bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 896: Enhancing mTOR targeted therapy in bladder cancer
Authors: Becker Marie N. , Copland John A. , Williams Christopher R. 
Published: August 2012

Abstract
Bladder cancer is the 4th most commonly diagnosed cancer in the United States. Because superficial bladder cancer (SBC) recurs in about 60% of cases, standard treatment involves tumor resection followed by intravesical therapies to prevent recurrence, as well as lifelong periodic cystoscopy. There is an urgent need for better intravesical therapies to prevent both the recurrence and progression of SBC. The Mammalian Target Of Rapamycin (mTOR) complex is upregulated in many bladder cancer tumors. We have targeted both the mTORc1 and mTORc2 complexes with drugs that inhibit both complexes. We used PP242 and a second inhibitor, OSI-027, which is currently in a phase I clinical trial for solid tumors (NCT00698243). Our in vitro model targets cell proliferation in three bladder cancer cell line (HT1376, T24 and UM-UC-3). Both drugs are effective in inhibiting the growth of bladder cancer cell lines with IC50 values between 0.6 and 18µM. In comparison with rapamycin, both drugs demonstrate effects on downstream targets of both the mTORc1 and mTORc2 pathways including 4EBP1 and pAkt. Receptor tyrosine kinases are another therapeutic target for bladder cancer. Lapatinib which targets EGFR and Her3, in combination with OSI-027 forms a highly synergistic treatment that inhibits bladder cancer cell line growth. Downstream molecular targets of the combination therapy, including the apoptosis markers PARP and caspase 3, were evaluated by Western blots. Our in vitro data suggests that a combination of dual mTOR inhibitors with RTK inhibitors may provide a novel effective therapeutic treatment for bladder cancer. Future studies of the in vivo efficacy of these drug combinations in a mouse model are planned.
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 896. doi:1538-7445.AM2012-896
Abstract 903: The IKKα kinase is a potential therapeutic target in K-Ras-induced lung cancer
Authors: Basseres Daniela S. , Ebbs Aaron , Cogswell Patricia C. , Levantini Elena , Baldwin Albert S. 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer deaths in the world. In lung cancer, K-Ras oncogenic mutations are widespread, and compounds used to target the biological activity of the Ras proteins failed in clinical trials. Therefore, it is imperative to identify novel therapeutic targets that reduce K-Ras-induced lung tumorigenesis. We have previously shown that K-Ras-induced lung tumorigenesis is potentiated by the subunit p65 of the transcription factor NF-κB; and that K-Ras-induced NF-κB activation in the lung requires IKKα. Therefore, we hypothesized the following: (1) the IKKα kinase promotes K-Ras-induced oncogenesis; and (2) pharmacological inhibition of IKKα activity will be beneficial therapeutically. We used genetic and/or pharmacological approaches to inactivate IKKα in primary lung epithelial cells transformed by K-Ras, as well as K-Ras-positive lung cancer cell lines, and determined that IKKα inhibiton reduces oncogenic properties in vitro. In addition we used a highly specific IKKα inhibitor (CmpdA, Bayer) to treat a K-Ras-induced lung cancer mouse model combined with loss of the tumor suppressor p53 (LSL-K-RasG12D/p53fl/fl). We chose this model for the following reasons: (1) K-Ras activation coupled to p53 loss leads to aggressive lung adenocarcinomas in mice that better resemble human lung tumors; (2) lung cancer patients harboring K-Ras oncogenic mutations frequently display p53 inactivation; and (3) it has been recently demonstrated that p53 loss can enhance NF-κB activation by K-Ras in lung tumors. To induce concomitant K-Ras activation and p53 loss in murine lung epithelial cells, we infected the lungs of LSL-K-RasG12D/p53fl/fl mice by intranasal administration of a Cre-expressing adenovirus (AdCre). Two treatment regimens were used to treat infected animals: CmpdA was either administered daily for 2 weeks immediately following AdCre infection or daily for 4 weeks starting 8 weeks post-infection. In either case, mice treated with CmpdA presented smaller and lower grade tumors than mice treated with placebo. These results show that IKKα promotes lung cancer growth and progression both in vitro and in vivo. In addition, we have shown that pharmacological administration of an IKKα inhibitor slows lung tumor growth and progression in vivo, supporting our hypothesis that IKKα inhibition therapy will have clinical benefits in lung cancer. This research is supported by a FAMRI YCSA Award and a FAPESP Young Investigator Award to DB and a NIH grant (CA73756) to AB.
