bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4540: SAC abrogation by MPS1 kinase inhibition: preclinical proof of concept of a novel approach to tumor treatment
Authors: Mumberg Dominik , Siemeister Gerhard , Wengner Antje M. , Koppitz Marcus , Schulze Volker , Bader Benjamin , Prechtl Stefan , Kreft Bertolt , Ziegelbauer Karl 
Published: May 2015

Abstract
Cell cycle deregulation represents one of the classical hallmarks of cancer and consequently cell cycle arrest is the predominant mode of action of a number of antimitotic cancer drugs (e.g. taxanes and vinca alkaloids). Targeted disruption of the cell cycle checkpoint offers a novel approach to cancer treatment: driving tumor cells into cell division despite DNA damage or unattached/misattached chromosomes resulting in a lethal degree of DNA damage or aneuploidy.
MPS1, a mitotic kinase that is overexpressed in several human cancers, has been shown to function as the key kinase which activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the identification and functional characterization of novel inhibitors of MPS1 from two structurally unrelated chemical classes. In biochemical assays, these molecules inhibited the kinase activity of MPS1 with IC50 values in the single digit nanomolar range and have shown an exquisite selectivity against a panel of kinases. In cellular assays the compounds were able to abrogate nocodazole-induced SAC, to reduce time in mitosis, to induce multinuclearity and apoptotic cell death, and to inhibit tumor cell proliferation with IC50 values in the low nanomolar range. In combination experiments MPS1 inhibitors showed cooperativity with low concentrations of paclitaxel. MPS1 inhibitors showed limited efficacy in monotherapy (T/C ca. 0.6) in tumor xenograft studies. However, when combined with paclitaxel dosed at the maximal tolerated dose, low doses of MPS1 inhibitor strongly improved efficacy over paclitaxel or MPS inhibitor monotreatment in intrinsically paclitaxel-insensitive xenograft models. The combination treatment was well tolerated. These results validate the concept of SAC abrogation preclinically and pave the way to a clinical proof of concept.
Citation Format: Dominik Mumberg, Gerhard Siemeister, Antje M. Wengner, Marcus Koppitz, Volker Schulze, Benjamin Bader, Stefan Prechtl, Bertolt Kreft, Karl Ziegelbauer. SAC abrogation by MPS1 kinase inhibition: preclinical proof of concept of a novel approach to tumor treatment. [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 4540. doi:10.1158/1538-7445.AM2014-4540
Abstract 4544: Induction of KLF4 by LOR-253 as an innovative therapeutic approach to induce apoptosis in acute myeloid leukemia
Authors: Lum Ronnie , Javadi Mojib , Cheng Tiffany , Peralta Robert , Cukier Howard , Lightfoot Jeff , Lee Yoon , Young Aiping , Rice William G. 
Published: May 2015

Abstract
LOR-253, a small molecule anticancer agent that acts through induction of the tumor suppressor Krüppel-like factor 4 (KLF4), has demonstrated antitumor activity as a single agent in a Phase I study in patients with advanced or metastatic solid tumors. Recently, the vast majority of patients with acute myeloid leukemia (AML) were shown to inappropriately express the embryonic CDX2 gene in bone marrow stem and progenitor cells, resulting in down-regulation of KLF4 expression as the leukemogenic event. Consequently, we examined the antitumor activity and mechanism of action for LOR-253 in AML cells and cells representing other hematological malignancies. Indeed, LOR-253 was found to inhibit proliferation of various human leukemia and lymphoma cell lines in vitro with low nM IC50 values. Further LOR-253 induced high levels of KLF4 mRNA expression in AML cells and a resultant significant increase in expression of p21, a cyclin-dependent kinase inhibitor that is transcriptionally regulated by KLF4. Consistent with these findings, in AML cells we found that LOR-253 induced G1/S cell cycle arrest and apoptosis, based on positive Annexin V staining, activated caspase-3, and increased BAX mRNA expression. Studies are underway to further characterize the pathway that mediates KLF4 induction by LOR-253, to characterize the effects of LOR-253 in combination with approved chemotherapies for AML, and to assess the efficacy of LOR-253 in animal models of AML. Induction of KLF4 represents a novel approach to the treatment of AML and other hematologic malignancies, and LOR-253 is the only clinical stage agent to act through this mechanism of action.
Citation Format: Ronnie Lum, Mojib Javadi, Tiffany Cheng, Robert Peralta, Howard Cukier, Jeff Lightfoot, Yoon Lee, Aiping Young, William G. Rice. Induction of KLF4 by LOR-253 as an innovative therapeutic approach to induce apoptosis in acute myeloid leukemia. [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 4544. doi:10.1158/1538-7445.AM2014-4544
Abstract 455: Increased copy number of Septin 9 (SEPT9) in women with high grade endometrial adenocarcinoma(EMCA): Is there a potential link to paclitaxel resistance
Authors: Zechmeister Jenna R. , Goldberg Gary L. , Montagna Cristina 
Published: May 2015

