bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 859: CDK11 (PITSLRE) kinase expression is critical for human cancer cell growth and proliferation
Authors: Duan Zhenfeng , Choy Edwin , Harmon David , Mankin Henry , Hornicek Francis 
Published: August 2012

Abstract
In the search to identify kinases required for human cancer cell growth, we found CDK11 (PITSLRE) by a comprehensive human kinome-wide shRNA screen to be critical for human cancer cell growth and proliferation. We observed that the expression level of CDK11 was elevated in a variety of human cancer cells and tumor tissues. Furthermore, knock-down of CDK11 either by lentiviral shRNA or by synthetic siRNA inhibits cell growth and induces apoptosis in human cancer cells. In these cells, suppression of CDK11 reduces the expression of several antiapoptotic genes essential for tumor cell survival and proliferation including MCL-1, BcL-XL and survivin. We showed by immunohistochemical analysis that osteosarcoma and ovarian cancer patients with high CDK11 tumor expression levels were associated with significantly shorter survival than patients with lower expression levels of CDK11 expression. Systemic administration of In Vivo Ready siRNA of CDK11 reduced tumor growth in an osteosarcoma s.c. xenograft model. Taken together, these observations suggest that CDK11 signaling is essential in human cancer cell growth and survival. CDK11 may serve as a promising therapeutic target in the treatment of human cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 859. doi:1538-7445.AM2012-859
Abstract 864: Novel synthetic berbamine derivatives inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells
Authors: Nam Sangkil , Xie Jun , Perkins Angela , Ma Yuelong , Yang Fan , Wu Jun , Wang Yan , Xu Rong-zhen , Huang Wendong , Horne David A. , Jove Richard 
Published: August 2012

Abstract
Persistent Jak/Stat3 signal transduction plays a crucial role in tumorigenesis and immune development. Activated Jak/Stat3 signaling has been validated as a promising molecular target for cancer therapeutics discovery and development. Berbamine (BBM), a natural bis-benzylisoquinoline alkaloid, was identified from the traditional Chinese herbal medicine Berberis amurensis used for treatment of cancer patients. While BBM has been shown to have potent antitumor activities with low toxicity in various cancer types, the molecular mechanism of action of BBM remains largely unknown. Here, we determine the antitumor activities of thirteen synthetic berbamine derivatives (BBMDs) against human solid tumor cells. BBMD3, which is the most potent in this series of novel BBMDs, exhibits over 6-fold increase in biological activity compared to natural BBM. Moreover, BBMD3, directly inhibits Jak2 autophosphorylation kinase activity in vitro with IC50 = 0.69 μM. Autophosphorylation of Jak2 kinase at Tyr1007/1008 sites also was strongly inhibited in the range of 1 μM to 5 μM of BBMD3 in human melanoma cells 4 h after treatment. Following inhibition of autophosphorylation of Jak2, BBMD3 blocked constitutive activation of downstream Stat3 signaling in melanoma cells. BBMD3 also down-regulated expression of Stat3 target proteins Mcl-1and Bcl-xL, associated with induction of apoptosis. In sum, our findings demonstrate that the novel berbamine derivative BBMD3 is an inhibitor of the Jak2/Stat3 signaling pathway, suggesting evidence for a molecular mechanism whereby BBMD3 exerts at least part of apoptosis of human melanoma cells. In addition, BBMD3 represents a promising lead compound for development of new therapeutics for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 864. doi:1538-7445.AM2012-864
Abstract 873: Combined targeting of Akt and MEK with the Akt inhibitor GDC-0068 and MEK inhibitor GDC-0973 demonstrates synergistic anti-tumor effects
Authors: Nannini Michelle A. , Hong Rebecca , Lee Brian B. , Arrazate Alfonso , Kassees Robert , Lin Jie , Degtyarev Michael , Sampath Deepak , Lin Kui 
Published: August 2012