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 903. doi:1538-7445.AM2012-903
Abstract 907: The efficiency of Nek2 siRNA for liver metastasis of pancreatic cancer
Authors: Kokuryo Toshio , Yokoyama Yukihiro , Nagino Masato 
Published: August 2012

Abstract
Background: Nek2 (NIMA-related kinase 2) is a member of the serine/threonine kinase family, which related to the essential mitotic regulator NIMA. Nek2 is involved in cell division and mitotic regulation by centrosome splitting. We reported that the efficiency of Nek2 as molecular target for several cancers, such as cholangiocarcinoma, breast cancer and colorectal cancer. Methods: We examined the effect of Nek2 siRNA treatment on the tumor of pancreatic cancer in xenograft mouse model. We also challenged Nek2 siRNA in the liver metastasis model of pancreatic cancer. Results and Discussion: Nek2 siRNA suppressed the growth of tumors in xenograft pancreas cancer model. In liver metastasis model, Nek2 siRNA decreased the number of metastasis and resulted in reduction of metastasis volume. Liver metastasis is one of the major undesirable complications frequently associated with inoperable cases. The Nek2 suppression with siRNA is also effective in the inhibition of liver metastasis of pancreas cancer. Conclusions: Nek2 plays a critical role in tumorigenic growth of various cancers, and inhibition of Nek2 expression with its siRNA causes suppression of cancer growth. Our data provides a strong rationale for the further investigation of Nek2 inhibitors as a new cancer therapy, holding the potential to provide regression of multiple human malignancies.
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 907. doi:1538-7445.AM2012-907
Abstract 909: ErbB-2 restricts Mib-1 and Jagged-1 association to inhibit Notch-1 activation in ErbB-2 positive breast cancer
Authors: Pandya Kinnari , Osipo Clodia 
Published: August 2012

Abstract
We have recently published that Notch could be an important target in recurrent, or possibly trastuzumab resistant, ErbB-2-positive breast cancer to prevent disease progression. Coincidentally, co-overexpression of Notch-1 ligand, Jagged-1, in breast cancer have been associated with the poorest overall survival. Preliminary results from our lab demonstrated that trastuzumab or lapatinib treatment of SKBr3 cells increased Jagged-1 protein expression by Flow Cytometry. Cell surface biotinylation assays showed that Jagged-1 was enriched on the cell surface in response to trastuzumab treatment and this was mimicked by expression of K44A Dynamin. The precise role of Jagged-1 in ErbB-2-mediated inhibition of Notch-1 is not yet known. The results showed that a combined inhibition of Jagged-1 by siRNA and ErbB-2 by trastuzumab, inhibited cell proliferation and induced apoptosis in 95% of SKBR3 cells. Thus, we asked what is the molecular mechanism by which ErbB-2 inhibits Notch activity. Specifically, ErbB-2 inhibited the association of Mib1, an E3 ubiquitin ligase that is necessary for Notch activation, with Jagged-1 and this was reversed in response to trastuzumab or lapatanib. Recent evidence suggests that ErbB-2 activates PKC∈ and that PKC∈ is critical for ErbB-2-mediated cancer cell invasion. We observed that ErbB-2 increased the amount of PKC∈ found in a complex with Jagged-1. This result suggests that PKC may phosphorylate Jagged-1 or other associated proteins to restrict Jagged-1/Mib1 interaction and thus restrict Notch activation. Interestingly, we identified a substrate of PKC∈ kinase activity, approximately 100 kDa, which was in a complex with Jagged-1 in response to lapatinib treatment. Taken together, these results suggest a possible the role for PKC∈ in ErbB-2-mediated suppression of Notch-1 activity by inhibiting the ability of Jagged-1 to interact with Mib-1.
