crizotinib in combination with radiation on ALK signaling, cell proliferation, cell cycle distribution and radiosensitivity in ALK-positive NSCLC cell lines H3122 and H2228 in vitro. We also examined the in-vivo effects of crizotinib in combination with radiation in H3122 and H2228 xenograft models.
Crizotinib blocked phosphorylation of ALK and its downstream effectors and inhibited cell proliferation in a dose-dependent manner. The combination of crizotinib and radiation resulted in increased inhibition of cell growth. Although cells were sensitized to radiation by crizotinib, molecular knockdown of ALK by siRNA had only modest impact on cell radiosensitivity. Cell cycle analysis by flow cytometry showed that ALK-siRNA induced G1 arrest. Interestingly, low dose crizotinib induced G1 arrest, while doses above 2µM induced G2 arrest. Combination treatment induced arrest in G1 and G2 phases and decreased the cell population in S-phase. Moreover, in xenograft tumor models, we observed combined treatment to produce additive tumor growth inhibition over that observed with either drug or radiation alone.
We further examined the capacity of crizotinib overcome cetuximab resistance in our established in vitro resistance models. Compared with parental cells, cetuximab-resistant cells showed cross-resistance to radiation. Crizotinib inhibited the growth of cetuximab-resistant cells and resensitized cells to radiation. Compared with single-agent treatment, the combination of crizotinib and erlotinib resulted in increased growth inhibition and further re-sensitization to radiation.
These data suggest that crizotinib in combination with radiation can enhance the inhibitory effect on ALK-positive tumor cell growth in vitro and in-vivo and also suggest the potential value of using crizotinib in combination with other EGFR-targeting therapeutics. Ultimately however, the potential value of crizotinib as a radiation sensitizer requires systematic clinical investigation.
Citation Format: Chunrong Li, Shyhmin Huang, Noah Walters, Eric A. Armstrong, Paul M. Harari. Combination of crizotinib and radiation in the treatment of ALK-positive and cetuximab-resistant lung 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 856. doi:10.1158/1538-7445.AM2014-856
Abstract 86: Heterozygous expression of an oncogenic Pik3ca mutation during murine development results in fatal embryonic and extra-embryonic defects
Authors: Hare Lauren M. , Schwarz Quenten , Gurung Rajendra , Montgomery Karen G. , Mitchell Christina , Phillips Wayne A. 
Published: May 2015

Abstract
The PI3K/Akt signalling pathway regulates many important cellular functions including proliferation, migration, survival and angiogenesis. The PIK3CA gene, encoding the p110α catalytic subunit of the PI3K enzyme, is somatically mutated in a range of human cancers and overgrowth syndromes. We have previously described a novel mouse model with a Cre-recombinase (Cre)-mediated knock-in of the common cancer-associated Pik3ca(H1047R) mutation that can be targeted to selected tissues using various Cre-expressing mouse strains. As the mutation is knocked in to the endogenous gene, the mutant protein is expressed at normal physiological levels.
We have used the Cre-deleter mouse to induce expression of the Pik3ca(H1047R) mutation ubiquitously from the 2-cell stage of development. This results in embryonic lethality by E10.5 with embryos at E9.5 demonstrating stunted growth, failed ‘turning’ and abnormal cardiovascular development in both the embryo proper and extraembryonic yolk sac. These tissues also showed increased expression of vascular endothelial growth factor (VEGF) family proteins. We then selectively targeted the mutation to the endothelial cells of the developing embryo using the Tie2-Cre mouse strain. No Tie2-Cre:Pik3ca(H1047R) mutant embryos survived to E11.5 and at E10.5, while successfully turned, embryos were severely underdeveloped and no longer viable. At E9.5, vascular remodelling was disorganised and truncated in the embryo proper and yolk sacs. Development of the heart was also affected with clear disruption to anterior cardinal vein and dorsal aorta development.
Our results demonstrate the importance of PI3K/Akt signalling in embryonic development and cardiovascular formation in the mouse. The observed cell autonomous role in vessel development was further confirmed upon targeted expression to endothelial cells while the increased expression of various VEGF family proteins suggests probable crosstalk between the PI3K/Akt and VEGF signalling pathways during cardiovascular development. The lethality associated with expression of Pik3ca(H1047R) mutation during development likely explains the lack of inherited germline PIK3CA mutations in humans.
Citation Format: Lauren M. Hare, Quenten Schwarz, Rajendra Gurung, Karen G. Montgomery, Christina Mitchell, Wayne A. Phillips. Heterozygous expression of an oncogenic Pik3ca mutation during murine development results in fatal embryonic and extra-embryonic defects. [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 86. doi:10.1158/1538-7445.AM2014-86
Abstract 863: Clinical significance of mucinous production in rectal cancer after preoperative chemoradiotherapy
Authors: Kaneko Kensuke 
Published: May 2015

Abstract
Background: Mucinous adenocarcinoma (MA) is a relatively rare histological subtype of colorectal cancer, in which more than 50% of the tumor is occupied by extracellular mucin. MA has been reported to be associated with poor response to neoadjuvant chemoradiotherapy (CRT), but the prognostic significance still remains to be evaluated. Here, we aimed to analyze the prognostic significance of mucin production in the response of rectal cancer to neoadjuvant CRT.
Methods: The medical records of 141 consecutive patients receiving rectal resection after neoadjuvant CRT for the treatment of rectal cancer at our institution, in the period between October 2003 and December 2012, were retrospectively reviewed. For the histological evaluation, Hematoxylin-Eosin (HE) and Periodic Acid Schiff/Alcian Blue (PAS/AB) stainings were used. Mucin production was evaluated according to the proportion of the tumor area occupied by extracellular mucin, and cases were sorted, according to the mucin occupancy rate, into three groups, namely, low (0 - 5%), medium (5 - 25%) and high (&gt;25%).
Results: The number of patients in the low, medium and high mucin rate groups was 89 (63.1%), 28 (19.9%) and 24 (17.0%), respectively. Only advanced tumor stage out of histological features had a significant correlation with the high mucin rate group. Compared to the low mucin rate group, patients in the high group had a worse prognosis in disease free survival, and also a worse prognosis in distant recurrence free survival, compared to the medium group, while no significant difference was observed among the three groups in overall and local recurrence-free survivals. Multivariate analysis showed that the high mucin rate group had an independent association with shorter disease-free survival, and those advanced stage tumors (T3 and T4) with a high mucin rate had an independent association with shorter distant recurrence-free survival.
Conclusion: Mucinous production in rectal cancer may be associated with resistance to neoadjuvant CRT. Thus, careful histological analysis for the presence of extracellular mucin should be indicated for rectal patients receiving neoadjuvant CRT, and those cases with high mucin rate (&gt; 25% mucinous component) should be closely followed-up.
Citation Format: Kensuke Kaneko. Clinical significance of mucinous production in rectal cancer after preoperative chemoradiotherapy. [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 863. doi:10.1158/1538-7445.AM2014-863