Abstract
Background: Akt, a serine/threonine protein kinase, and MEK, a dual specificity kinase, are key signaling nodes in the PI3K/Akt/mTOR and the Ras/Raf/MAPK pathway, respectively. Both Akt and MEK play key roles in regulating numerous cellular processes such as cell proliferation, growth, survival, protein synthesis and oncogenic transformation. Many cancer types have alterations in both of these pathways and inhibiting only one of these pathways can result in up-regulation of the other pathway. We previously reported on a potent highly selective ATP-competitive pan-Akt inhibitor, GDC-0068 as well as a potent selective inhibitor of MEK, GDC-0973 that are currently in Phase 1 clinical trials. We hypothesized that dual inhibition of both MEK and Akt pathways with the combination of these two agents would induce synergistic antitumor activity. Methods: In these studies, we evaluated the efficacy of GDC-0068 and GDC-0973 both individually and in combination on a panel of cancer cell lines. Cells were treated with either GDC-0068 or GDC-0973 or in combination at increasing concentrations and assayed after 4 days for viability. For in vivo studies, tumor cells were subcutaneously implanted in the flank of female NCR.nude mice. Once tumors reached sufficient size, mice were dosed orally for 21 days with GDC-0068, GDC-0973 or the combination of both compounds. Results: In vitro, the combination of GDC-0068 and GDC-0973 results in enhanced inhibition of cell viability compared to either single agent alone. Synergistic effects are observed in multiple cell lines; especially in cell lines that have activation of the Ras/Raf/MAPK pathway or both pathways (e.g. via the combination of PTEN loss or PI3K mutations and Ras or BRaf mutations). Combined knockdown of downstream targets of both Akt and MEK is observed at concentrations where a synergistic effect is observed, with enhanced knockdown of several converged targets. Increased cell death is also observed. These results were recapitulated in vivo in xenograft models, where the combination of GDC-0068 and GDC-0973 resulted in increased tumor growth inhibition or regression compared to either single agent alone. All combinations tested were well tolerated as assessed by animal body weights and mortalities. Conclusions: Our studies demonstrate significant combination benefit between GDC-0068 and GDC-0973 on cell viability in vitro and tumor growth in vivo. These data support the clinical development of the combination of these two compounds.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 873. doi:1538-7445.AM2012-873
Abstract 90: An evaluation of the genes involved in the Base Excision Repair (BER) pathway as potential phenotypic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.
Authors: Vaclová Tereza , Milne Roger L , Saucedo-Cuevas Laura P , Radice Paolo , Blanco Ignacio , de la Hoya Miguel , Durán Mercedes , Díez Orland , Cajal Teresa Ramón y , Martínez-Bouzas Cristina , Fostira Florentia , Godino Javier , Benitez Javier , Osorio Ana 
Published: August 2012

Abstract
Germ-line mutations in the BRCA1 and BRCA2 genes confer a high lifetime risk of developing breast and other cancers. However, remarkable differences exist regarding disease manifestation in mutation carriers, suggesting the existence of other genetic modifier factors. Given that both BRCA1 and BRCA2 are involved in the repair of double-strand breaks (DSBs) mainly by Homologous Recombination, SNPs in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers. The Base Excision Repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of this pathway, PARP1, and both BRCA1 and BRCA2. To test our hypothesis we have performed a comprehensive analysis of the 18 genes involved in BER, in a series of 2000 BRCA1 and BRCA2 mutation carriers from the Spanish Consortium for the Study of Hereditary Breast Cancer, the Istituto Nazionale Tumori and the National Centre for Scientific Research “Demokritos”. For this purpose we have used a tagging SNP approach in which we have evaluated the common genetic variation in the 18 genes using the VeraCode GoldenGate 144 SNP Genotyping Kit. Preliminary results have showed statistically significant associations with cancer risk in BRCA1 and/or BRCA2 mutation carriers for 46 SNPs (p&lt;0.05), seven of them showing associations with p&lt;10−3. Genetic and functional analyses are currently on-going to validate the most statistically significant effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 90. doi:1538-7445.AM2012-90
Abstract 904: The TNIK kinase is a potential target in non-small cell lung and gastric cancer
Authors: Yu Derek Dehua , Zhang Xiuhua , Wang Christina , Hu Eva , Dong Harvey , Zhu Mike , Qian Ziliang , Gao Zeren , Gao Zeren , Fan Joan , Su Xinying , Xu Jessie , Zheng Li , Yin Lucy , Ji Qunsheng 
Published: August 2012

