bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract DDT01-02: CH5424802: A selective ALK inhibitor
Authors: Sakamoto Hiroshi , Oikawa Nobuhiro , Tsukuda Takuo , Shimma Nobuo , Ishii Nobuya , Aoki Yuko 
Published: June 2012

Abstract
Recent development of targeted protein kinase inhibitors provides new opportunity in cancer treatment. On the other hand, there are some cases limiting the efficacy of cancer therapies, owing to narrow therapeutic index by inhibiting multiple kinase, and the emergence of resistant mutants. Thus, the development of kinase inhibitors with more potent and selective properties and effectiveness to resistant mutants is needed. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in some cancers, due to gene alterations such as chromosomal translocation, amplification, or point mutation. Here we have identified CH5424802, a potent, selective and orally available ALK inhibitor with a new chemical scaffold. CH5424802 showed preferential antitumor activity against cancers with gene alterations of ALK, such as non-small cell lung cancer (NSCLC) cells expressing EML4-ALK fusion, anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion, and neuroblastoma with gene amplification of ALK in vitro and in vivo. Also, CH5424802 could inhibit ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and block the growth of EML4-ALK L1196M-driven cells. CH5424802 is currently being investigated in phase I/II clinical trials for patients with ALK-positive NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT01-02. doi:10.1158/1538-7445.AM2011-DDT01-02
Abstract LB-113: Non-small cell lung cancer cells with high ALDH1 activity display cancer stem cell properties and show chemoresistance
Authors: Wong S , Leung E , Tin V , Wong M 
Published: June 2012

Abstract
Introduction Cancer stem cells (CSC) are believed to possess tissue stem cell-like properties such as self-renewal and toxicity resistance. These characteristics would facilitate tumor propagation and development of chemoresistance. The biology and regulation of CSC have mostly been studied in acute leukemia and certain solid tumors such as breast cancer. Relatively little data are available regarding CSC in non-small cell lung cancer (NSCLC) due to the lack of a specific CSC marker. This study aims to analyze the applicability of candidate CSC markers by utilizing chemotherapy treatment to enhance CSC proliferation in NSCLC cells. Methodology The expression or activity of 4 putative stem cell markers, CD24, CD44, CD133 and aldehyde dehydrogenase (ALDH1) were measured by flow cytometry in the NSCLC cell lines H1650, HCC827 and H358 before and after chemotherapy treatment for 24 hours. Tumor cells with enhanced marker expression after treatment were regarded as potential CSC, and were selected by fluorescence-activated cell sorting (FACS). Functional analysis was used to test for CSC properties in the marker+ and marker-subpopulations of untreated cells. The expression of genes involved in tissue stem cell functions were also compared by quantitative RT-PCR. Results Flow cytometry analysis showed amongst the 4 markers, only ALDH1+ subpopulation was significantly enhanced by chemotherapeutic treatment, suggesting ALDH1 could be a CSC marker. Untreated ALDH1+ cells formed significantly higher numbers and larger cell spheres in non-adherent culture medium than ALDH1− cells. Likewise, ALDH1+ cells formed significantly more and larger colonies in colony formation assay. Furthermore, MTT assay demonstrated higher resistance to cisplatin and etoposide treatments in ALDH1+ than ALDH1− cells. In addition, ALDH1+ cells showed more prominent tumorigenicity than ALDH1− cells in vivo; as few as 500 ALDH1+ cells formed xenograft tumor in SCID mice which were serially transplantable to 2nd and 3rd recipients, while no tumor was formed from ALDH− cells. Finally, expression analysis of sorted cells revealed higher expression of the pluripotency genes, OCT4, NANOG, BMI1 and SOX9, in ALDH1+ cells. Conclusion NSCLC cells expressing ALDH1 displayed higher capacity for cell renewal, tumorigenecity and drug resistance, as well as showed higher expression of pluripotency genes, suggesting that ALDH1 could be a useful CSC marker in NSCLC. Pathways mediated by the differentially expressed genes studied could be involved in CSC maintenance and/or chemoresistance in NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-113. doi:10.1158/1538-7445.AM2011-LB-113
Abstract LB-138: TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation
Authors: Zhao Dong , Zhi Xu , Zhou Zhongmei , Chen Ceshi 
Published: June 2012