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 909. doi:1538-7445.AM2012-909
Abstract 914: Ciclopirox olamine (CPX) inhibits breast cancer cell proliferation by blocking the formation of a PEAK1-Src-eIF5a protein complex
Authors: Weems Jessica M. , Reno Theresa A. , Klemke Richard L. 
Published: August 2012

Abstract
The antimycotic drug ciclopirox olamine (CPX) is being evaluated in clinical trials as a re-positioned anti-cancer agent. Although low micromolar concentrations of CPX have been shown to inhibit cell proliferation and solid tumor growth in preclinical models, the mechanism of action remains poorly characterized. In the present study, we demonstrated that CPX treatment potently inhibits cell proliferation and protein expression of the novel tyrosine kinase pseudopodium-enriched atypical kinase 1 (PEAK1) in several breast cancer cell lines, whereas forced overexpression of PEAK1 results in decreased sensitivity to CPX treatment and increased proliferation. PEAK1 protein expression modulates Src kinase activity in proliferating cancer cells and is upregulated in a number of human malignancies, but the mechanisms that regulate its expression have not been characterized (PNAS, 107(24), 10920-5). Here we demonstrate that CPX treatment inhibits the hypusination of eukaryotic translation initiation factor 5a (eIF5a), leading to decreased PEAK1 protein expression and Src kinase activity. siRNA knockdown of eIF5a inhibited PEAK1 expression and Src activity. Likewise, inhibition of Src kinase in cancer cells prevented eIF5a and PEAK1 protein expression, indicating that these proteins tightly regulate one another. Further investigation revealed that in breast cancer cells PEAK1, Src, and eIF5a form a complex which is disassociated by CPX treatment. These findings support a model in which PEAK1 amplification in malignant cells promotes increased Src kinase activity thereby leading to increased eIF5a-mediated PEAK1 protein expression levels. Taken together, these data indicate that CPX has significant potential as a repositioned therapeutic to combat PEAK1 and Src driven human cancers.
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 914. doi:1538-7445.AM2012-914
Abstract 917: AZD2014, a dual mTORC1 and mTORC2 inhibitor is differentiated from allosteric inhibitors of mTORC1 in ER+ breast cancer
Authors: Guichard Sylvie M. , Howard Zoe , Heathcote Dan , Roth Mark , Hughes Gareth , Curwen Jon , Yates James , Logie Armelle , Holt Sarah , Chresta Christine M. , Davies Barry R. , Malagu Karine , Hummersone Marc , Pass Sarah L. , Green Stephen , Pass Martin 
Published: August 2012

Abstract
The mammalian target of rapamycin (mTOR) is a major sensor of nutrients and energy and is part of two multiprotein complexes mTORC1 and mTORC2. mTOR activation is widely reported in cancer and is associated with poor prognosis and resistance to standard of care treatment. Allosteric inhibitors of mTOR such as rapamycin partially inhibit mTORC1 and do not inhibit mTORC2. AZD2014 is a close analogue of AZD8055 and a selective inhibitor of mTOR kinase. AZD2014 has greater inhibitory activity against mTORC1 compared to rapamycin: AZD2014 decreases p4EBP1 Thr37/46, inhibits the translation initiation complex and decreases overall protein synthesis while rapamycin has no effect. AZD2014 also inhibits the mTORC2 biomarkers pAKTSer473 and pNDRG1Thr346. AZD2014 has broad antiproliferative activity across multiple tumour cell lines. In particular, AZD2014 induces growth inhibition and cell death in breast cancer cell lines, including ER+ cell lines with acquired resistance to hormone therapy. In vitro, the potency of AZD2014 is ∼ 5-fold lower compared to AZD8055. However, AZD2014 has improved pharmacokinetics compared to AZD8055. In vivo, AZD2014 induces tumour growth inhibition against several xenograft models including a human primary explant model of ER+ breast cancer refractory to tamoxifen. The antitumour activity is associated with modulation of both mTORC1 and mTORC2 substrates. Overall, AZD2014 is a potent mTOR kinase inhibitor with an in vitro profile comparable to AZD8055 but with improved pharmacokinetic properties over AZD8055. AZD2014 is currently in phase 1 clinical trials.