Abstract
Traf2- and Nck-interacting kinase (TNIK) is one of germinal centre kinase (GCK) family members involved in cytoskeleton organization and neuronal dendrite extension. Emerging evidence indicated that TNIK is essential in activation of WNT pathway and colon cancer growth. To search for novel genetic aberrations that drive carcinogenesis, we performed microarray-based comparative hybridization (aGCH) to screen gene copy number variations in primary tumor samples and found TNIK gene is amplified in 19.2 % (29/151) of Chinese non-small cell lung cancer and 7 % (8/106) of Chinese gastric cancer patients. Interestingly, the amplification in NSCLC is highly enriched in squamous NSCLC patients (41.1%, 28/68). Theses amplifications were confirmed by fluorescence in situ hybridization (FISH) analysis. To further understand the function of TNIK gene amplification, PAMC82 human gastric cancer and T47D colon cancer cell lines with TNIK amplification were identified. RNA-interference-mediated silencing of TNIK resulted in significantly reduced cell growth and increased cell death in the TNIK amplified, but not in the non-amplified, tested cell lines. Together, our results suggest that TNIK is a novel therapeutic target in NSCLC and gastric cancer and TNIK amplification can be potentially used for patient selection.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 904. doi:1538-7445.AM2012-904
Abstract 910: Selective inhibition of Rac1 and Cdc42 in ovarian cancer using the R-enantiomer of ketorolac
Authors: Kenney Shelby R. , Oprea Tudor , Ursu Oleg , Sklar Larry , Lomo Lesley , Muller Carolyn , Gao Yuna , Wandinger-Ness Angela , Hudson Laurie 
Published: August 2012