Abstract
Krüppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting breast cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitinated by E3 ubiquitin ligases, such as WWP1 and SCFFbw7. In this study, we demonstrate that transcriptional co-activator with PDZ binding motif (TAZ) upregulated KLF5 through antagonizing the WWP1-mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain and the PY motif, which is the binding site of WWP1. TAZ inhibited WWP1-mediated KLF5 ubiquitination and degradation. Overexpression of TAZ up-regulated the protein levels of KLF5 and FGF-BP, which is a well established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 breast cells dramatically down-regulated protein levels of KLF5 and FGF-BP and inhibited cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in SCID mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted cell proliferation through TAZ. Finally, both KLF5 and TAZ are co-expressed in a subset of ER-negative breast cell lines. These results, for the first time, suggest that TAZ promotes breast cell growth partially through protecting KLF5 from WWP1-mediated degradation, and enhancing KLF5's activities. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-138. doi:10.1158/1538-7445.AM2011-LB-138
Abstract LB-145: Absence of pro-apoptotic protein Bax extended the life span of ku70−/− mice with accelerated aging phenotype
Authors: Ngo Justine , Matsuyama Mieko , Watanabe Michiko , Gerson Stanton , Smith Mark , Matsuyama Shigemi 
Published: June 2012

Abstract
Bax is a proapoptotic Bcl-2 family protein. Previously, we found that Ku70 functions as a Bax inhibitor in the cell. Ku70 is 70 kDa protein expressed in the cytosol and nucleus, and Ku70 is required for the nonhomologous end-joining (NHEJ) pathway of DNA double strand break (DSB) repair in the nucleus. In the cytosol, Ku70 binds to Bax, and this interaction inhibits the cytotoxic activity of Bax. Ku70 null mice show a premature aging phenotype due to the absence of NHEJ-dependent DSB repair. We hypothesized that increased sensitivity to Bax-mediated cell death may contribute to the disease phenotype of Ku70 null mice. To determine our hypothesis, ku70−/−bax+/− and ku70−/−bax−/− mice were generated (all mice were on C57BL background). Interestingly, both ku70−/−bax+/− and ku70−/−bax−/− had a longer life spans than ku70−/− mice. The 50% mortality of ku70−/−, ku70−/−bax+/−, ku70−/−bax−/− was 21 weeks (n=36), 36 weeks (n=20), and 37 weeks (n=7) respectively. Some of these mutant mice developed T-lymphoma (ku70−/− (17%&lt;), ku70−/−bax+/− (33%), and ku70−/−bax−/− (20%)). Ku70−/− MEFs (mouse embryonic fibroblasts) showed increased apoptosis sensitivity and accelerated cellular senescence during passage in comparison with wild type MEFs, as previously reported. ku70−/−bax+/− and ku70−/−bax−/− showed significantly higher survival in the apoptosis sensitivity test than ku70−/− MEFs. Cellular senescence of MEFs was analyzed including expressions of senescence associated β-galactosidase and phospho-γ H2AX. Bax deficiency did not show significant effects on the onset of cellular senescence of ku70−/− MEFs. The lung alveoli of ku70−/− mice were structurally normal (single alveolar cell layer); however, the lungs of ku70−/−bax+/− and ku70−/−bax−/− mice had abnormal multiple alveolar cell layers. The mechanism of this abnormal alveolar development is under investigation. We analyzed histology of several organs, blood cell count, and locomotion activities of these mutant mice. These data suggest that Bax-deficiency improved the overall health condition of Ku70 null mice. Previous studies demonstrated that p53 deletion was not able to extend the life span of Ku70 or Ku80 null mice due to increased cancer development (Li et al. 2009). In addition, p21 deletion was not able to extend the life span of Ku80 null mice even though p21 deletion significantly delayed cellular senescence of Ku80 null MEFs (Zhao et al, 2009). The present study suggests that increased Bax-mediated apoptosis rather than increased cellular senescence may be the major cause of the shortened life span of Ku70 null and NHEJ-defective mutant mice.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-145. doi:10.1158/1538-7445.AM2011-LB-145
Abstract LB-153: Introduction of Th1 help by a novel cancer vaccine, helper/killer hybrid epitope long peptide (H/K-HELP): From basic to clinical study
Authors: Nishimura Takashi , Ohkuri Takayuki , Wakita Daiko , Kitamura Hidemitsu 
Published: June 2012

