bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4497: NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials, shows significant antitumor activity in xenograft and primary tumor models
Authors: Maira Michel , Menezes Daniel , Pecchi Sabina , Shoemaker Kevin , Burger Matthew , Schnell christian , Fritsch christine , Brachmann Saskia , Nagel Tobi , Sellers William R. , Garcia-Echeverria Carlos , Wiesmann Marion , Voliva charles F. 
Published: February 2011

Abstract
A substantial number of epidemiological and experimental studies support an important role for PI3K in the biology of human cancer. The activation of PI3K, and its downstream effectors, has been clearly validated as an essential step for the initiation and maintenance of the tumorigenic phenotype. Parallel to the clinical development of our dual pan-PI3K/mTOR modulators (e.g., NVP-BEZ235), we continued our drug discovery activities to identify PI3K inhibitors with distinct biological and pharmacological profiles. Following a structure-based design strategy, we have identified a new clinical candidate, NVP-BKM120. This 2,6-dimorpholino pyrimidine derivative is a potent pan-PI3K (e.g., IC50= 35 nM, p110α) that does not significantly inhibit other protein or lipid kinases (e.g., IC50= 4.6 μM, mTOR). The compound exhibits potent antiproliferative activity against a broad panel of tumour cell lines by specifically blocking the biological function of PI3K signaling components (e.g. IC50 = 93 nM S473P-Akt in Rat1-p110α cells). The activity of this pan-PI3K inhibitor in cellular settings translates well in in vivo models of human cancer. NVP-BKM120 shows good oral bioavailability in preclinical species and demonstrated significant antitumor activity (growth inhibition or regression) at tolerated doses in xenografts of diverse cancer lineage in mice and rat models. Consistent with its mechanism of action, transient increases in plasma insulin and glucose levels are observed in these studies. Analyses of tumor tissues after acute dosing or at the end of efficacy studies showed a good correlation between compound exposure, PI3K pathway blockade (reduction in P-Akt levels) and antitumor activity. Dose dependent tumor growth delay or regression is also observed in primary tumor models, and, as demonstrated previously with our dual pan-PI3K/mTOR inhibitor NVP-BEZ235, in vivo synergistic activity is observed when NVP-BKM120 is combined with a MEK inhibitor in K-Ras human cancer models. NVP-BKM120 is currently undergoing Phase I/II human clinical trials for the treatment of solid tumors and hematological malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4497.
Abstract 4498: Biological characterization of NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials
Authors: Voliva charles F. , Pecchi Sabina , Burger Matthew , Nagel Tobi , Schnell Christian , Fritsch christine , Brachmann saskia , Menezes Daniel , Knapp Mark , Shoemaker Kevin , Wiesmann Marion , Huh kay , Zaror Isabel , Dorsch Marion , Sellers William R. , Garcia-Echeverria Carlos , Maira Michel 
Published: February 2011

Abstract
The PI3K/Akt/mTor signaling pathway plays an important role in controlling cell growth, proliferation and survival. Through various mechanisms, the pathway is frequently dysregulated in human cancers, suggesting the use of PI3K inhibitors as novel targeted anticancer therapeutic agents. To this end, substantial drug discovery efforts have been devoted both in pharmaceutical companies and in academia to identify and develop therapeutic agents able to specifically down regulate PI3K or other components of this pathway in tumors cells. Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional PI3K inhibitors from different chemical classes with more stringent selectivity profiles. The key to achieve these objectives was to pursue a structure-based design approach coupled with intensive pharmacological evaluation of selected compounds during the medicinal chemistry optimization process. Here we report on the biological characterization of the pan-PI3K pyrimidine-derived inhibitor NVP-BKM120. This compound inhibits all four Class I PI3K isoforms (IC50 values in the 35 to 248 nM range) with at least 50-fold selectivity (compared to p110α) towards protein kinases. The compound is also active against the most common somatic PI3Kα mutations (H1047R, E542K and E545K). NVP-BKM120 does not significantly inhibit the related Class III (Vps34) and Class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic and relevant tumor cell lines (e.g., IC50 for S473P-Akt in Rat1-p110α cells of 93 nM). This biological activity correlates with inhibition of various Akt downstream signaling pathway components, and with its anti-proliferative activity. Thus, the compound demonstrates significant, concentration dependent cell growth inhibition and induction of apoptosis in a variety of tumor cancer cells, particularly for those harboring p110α mutants and/or over-expressing erbB2. In addition, NVP-BKM120 demonstrates significant, dose dependent in vivo pharmacodynamic activity as measured by inhibition of p-Akt in relevant xenograft models. The pharmacological, biological and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is currently undergoing Phase 1/II clinical trials in cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4498.
Abstract 4503: Targeting sphingosine kinase 1 is promising novel strategy against breast cancer
Authors: Nagahashi Masayuki , Ramachandran Subramaniam , Rashid Omar , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki 
Published: February 2011