Abstract
Septins are a unique family of GTPases that are important in the regulation of a variety of essential cellular functions. Specifically, SEPT9 has been demonstrated to be vital in normal development in a mouse model. When a full knockout is generated, the phenotype is embryonically lethal. SEPT9 has also been implicated in tumorigenesis and our group has identified SEPT9 as an oncogene which is amplified and overexpressed in breast cancer. We have demonstrated that in high grade breast carcinomas, the subtype with the worst clinical outcome, exhibit significant increases in SEPT9 copy number variation (CNV) when compared to other breast tumor grades. Therefore to explore a possible biomarker role of SEPT9 in other tumor types, we have investigated the CNV status of SEPT9 in EMCA using data from the publically available Cancer Genome Atlas (TCGA). Within the published dataset, 7.8% of patients have an increased CNV of the gene. The Kaplan-Meier survival curves between the 2 groups show a decreased overall survival in the EMCA patients who exhibit CNV (n=18) with a 5-year survival of 44% compared to 83% (p = 0.003) in the remaining EMCA patients without an alteration in CNV (n=214). Septins assemble into filaments that interact with the cytoskeleton. Published data on established cell lines with an overexpression of specific isoforms suggest an association between the overexpression and resistance to paclitaxel. Many high grade EMCA patients are treated with adjuvant paclitaxel-based regimens. We hypothesize that an increased CNV and overexpression of SEPT9 is associated with paclitaxel resistance on a molecular level and a worse clinical prognosis. To support our hypothesis, we will test established uterine papillary serous carcinoma cell lines (UPSC), an aggressive high grade EMCA, for CNV variation of SEPT9 and resistance to paclitaxel. In addition, tumor samples from patients with advanced stage (III-IV) UPSC will be investigated for an increased CNV of SEPT9.
Citation Format: Jenna R. Zechmeister, Gary L. Goldberg, Cristina Montagna. Increased copy number of Septin 9 (SEPT9) in women with high grade endometrial adenocarcinoma(EMCA): Is there a potential link to paclitaxel resistance. [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 455. doi:10.1158/1538-7445.AM2014-455
Abstract 4551: Emerging effects of Chinese herbal medicines on human cancer cells proliferation
Authors: Zhang Xufei , Li Hao , Espiritu Herschel Angela , Kim Anita , Zhong Li 
Published: May 2015