Abstract
Using mouse tumor model, we have demonstrated that there are strong immunosuppressive tumor escape mechanisms in tumor-bearing hosts. Especially, we have emphasized the following three mechanisms; (i) CD133+ cancer-stem cells (CSC) produced high levels of active TGF-β and they are resistant to CD8+ T cell-mediated immunosurveillance via inducing regulatory T cells (Tregs); (ii) Immature myeloid cells (ImC), which are abnormally increased in tumor-bearing mice, are classified into three distinct populations and MΦ-ImC and NeutSeg-ImC, but not NeutStab-ImC act as myeloid-derived suppressor cells (MDSC); (iii) IL-17-producing γδ T cells act as protumor cells during carcinogenesis and tumor progression via promoting angiogenesis. We have proposed that Th1-dominant immunity played a critical role for overcoming such immunosuppressive tumor-escape mechanisms to induce tumor-specific memory and CTL, which are essential for the cure of tumor. In addition, we have reported rational strategies such as Th1 cell therapy and its combination with chemo or radiation therapy. To apply these basic findings to a clinical trial, we first identified a novel helper epitopes of MAGE-A4 and Survivin tumor antigens, which can activate tumor-specific Th1 cells by combination with Th1 adjuvant, OK-432. To induce an efficient Th1-dependent antitumor immunity, we further developed a novel cancer vaccine, artificial helper/killer hybrid epitope long peptide (H/K-HELP) of MAGE-A4 or Survivin. In phase I study, H/K-HELP consisted of both killer and helper epitopes was mixed with adjuvants (OK-432 and Oil adjuvant) and subcutaneously administered into cancer patients 4 times with 2 wks interval. Both MAGE-A4-H/K-HELP and Survivin-H/K-HELP induced tumor-specific Th1 and Tc1 immune responses and tumor-specific C-fixing antibody (IgG1 and IgG3) responses in cancer patients. H/K-HELP vaccination inhibited the growth of tumor in patients with melanoma and colon cancer. Moreover, H/K-HELP vaccination induced a complete regression of chemo and radio-resistant lateral deep cervical node recurrence of triple-negative breast cancer. Thus, our results propose that H/K-HELP vaccination or its combination with Th1 cells will become a promising tumor vaccine/cell therapy of human cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-153. doi:10.1158/1538-7445.AM2011-LB-153
Abstract LB-217: Long term safety observed with CEQ508: An oral RNAi drug targeting β-catenin of GI polyps
Authors: Silva Alison D. , Vaze Moreshwar B. , Borrelli Alex , Kotadia Naimesh J. , Lamriben Lydia , Polisky Barry 
Published: June 2012