Abstract
INTRODUCTION: Sphingosine kinase 1 (SphK1) is one of the key enzymes that regulates levels of the potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P). S1P promotes cancer cell survival, proliferation and angiogenesis. Expression of SphK1 is up-regulated in breast cancer and is associated with cancer progression. The aim of this study is to explore the therapeutic implications of targeting SphK1 for breast cancer treatment. We have examined the role of SphK1 in breast cancer proliferation with an isozyme-specific pharmacological inhibitor of SphK1, SK1-I, which does not inhibit other sphingosine kinases, or by gene silencing of SphK1.
METHODS: 4T1-luc2 cells, murine ER negative breast cancer cells that overexpress luciferase were used. siRNA targeted to a specific sequence of mouse SphK1 mRNA (siSphK1) was used for down-regulation of the gene. Western blotting, qPCR, luciferase and colony formation assays were used to investigate SphK1 expression and responsiveness to SK1-I.
RESULTS: qPCR demonstrated that 4T1-luc2 cells overexpress mRNA of SphK1, SphK2, S1P receptors 1, 2, and 4. Down-regulation of SphK1 mRNA using siSphK1 in these cells was confirmed both by qPCR and Western blotting. siSphK1 suppressed the growth of 4T1 cells determined by luciferase assays which also revealed that SK1-I inhibited 4T1 cell proliferation in a dose-dependent manner. Of note, SK1-I inhibited 4T1 cell growth synergistically with the chemotherapeutic drug doxorubicin. Moreover, siSphK1 or SK1-I also reduced colony formation of these cells.
CONCLUSIONS: Our results support the notion that SphK1 is an important factor in breast cancer proliferation and suggest that SK1-I, an isozyme-specific inhibitor of SphK1, deserves consideration as a new therapeutic agent for this disease. SK1-I could be an important adjunct to anticancer therapy, allowing the use of reduced doses of a cytotoxic chemotherapeutic drug with the same antitumoral efficacy.
This work was supported by NIH grant 5K12HD055881 and Susan G. Komen for the Cure Career Catalyst Research Grant KG090510 to KT, NCI grant R01CA61774 to SS, and Sumitomo Life Social Welfare Services Foundation to MN.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4503.
Abstract 4504: Genetic determinants of AKT-dependence in epithelial ovarian cancer
Authors: Hanrahan Aphrothiti J. , Scarperi Stefano , Sakr Rita A. , Westfal Maggie L. , Godsell Jason , Janakiraman Manickam , Levine Douglas A. , She Qing-Bai , Rosen Neal , Solit David B. 
Published: February 2011