Abstract
Chinese herbal medicine is a major aspect of traditional Chinese medicine, which focuses on restoring a balance of energy, body, andspirit to maintain health rather than treating a particular disease or medical condition. Some of Chinese herbs have shown therapeutic effects in cancer patients. Yunnan Baiyao (White Medicine from Yunnan, YNBY) and Snow daisy are popular Chinese herbs for routine clinical usage. YNBY is a Chinese herbal medicinal powder used to stop bleeding, reduce swelling and improve circulation in traumatic injuries. While Snow daisy has effects on maintaining blood pressure and reducing coronary heart diseases and inflammation when consumed in form of tea. Although it has been hypothesized that both YNBY and Snow daisy flower tea (SDFT) may help to prevent tumor proliferation and even reduce tumor growth, yet no systematic study and analysis have been carried out. Therefore, in this study the effects of YNBY and SDFT on tumor cell proliferation were evaluated and the signal transduction pathways mediating the effects were also determined. We tested tumor cells (lung, breast and oral cancer cell lines) and normal human fibroblast cells with different YNBY and SDFT dilution in cultured medium. Then the proliferation ability of these treated cells was tested by MTT assay and visualized via Dil (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindocarbocyanine Perchlorate) staining. Subsequently, several apoptosis factors (Fas pathway related, i.e., Fas/CD95, Fas Ligand, Caspase-8) which may be secreted by YNBY and SDFT treated tumor cells were tested using ELISA and Western Blot. The results showed that YNBY and SDFT can significantly inhibit lung tumor cells proliferation when its concentration was above 0.4mg/mL and 2mg/mL, respectively (P&lt;0.01). The data indicated that YNBY could induce lung tumor cells apoptosis through Fas related pathway. The expression of Fas/CD95 and caspase-8 in treated lung tumor cells was much higher than which in control groups (P&lt;0.01) suggesting that YNBY and SDFT may provoke tumor cells death by inducing cell apoptosis through Fas pathway. YNBY and SDFT may constitute potential therapeutic effects for lung cancer patients.
Citation Format: Xufei Zhang, Hao Li, Herschel Angela Espiritu, Anita Kim, Li Zhong. Emerging effects of Chinese herbal medicines on human cancer cells proliferation. [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 4551. doi:10.1158/1538-7445.AM2014-4551
Abstract 4557: Expression of p16 in colon cancer and cyclin D1 in gastric cancer predicts response to CDK4/6 inhibition in vitro
Authors: Wainberg Zev A. , Yufa Ann , Anghel Adrian , Rogers Amy M. , Manivong Tin , Adhami Shahriar , Hamidi Habib , Conklin Dylan , Finn Richard S. , Slamon Dennis J. 
Published: May 2015

Abstract
Background: Cyclin-dependent kinases (CDKs) play a significant role in regulating cell cycle progression through association with cyclins. CDK4 and CDK6 interact with cyclin D1 to mediate hyperphosphorylation of retinoblastoma (Rb) during early G1 phase. Palbociclib is a highly selective inhibitor of CDK4 and CDK6 which functions by blocking pRb phosphorylation resulting in G1 arrest in sensitive cell lines. We evaluated the effect of palbociclib in gastric and colon cancer cell lines to explore potential biomarkers of response and to guide patient selection in colon and gastric cancer.
Methods: Panels of 17 gastric and 27 colon cancer cell lines were exposed in vitro to palbociclib over various concentrations to generate dose response curves. Analysis of variance (ANOVA) was used to identify differentially expressed genes between sensitive and resistant cell lines. Genes identified by ANOVA and effects of palbociclib on pRB were analyzed via western blot.
Results: Palbociclib was found to have potent anti-proliferative activity in the low nanomolar range (&lt; 150 nM) for 14 of the 44 gastric and colon cancer cell lines tested. In gastric cancer, cyclin D1-amplified cells cells expressed greater sensitivity to the compound when compared to cyclin D1-negative cells. HER2 amplified cell lines were also statistically more sensitive than HER2 negative cells. Combination studies with palbociclib and trastuzumab demonstrated significant synergy in HER2 amplified gastric cancer models. Furthermore, cyclin E emerged as a biomarker for resistance to the compound in gastric cancers. Contrary to observations made in other cancers, expression levels of p16 (CDK4 inhibitor) and p21 (CDK2 inhibitor) in colon cancer indicated that p16 loss and p21 gain predict for resistance rather than sensitivity to CDK4 and CDK6 inhibition.
Conclusions: Palbociclib demonstrates anti-proliferative activity in several gastric and colon cancer cell lines. Molecular markers found to predict for sensitivity to this agent enhance patient selection for future clinical studies of palbociclib.
Citation Format: Zev A. Wainberg, Ann Yufa, Adrian Anghel, Amy M. Rogers, Tin Manivong, Shahriar Adhami, Habib Hamidi, Dylan Conklin, Richard S. Finn, Dennis J. Slamon. Expression of p16 in colon cancer and cyclin D1 in gastric cancer predicts response to CDK4/6 inhibition in vitro. [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 4557. doi:10.1158/1538-7445.AM2014-4557
Abstract 4565: Bet bromodomain inhibitors affects replication & cell cycle progression
Authors: Muralidharan Somsundar Veppil , Bhadury Joydeep , Green Lydia , Nilsson Lisa M. , Mclure Kevin G. , Nilsson Jonas A. 
Published: May 2015