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 917. doi:1538-7445.AM2012-917
Abstract 92: Odonogenic Ameloblast Associated Protein (ODAM) moderates cell growth and invasion in the human breast cancer line MDA-MB-231 in part through the TGF-β signaling pathway
Authors: Phipps Jonathan E. , Foster James S. , Bell John , Solomon Alan , Kestler Daniel P. 
Published: August 2012

Abstract
Breast neoplasms are the second leading cause of cancer deaths of women in the United States. Recently, it has been shown by immunohistochemical staining of tumor biopsy tissue that nuclear localization of the odontogenic ameloblast associated protein (ODAM) correlated with staging and increased survival in patients, leading to the proposal of this protein as a novel biomarker in breast cancer. Further, ectopic expression of recombinant ODAM protein in the invasive breast carcinoma line MDA-MB-231 (231-ODAM) was shown to slow cell growth to 30-50% of that seen in control 231 cells, increase apoptosis, effect developmental change, and decrease the ability of cells to migrate or invade through extracellular matrix in transwell barrier assays. Further, this expression reduced the ability of these cells to form solid tumors by greater than 10-fold in immunodeficient mice, or establish tumor colonization of the lungs after tail vein injection. Herein, we show results of microarray and qRT-PCR data collected from 231-ODAM and control cells revealing effects of ODAM on the expression of a number of genes which have been reported to be affected by or active in the TGF-β pathway including TGF-β I-II, HAS2, Gli-2, SMADs 2, 3 and 7, PLAU and others. This suggests that ODAM interacts in part with the TGF-β pathway. When challenged with neutralizing antibodies to block TGF-β activity we observed an increase in 231-ODAM cell growth which was approximately 80% that of the 231-control line. In addition, antibody blockade of TGF-β signaling restored the ability of 231-ODAM cells to invade and migrate through matrigel-coated barriers to that of the 231-control line. Taken together, these results and others suggest that ODAM acts in part through the TGF-β pathway, which has been implicated with invasion and metastasis in breast cancer and other malignancies.
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 92. doi:1538-7445.AM2012-92
Abstract 926: Experimental therapy of pancreatic cancer with KCN1, a novel anticancer agent targeting HIF-1α pathway
Authors: Wang Wei , Ao Lin , Zhang Xiangrong , Zhang Xu , Van Meir Erwin G. , Zhang Ruiwen 
Published: August 2012

Abstract
Hypoxia is a major driving force in a majority of human cancers and correlates with a poor outcome of cancer treatment. Hypoxia Inducible Factor-1 (HIF1) has been identified as the key orchestrator of hypoxic response due to its transactivation of genes that are involved in many aspects of malignant tumor growth from cell survival and metabolism to angiogenesis and invasion. Thus, pharmacological targeting of HIF-1 represents a promising strategy to inhibit tumor growth and progression. The purpose of the present study was to determine anti-cancer activity and pharmacological properties of KCN1, a novel small molecule HIF-1α pathway inhibitor. We investigated the in vitro activity of KCN1 on the survival of several human pancreatic cancer cell lines, including HPAC, Panc-1 and BxPC3 cells. KCN1 exerted potent effects against the various cell lines, leading to a significant decrease in cell viability, and inhibited cell proliferation and cell cycle progression, leading to an arrest in the G1 phase. We also found that the expression of numerous proliferation-associated and cell cycle regulatory proteins were affected by KCN1. It reduced the expression of E2F1, Cyclin D1, Cyclin E, Cdc25c and CDK 2, 4, and 6 and, conversely, increased p21 expression. Moreover, KCN1 inhibited the growth of pancreatic cancer xenograft tumors in nude mice. There were no significant host toxicity and no gross organ abnormalities upon necropsy. We also developed an HPLC method for KCN1 quantitation and accomplished experiments to derive preclinical information for its further development. The HPLC method provided a linear detection of KCN1 in biological matrices in the range from 0.1 to 100 μM, and had a limit of quantitation of 0.085 μM in mouse plasma. KCN1 was relatively stable in plasma, being largely intact after an 8-hr incubation in mouse plasma at 37°C. The compound was extensively plasma bound, and was metabolized by S9 microsomal enzymes. Pharmacokinetic studies indicated that KCN1 could be detected in tumors and all of the normal tissues examined. In conclusion, our preclinical data indicate that KCN1 is a potential therapeutic agent for pancreatic cancer. The initial pharmacological data provide a basis for its future development as a preclinical and clinical lead HIF1 inhibitor. (This work was supported by NIH/NCI grant R01 CA116804.)