Abstract
Ovarian cancer is the 5th leading cause of cancer death for women in the United States and is frequently diagnosed at late stage with multiple secondary metastases. Ras-homologous (Rho) family GTPases contribute to metastatic dissemination through regulation of actin reorganization, cell motility, cell-cell and cell-extracellular matrix adhesion. Rho GTPases are altered in a number of human cancers and our work provides the first evidence for dysregulation of Rac1 and Cdc42 in ovarian cancer. These findings suggest that Rac1 and Cdc42 inhibitors represent potential therapeutics for ovarian cancer. Using high throughput screening we identified the R-enantiomers of ketorolac and naproxen as novel inhibitors of Rac1 and Cdc42. Although it has been noted that R-enantiomers of nonsteroidal anti-inflammatory drugs are poor inhibitors of cyclooxygenase (COX) activity, little is known about the pharmacologic activities or targets of the R-enantiomers. The objective of this study was to investigate the effects of R-ketorolac on ovarian cancer. The effects of racemic, R- and S-ketorolac were investigated using SKOV3ip ovarian cancer cells. The compounds NSC23766 and MLS0000693334 were used as positive controls for Rac1 and Cdc42 respectively. An in vitro G-LISA assay indicated R-ketorolac, and not S-ketorolac, inhibits Rac1 and Cdc42 activity. In cells, R-Ketorolac, not S-ketorolac, inhibits cell:cell adhesion and cell migration. An intra-peritoneal xenograft model of tumor implantation was used to determine the effects of drugs in vivo. Racemic ketorolac decreased the number of implanted tumors by 70%. To elucidate the mechanism of GTPase inhibition by R-ketorolac, a targeted microarray analysis was performed. Preliminary results show an alteration to the gene expression profile of human cytoskeletal regulators in response to ketorolac treatment. These effects may be due to inhibition of Rac1 and Cdc42 directly or through upstream or downstream inhibition. This analysis also provides biomarkers that can be used to analyze tumor tissues from primary patients and animal studies. Together, these findings indicate that R-ketorolac is a novel inhibitor of Rac1 and/or Cdc42, and inhibit cellular processes necessary for ovarian cancer metastasis. The mechanism behind ketorolac inhibition will require further investigation. In the future, this drug may offer benefit to ovarian cancer patients through inhibition of these GTPase targets
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 910. doi:1538-7445.AM2012-910
Abstract 923: Interrelations between roles of phospholipase C-gamma 1 inhibition, mTOR and glycolytic enzymes in growth and survival of glioblastoma cells
Authors: Jain Aditi , Lai James C.K. , Chowdhury Golam MI , Behar Kevin , Bhushan Alok 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is a deadly and a frequently occurring brain tumor in humans. Patients with this disease survive on an average for 12-14 months after diagnosis. Conventional approaches to treat the cancer are not effective in improving patient survival. Thus, it is imperative to seek new drug targets and therapies that could effectively treat brain tumors and enhance patient survival. Phospholipase C-gamma 1 (PLCα1) plays an important role in regulating intracellular calcium stores and acts as a point of convergence in several cell signaling cascades. Inhibition of PLCα1 is known to decrease cell differentiation, invasion and motility in several cancers. We previously demonstrated inhibition of PLCα1 blocks invasion of glioma cells. In this study, we investigated the effects of PLCα1 inhibition on cell viability, cell signaling and metabolism in brain tumor (U-87 MG) cells. We investigated the hypothesis that inhibition of PLCα1 blocks cellular progression of U-87 MG. U73122, an inhibitor of PLCα1, induced a dose-related decrease in survival of U-87 MG cells, with a maximal effect at 2 µM: this finding correlated with the U73122-induced decrease in expression of lactate dehydrogenase, a protein important in U-87 MG cell survival and metabolism. Moreover, U73122 was effective in enhancing the cytotoxic potential of temozolomide, a modestly effective drug used currently for the treatment of glioblastoma. Western blot analysis of U-87 MG cells treated with U73122 at concentrations between 0.5 and 2 µM showed biphasic effects on expression of phospho-ERK and mTOR, proteins involved in PLCα1 signaling as well as hexokinase II, an important glycolytic enzyme. Employing 1H-[13C]-NMR spectroscopy, we noted that treatment with 2 µM U73122 for 72 hours induced increased glycolytic flux in U-87 MG cells. Thus, our results suggest important mechanistic interrelations between PLCα1 signaling and roles of mTOR and glycolytic enzymes in regulating survival of brain tumor cells. Furthermore, our results also suggest that inhibition of PLCα1 may be exploited in combination with conventional therapies in treating patients with glioblastoma to improve their outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 923. doi:1538-7445.AM2012-923
Abstract 932: Selective requirement of BH3-only proteins for apoptosis induced by targeted therapies in colon cancer cells and xenografts
Authors: Zheng Xingnan , He Kan , Sun Jing , Sun Quanhong , Brown Matthew F. , Zhang Lin , Yu Jian 
Published: August 2012