Abstract
Marina Biotech is developing a proprietary drug discovery and delivery platform called transkingdom RNAi (tkRNAi), to develop RNAi-based therapeutics in which non-pathogenic bacteria are engineered to: (1) express short hairpin RNA (shRNA), (2) invade via a specific cell surface receptor and (3) deliver shRNA to the cytoplasm of a targeted cell. CEQ508, an E. coli derivative delivered orally, is the first drug candidate utilizing this approach. CEQ508 expresses a shRNA directed against β-catenin, and has been shown in previous work to significantly reduce β-catenin mRNA levels in vitro and in vivo. In the colorectal cancer cell line, SW480, we observed 90% suppression of β-catenin mRNA. In the non-human primate distal ileum 65% knockdown of β-catenin mRNA was detected. β-catenin is a key oncogene implicated in Colorectal Cancer (CRC) and Familial Adenomatous Polyposis (FAP). FAP is a hereditary disease in which the formation of hundreds of polyps in the gastrointestinal tract ultimately leads to the development of colon cancer. CEQ508 will be tested in a Phase Ib/IIa clinical trial in FAP patients at Massachusetts General Hospital with first patient dosing expected in the first quarter of 2011. CEQ508 was recently granted orphan drug status for the intended treatment of FAP patients by the FDA's Office of Orphan Products Development.
In preparation for later pivotal clinical trials, we recently completed a 9 month GLP non-human primate toxicology study assessing the safety of daily, oral chronic administration of CEQ508. In this study, 18 animals were dosed with either CEQ508 or two control articles. No CEQ508-related adverse responses were identified in the following study parameters analyzed: clinical observations, body weights and temperatures, serum chemistry, coagulation, hematology, urinalysis, cytokines and gross pathology. Preliminary conclusions identify the No Observed Adverse Effect Level (NOAEL) for long-term daily oral administration of CEQ508 as 1×1011 colony forming units (cfu)/day. In addition to presenting additional details of long term toxicology study, a clinical update on our Phase Ib/IIa trial will be provided.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2011-LB-217
Abstract LB-218: Profiling kinase inhibition in cancer cell extracts using active-site probes and targeted high resolution, accurate mass spectrometry
Authors: Bomgarden Ryan D. , Peterman Scott M. , Viner Rosa I. , Rosenblatt Michael M. , Etienne Chris L. , Rogers John C. 
Published: June 2012

Abstract
Protein kinases are enzymes that play key roles in signal transduction pathways which regulate cellular processes including growth, division, differentiation and metabolism. Kinase inhibitors are essential tools used by researchers to understand kinase function and are also therapeutic compounds used in treating cancer and other diseases. Active-site probes are one technology that can be used to determine the specificity and potency of kinase inhibitors. Desthiobiotin-ATP and -ADP are two nucleotide derivatives that have been shown to selectively label kinase active sites. Using these probes to enrich kinase active-site peptides, we identified over 150 kinases from K562 chronic myelogenous leukemia and A549 lung carcinoma cell extracts using high resolution, accurate mass (HR/AM) spectrometry. We also assessed specificity of kinase inhibitors including staurosporine and wortmannin by determining the relative quantitation of kinase active-site peptides after drug treatment. In addition, we validated kinase inhibitor targets using a parallel Western blot workflow. Overall, kinase inhibition measured using high resolution, accurate mass spectrometry had strong correlation with Western blot data and enabled global profiling of kinase inhibitor target and off-targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-218. doi:10.1158/1538-7445.AM2011-LB-218
Abstract LB-228: Resistance to BRAF inhibition in BRAF V600E colorectal cancer is associated with PI3K/AKT activation and hypermethylation
Authors: Mao Muling , Tsao Lawrence , Dayyani Farshid , Nanda Vashisht Gopal Yennu , Mills Gordon , Bollag Gideon , Davies Michael , Gallick Gary , Kopetz Scott 
Published: June 2012