Abstract
Myc family of transcription factors contribute to pathogenesis in most cancers and their expression projects a poor prognosis. Genetic and pharmacological inhibition of Myc and several Myc targets leads to apoptosis and tumor regression. Recently, inhibitors of BET Bromodomain proteins (BETi) were shown to have anti-tumor properties and this has been attributed to Myc down-regulation. In this study, we show that two structurally distinct BETi affects replication and cell cycle progression at low concentrations where the transcriptome remains largely unaltered. At these concentrations, S-phase progression is hindered, as assessed by thymidine incorporation and flow cytometry analyses. However, in a cell-free system replication is not impaired suggesting that BETi-mediated block of replication is linked to effects on chromatin. Furthermore, at higher concentration of BET, S-phase entry of cells is completely abrogated. Ectopic expression of Myc fails to rescue these phenotypes, suggesting a novel function of BET bromodomain proteins in replication and cell cycle regulation.
Citation Format: Somsundar Veppil Muralidharan, Joydeep Bhadury, Lydia Green, Lisa M. Nilsson, Kevin G. Mclure, Jonas A. Nilsson. Bet bromodomain inhibitors affects replication & cell cycle progression. [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 4565. doi:10.1158/1538-7445.AM2014-4565
Abstract 4920: Luminol-based in situ photodynamic therapy for breast adenocarcinoma
Authors: Alshetaiwi Hamad S. , Shrestha Tej B. , Balivada Sivasai , Basel Matthew T. , Pyle Marla , Wang Hongwang , Bossmann Stefan H. , Troyer Deryl L. 
Published: May 2015

Abstract
Photodynamic therapy (PDT) is a cancer treatment that uses a photosensitizer and a specific wavelength of light. When tumor cells which have absorbed photosensitizer are exposed to the correct wavelength of light, reactive oxygen species are generated, resulting in tumor cell death. Poor tissue penetration of light is a major limitation in PDT, restricting its use to treatment of localized tumors. Light generation at the tumor area might increase the effectiveness of PDT and can expand its use for metastatic tumors. Infiltration of tumor-activated polymorphonuclear neutrophils (PMNs) produces luminescence in the presence of luminol; this bioluminescence has been used for tumor detection in pre-clinical trials. Based on this rationale, we hypothesized that luminol-based bioluminescence can cause targeted PDT in breast adenocarcinoma tumors in the presence of the photosensitizer 5-aminolevulinic acid (ALA). To test this hypothesis, BALB/c mice were transplanted with 4T1 mammary adenocarcinoma cells to establish a breast adenocarcinoma model. After tumor formation, ALA and luminol were administered to mice through intraperitoneal and intravenous routes, respectively. This treatment regimen was repeated six times and ALA alone/luminol alone/saline treated tumor-bearing mice were used as controls. Relative differences in the increase of tumor volume and final tumor weights were analyzed to test the treatment hypothesis. Analysis of the data showed that treatment with a combination of luminol and ALA as well as treatment with luminol alone results in breast adenocarcinoma tumor growth attenuation. This study gives evidence for the antitumor activity of luminol on breast adenocarcinoma, possibly through PDT.
Citation Format: Hamad S. Alshetaiwi, Tej B. Shrestha, Sivasai Balivada, Matthew T. Basel, Marla Pyle, Hongwang Wang, Stefan H. Bossmann, Deryl L. Troyer. Luminol-based in situ photodynamic therapy for breast adenocarcinoma. [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 4920. doi:10.1158/1538-7445.AM2014-4920
Abstract 4992: Zkscan3 facilitates invasion of colorectal cancer associated with ceacam5
Authors: Roh Seon A. , Kim Chan Wook , Tak Ka Hee , Kim Jin Cheon 
Published: May 2015