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 926. doi:1538-7445.AM2012-926
Abstract 938: Metabolomic analysis on pharmacological responses to oxaliplatin plus 5-FU in colorectal cancer cells
Authors: Nishimuta Akito , Tsuzaki Junya , Ikoma Yusuke , Otani Yuki , Irie Hidehiro , Suzuki Tetsuya , Sugimoto Masahiro , Soga Tomoyoshi , Tanigawara Yusuke 
Published: August 2012

Abstract
Purpose: Oxaliplatin (L-OHP) in combination with 5-fluorouracil (5-FU)/leucovorin (FOLFOX regimen) is an important treatment of metastatic colorectal cancer. However, metabolic functions to determine pharmacological response to L-OHP in combination with 5-FU are still unclear. The purpose of this study is to elucidate metabolomic responses to L-OHP in combination with 5-FU and key pathways relating to chemosensitivity. Experimental Procedures: Human colorectal carcinoma, HCT116 (high-sensitive) and DLD-1 (low-sensitive) cells, were exposed to L-OHP, 5-FU or L-OHP plus 5-FU. After treatment with the anti-cancer agents, the intracellular metabolites were extracted by liquid-liquid extraction and simultaneously and quantitatively analyzed by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). The mRNA expression level of spermidine/spermine N1-acetyltransferase (SSAT) was measured by real-time quantitative RT-PCR (Taqman PCR). Results: N1-acetylspermine and N8-acetylspermidine in polyamine metabolism were accumulated to a greater extent after L-OHP exposure in drug-sensitive cancer cells. The mRNA expression level of SSAT-1, a key enzyme in polyamine catabolism, increased after L-OHP exposure in drug-sensitive cancer cells but not drug-resistant cancer cells. In addition to the up-regulation of polyamine metabolism in drug-sensitive cancer cells, the intracellular levels of endogenous nucleotides remarkably increased after L-OHP exposure in drug-sensitive cancer cells. These results imply the changes in nucleotide metabolism due to the disruption of DNA synthesis by L-OHP. The intracellular level of α-alanine also accumulated after L-OHP exposure in drug-sensitive cancer cells. α-alanine is known as a pyrimidine catabolite of uracil. These results show that nucleotide metabolism and polyamine metabolism may be important metabolic pathways relating to L-OHP chemosensitivity. Furthermore, in drug-sensitive cancer cells, polyamine metabolism, glutathione metabolism, and nucleotide metabolism were up-regulated after exposure to L-OHP plus 5-FU. On the other hand, metabolites belonging to each metabolic pathway on the whole increased moderately after exposure to L-OHP plus 5-FU in drug-resistant cancer cells. Conclusions: Polyamine metabolism, glutathione metabolism, and nucleotide metabolism are important metabolic pathways relating to responsiveness to L-OHP plus 5-FU. The present CE-TOFMS metabolome analysis created a new finding on metabolomic response to L-OHP plus 5-FU in colorectal cancer cells with different chemosensitivities.
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 938. doi:1538-7445.AM2012-938