Abstract
BRAF V600E mutation has been detected in approximately 8% of metastatic colorectal cancers (CRC) and results in constitutive activation of BRAF and the downstream MEK-ERK1/2 pathway. PLX4032, a selective inhibitor of BRAF V600E, has shown meaningful activity in melanoma (greater than 70% response) but only modest activity in BRAF V600E CRC (5%). The resistance of BRAF V600E CRC to BRAF inhibitors has been poorly understood. To explore these differences, BRAF V600E CRC cell lines were compared to BRAF V600E melanoma cell lines by reverse-phase proteomic array, which demonstrated higher levels of phospho-AKT and associated downstream pathway activation in CRC cell lines. Both colorectal cancer cells inherently resistant to PLX4720, an analog of PLX4032, and resistant subclones that were derived from BRAF V600E positive cells, showed increased expression of phospho-AKT and phospho-GSK3β, despite the sustained ability of PLX4720 to effectively inhibit MEK signaling. Silencing of PTEN, which in turn induced AKT activation, desensitized cells to the BRAF inhibitor. Furthermore, combined treatment of PLX4720 with two different PI3K inhibitors, LY294002 and GDC-0941, synergistically inhibited growth in a panel of BRAF V600E cells through both apoptosis and G1 phase arrest. It has been previously shown that BRAF V600E colorectal cancers are commonly associated with the CpG island methylation phenotype (CIMP), which is associated with epigenetically diminished PTEN expression. Combination treatment with the demethylating agent azacitadine and PLX4032 was also synergistic in cell lines with intact but suppressed PTEN, and was associated with PTEN re-expression. This was not seen in non-CIMP or PTEN BRAF V600E cell lines. Thus, colorectal cancer cells appear to escape BRAF targeting through a mechanism of increased PI3K/AKT activity, providing evidence to support investigation of new combination therapies with PI3K/AKT pathway inhibitors or demethylating agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-228. doi:10.1158/1538-7445.AM2011-LB-228
Abstract LB-23: In vivo exposure of infant leukemia to the BH3-mimetic ABT-263 selects for a cell death-resistant phenotype
Authors: High Laura M. , Papa Rachael A. , Armstrong Scott A. , Lock Richard B. 
Published: June 2012

Abstract
The development of acquired resistance to chemotherapy in the clinic remains a major obstacle to improve patient outcome and a better understanding of the underlying molecular events is essential to target refractory cancers, including leukemia. Infants with acute lymphoblastic leukemia involving translocations of the mixed-lineage leukemia (MLL) gene have a poorer prognosis than other age groups and this has been attributed to early relapse and resistance to traditional chemotherapies. The purpose of this study was to assess the in vivo sensitivity and mechanisms of resistance of a panel of 8 MLL xenografts established from primary biopsies in immune-deficient (NOD/SCID) mice to the BH3-mimetic and Bcl-2, Bcl-XL and Bcl-W inhibitor ABT-263. Leukaemia engraftment and progression were assessed by flow cytometric enumeration of the proportion of human CD45+ cells in the peripheral blood at weekly intervals. ABT-263 (100 mg/kg daily × 21 per oral gavage) significantly delayed the progression of 8/8 xenografts compared with vehicle-treated controls (p &lt; 0.05), with progression delayed by between 2 and 27 days across the entire panel. However, quantification of Bcl-2 protein family members by immunoblot did not reveal that expression of a single member significantly correlated with in vivo ABT-263 sensitivity. Continuous ABT-263 treatment of xenografts in vivo resulted in the outgrowth of 5 independent ABT-263-resistant xenograft lines. Resistance was confirmed to be approximately 15-fold compared with passage-matched controls by in vitro cytotoxicity assay (n = 6; p &lt; 0.0001). Subsequent inoculation of ABT-263-selected xenograft lines into NOD/SCID mice also confirmed their in vivo resistance compared with passage-matched controls. ABT-263-selected lines showed a 5-fold increase in cell viability compared with passage-matched control lines after 4 days of ex vivo culture (p = 0.02). Moreover, the ABT-263-selected cells were significantly resistant in vitro to 2 established drugs used in the treatment of pediatric acute lymphoblastic leukemia, dexamethasone (p = 0.001) and daunorubicin (p = 0.006). This cell death-resistant phenotype could not be attributed to altered protein expression of known ABT-263 resistance modifiers, including Bcl-2, Mcl-1 and Bim. In conclusion, this study has demonstrated that ABT-263 has significant in vivo efficacy against MLL xenografts derived from direct patient explants, but that ABT-263 resistance can readily arise in vivo leading to a cell death-resistant phenotype via a unique mechanism. (Supported in part by NCI NO1CM42216)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-23. doi:10.1158/1538-7445.AM2011-LB-23