Abstract
Constitutive activation of pro-survival kinases has become a promising target of recently developed small molecules, while their biomarkers and resistance mechanisms remain largely unknown. In this study, we investigated the role of several BH3-only proteins PUMA, Bim and Noxa in apoptosis and growth suppression induced by different classes of targeted agents, including selective small molecule inhibitors to c-Met, IGFR, Hsp90, VEGFR and non selective kinases inhibitors in colon cancer cells and xenografts. Using isogenic colon cancer cells with targeted deletion in PUMA, Bim or Noxa, we demonstrated universal and persistent PUMA induction by all of these agents, which is mediated by either p53-dependent or -independent mechanisms. PUMA deficiency led to impaired apoptosis and caspase activation in colon cancer cells, and significantly blocked tumor cell apoptosis and therapeutic responses to these agents in xenografts. On the contrary, modulation of upstream signaling such as phosphorylation of PI3K/AKT was transient and involves diverse transcription factors. Interestingly, only a small subset of agents induced the expression of Bim or Noxa, or required Bim or Noxa for apoptosis induction. Moreover, small molecule BH3 mimetics, or enhanced PUMA levels resulted from another drug sensitized colon cancer cells to apoptosis induced by majority of these agents. Our results establish a critical role of the mitochondrial pathway and BH3-only proteins in mediating sensitivity of colon cancer cells to a wide variety of targeted-agents, and shed light on resistance mechanisms. In light of recent data on BH3-only proteins in therapy-induced apoptosis in other tumor types, our data suggest that modulations of selected BH3-only proteins, rather than their steady-state levels, might sever as potential biomarkers for predicting therapeutic responses in both treatment-naïve and pretreated patients, and provide a rationale for combination therapy in clinical trials. These novel preclinical findings can help guide future development and clinical use of targeted agents. Key words: kinase inhibitors; PUMA; Bim; Noxa; apoptosis; resistance mechanisms, colon cancer
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 932. doi:1538-7445.AM2012-932
Abstract 94: Epigenetic silencing of CDO1 sustains viability of breast cancer cells via the reduction of cellular ROS
Authors: Jeschke Jana , O'Hagan Heather , Zhang Wei , Calmon Marilia F. , Dhir Mashaal , van Neste Leander , Bijsmans Ingrid , Gabrielson Edward , Schuebel Kornel E. , Baylin Stephen B. , Winterpacht Andreas , Herman James G. , Ahuja Nita 
Published: August 2012

Abstract
Approaches to analyze genome-wide methylation changes have become an extraordinary useful tool to identify thousands of new candidate hypermethylated genes in cancer. Numerous comprehensive approaches have been initiated to begin to understand the biological significance of the vast amount of methylation data generated and by this, novel tumor suppressor genes, biomarkers for early detection and prognosis prediction of cancer, and molecular mechanisms underlying tumor growth control have been discovered. In this study, we explore the candidate hypermethylated gene Cysteine Dioxygenase Type 1 (CDO1), which was recently identified in breast cancer using a functionally proven genome-wide gene expression approach. Here, we show that the epigenetic inactivation of CDO1 enhances tumor growth and sustains viability of breast cancer cells via the reduction of cellular ROS. Moreover, we observed a cancer stage-dependent increase in CDO1 methylation frequency (DCIS: 50%, stage 1-2: 65% and stage 3-4: 90%) that coincides with elevated oxidative stress levels in advanced cancers. These findings support the hypothesis that cancer cells upregulate their antioxidant capacity in adaptation to intrinsic oxidative stress. Lastly, we correlated CDO1 methylation status with clinicopathologic patient characteristics in a cohort of 186 patients. Methylation of CDO1 is significantly associated with prognostic parameters such as tumor stage, lymphovascular and perinodal invasion and predicts worse patient outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 94. doi:1538-7445.AM2012-94
Abstract 948: IGF-I receptor expression is associated with stage and has therapeutic activity in human biliary tract cancers
Authors: Adachi Yasushi , Yamamoto Hiroyuki , Ohashi Hirokazu , Taniguchi Hiroaki , Nosho Katsuhiko , Suzuki Hiromu , Arimura Yoshiaki , Endo Takao , Imai Kohzoh , Carbone David P. , Shinomura Yasuhisa 
Published: August 2012

Abstract
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target has not been well studied in biliary tract carcinomas. We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53, and the methylation status of the IGFBP-3 promoter in 80 surgically resected biliary tract carcinomas. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation, and survival in 3 biliary tract cancer cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenografts models. IGF-I was expressed in 60% and IGF-II in 50% of tumors and high expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated to advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor up-regulated chemotherapy-induced apoptosis in a dose dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of biliary tract cancers with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 may have significant therapeutic utility.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 948. doi:1538-7445.AM2012-948