Abstract
Purpose: ZKSCAN3 is over-expressed in invasive colonic tumor cells and regulate the expression of several genes favoring tumor progression including integrin β4. We evaluated the role of ZKSCAN3 in invasive signaling pathway with stage 4 colorectal cancer (CRC).
Materials and methods: 119 metastatic CRC (mCRC) patients who palliatively or curatively resected and 331 sporadic CRC patients who curatively resected from January 2004 to December 2009 were used to identify correlations between single-nucleotide polymorphism (SNP) rs733743 and clinically prognostic parameters. To validation of prior correlation, the genotypes of SNP identified by pyrosequencing using 81 patients (33 with mCRC and 48 CRC patients) and CRC cell lines. We then performed immunohistochemistry (IHC) and Western blot on 36 mCRC patients and 49 CRC patients. Up-regulated putative down-stream targets included genes contributing tumor aggressiveness and invasiveness; VEGF, cyclin D2, Akt, phospho-Akt, integrin β4, KRAS, CEACAM5, and integrin α5β1. To test biological utility assay, ZKSCAN3 mRNA was knocked down by ZKSCAN3 specific siRNA in metastatic CRC cells (LOVO) and ZKSCAN3 cDNA was overexpressed in the low-ZKSCAN3 expressed CRC cells (HCT116).
Results: Wild-type alleles (GG) of ZKSCAN3 rs733743 was related with male dominant, family history of malignancy, high CEA concentration, and mCRC. The wild-type alleles of ZKSCAN3 rs733743 using tissue sample was related with lymphvascular invasion. ZKSCAN3 IHC positive tissue was related with lymphovascular invasion. ZKSCAN expression was higher in LOVO and SW620 cell lines which were derived from metastatic site. ZKSCAN3 high groups were related with CEA, integrin β4, VEGF, and AKT and ZKSCAN3 low groups were related with RAS, VEGF, AKT, and PAKT in metastatic tumor tissue. Therefore, ZKSCAN3 seemed to be related with CEA and integrin β4 to metastasis. Additional CEA expression was observed a significant decrease in ZKSCAN3 knockdowned LOVO cell (1.0 vs 0.89, P= 0.046) and invasiveness of the ZKSCAN3 overexpressed HCT116 cells was higher in CEA coated filters (75.6±6.0 vs 91.3±4.5, P=0.023).
Conclusion: ZKSCAN3 is related with colorectal tumor progression and invasion. ZKSCAN3 overexpression tumor may facilitate metastasis of colorectal cancer associated with CEACAM5.
Citation Format: Seon Ae Roh, Chan Wook Kim, Ka Hee Tak, Jin Cheon Kim. Zkscan3 facilitates invasion of colorectal cancer associated with ceacam5. [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 4992. doi:10.1158/1538-7445.AM2014-4992
Abstract 5116: Inhibition of PI3K/AKT signaling by NVP-BKM120 promotes ABT-737-induced toxicity in established and primary cultured glioblastoma cells
Authors: Jane Esther P. , Premkumar Daniel R. , Morales Alejandro , Foster Kimberly A. , Pollack Ian 
Published: May 2015

Abstract
Identification of therapeutic strategies that might enhance the efficacy of Bcl-2 inhibitor ABT-737 is of great interest in many cancers including glioma. Our recent study suggested that Akt is a crucial mediator of apoptosis sensitivity in response to ABT-737 in glioma cell lines. Inhibitors of PI3-K/Akt are currently being assessed clinically in patients with glioma, as PI3K/Akt inhibition would be expected to have many pro-apoptotic effects, we hypothesized that there may be unique synergy between PI3-K inhibitors and BH3-mimetics. We assessed the combination of the PI3K inhibitor BKM120 and the Bcl-2 family inhibitor ABT-737 in established and primary cultured glioma cells. We found that the combined treatment with these agents led to a significant activation of caspase-8, 3, PARP and cell death irrespective of PTEN status. The enhanced lethality observed with the combination also appears dependent upon the loss of mitochondrial membrane potential, release of cytochrome c, smac/DIABLO and apoptosis-inducing factor to the cytosol. Further study revealed that the upregulation of Noxa, truncation of Bid, activation of Bax and Bak caused by these inhibitors was the key factor for the synergy. In addition, we demonstrated the release of proapoptotic proteins Bim and Bak from Mcl-1. We found defects in chromosome segregation leading to multinuclear cells and loss of colony forming ability, suggesting the potential use of BKM120 as a promising agent to improve the anti-cancer activities of ABT-737.
Citation Format: Esther P. Jane, Daniel R. Premkumar, Alejandro Morales, Kimberly A. Foster, Ian Pollack. Inhibition of PI3K/AKT signaling by NVP-BKM120 promotes ABT-737-induced toxicity in established and primary cultured glioblastoma cells. [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 5116. doi:10.1158/1538-7445.AM2014-5116