Abstract
Ovarian cancer is a genetically complex disease. Recent data compiled by The Cancer Genome Atlas Project highlights the heterogeneity within this disease, though distinct genetic signatures, such as PI3K pathway aberration, KRas alteration and Rb loss, are emerging that may condition treatment response. The high frequency of AKT activation in ovarian cancer, via PTEN mutation/deletion, PIK3CA/AKT mutation/amplification, RAS mutation, or mutation/amplification of upstream receptor tyrosine kinases (RTK), suggests that inhibitors of this pathway may be particularly effective treatments for this disease. We utilized a selective, allosteric inhibitor of AKT to determine the AKT-dependence of a panel of ovarian cancer cell lines. This AKT1/2 inhibitor (Merck AKTi-1/2) has been extensively tested against panels of kinases and PH-domain containing proteins and based upon these studies appears to be highly selective for AKT1 and AKT2. The drug effectively inhibited AKT activity as measured by a decrease in AKT phosphorylation at serine 473 in all cell lines. Of the 17 cell lines tested to date, 3 were hypersensitive (IC50 = 0.1um) to AKT inhibition, while 1 demonstrated intermediate sensitivity (IC50 = 2uM) and 13 were resistant (IC50 &gt;=5uM). Levels of AKT phosphorylation at serine 473 were inversely correlated with Merck AKTi-1/2 IC50 (p = 0.036) but AKT activation alone was insufficient to confer sensitivity. Activation of the MAPK pathway, via KRas/BRaf/MEK1 mutation or KRas amplification, and Rb loss were predictive of resistance to AKT inhibition. In sensitive cell lines, AKT inhibition resulted in hypophosphorylation of RB and accumulation of cells in G1. Significant induction of apoptosis was not observed even in PTEN null, AKT2 amplified and PIK3CA mutant models. Treatment of a PTEN-mutant xenograft model of ovarian cancer with the AKTi-1/2 was also effective in inhibiting AKT phosphorylation and downstream signaling and resulted in a cytostatic tumor response. Ongoing studies are focused on the identification of rational combination strategies that result in induction of apoptosis in the cell lines in which the AKTi-1/2 alone induces growth arrest. The long-term goal will be to identify genetic predictors of AKT-dependence and AKT-inhibitor resistance to guide patient selection for future clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4504.
Abstract 4505: Akt1 is a potent molecular target for treatment of oral squamous cell carcinoma
Authors: Goda Hiroyuki , Nakashiro Koh-ichi , Hamakawa Hiroyuki 
Published: February 2011

Abstract
Oral cancer has a severe impact on the quality of life (QOL) of patients. Treatment for the advanced cases is given priority for reducing deaths due to oral cancer and keeping QOL after the treatment. Several reports have demonstrated that inactivation of a single critical oncogene in cancer cells can induce the terminal differentiation or apoptosis. In this study, we have attempted to identify a critical oncogene for oral cancer progression. Using Applied Biosystems Human Genome Survey Arrays, we determined the gene expression profiles in 10 oral squamous cell carcinoma (OSCC) primary tissues and 10 human OSCC cell lines. This array contains 32,878 60-mer oligonucleotides probes representing a set of 29,098 individual human genes. We identified Akt1 mRNA that was commonly expressed in all OSCC tissues and cultured cells but not in non-neoplastic tissues and cells. Subsequently, immunohistochemical examination and Western blot analysis showed the overexpression of Akt1 protein in 59 of 63 OSCC primary tissues (94%) but not in oral normal epithelium. Overexpression of Akt1 and phosphorylated Akt1 proteins was also detected in all human OSCC cultured cells by sandwich ELISA. Akt is frequently activated in many types of human cancer, and has been implicated in tumorigenesis and malignancy. To clarify the oncogenic function of Akt1 in human OSCC cells, we used RNA interfering (RNAi) method. We designed and synthesized 8 small interfering RNAs for specific Akt1 (siAkt1), and then tested their RNAi effects. Akt in mammals comprises three highly homologous members known as Akt1, Akt2 and Akt3. Transfection with siAkt1 at the concentration of 1 nM markedly suppressed the expression of Akt1 protein but not Akt2 and Akt3, and significantly reduced the growth rate of human OSCC cells on the plastic surface and in collagen gels. Furthermore, atelocollagen-mediated systemic siAkt1 administration markedly inhibited the growth of human OSCC tumors which had been subcutaneously xenografted in athymic nude mice without interferon responses. These results suggest that Akt1 functions as a critical oncogene in human OSCC cells and targeting Akt1 appears a novel approach for treatment with oral cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4505.
Abstract 4509: Epigallocatechin gallate suppresses tumorigenesis of lung cancer cells by targeting Ras-GTPase-activating protein SH3-domain binding protein 1
Authors: Shim Jung-Hyun , Su Zheng-Yuan , Chae Jung-II , Kim Dong-Joon , Zhu Feng , Ma Wei-Ya , Bode Ann M. , Yang Chung S. , Cho Nam-Pyo , Dong Zigang 
Published: February 2011

Abstract
(−)-Epigallocatechin gallate (EGCG) is one of the major green tea catechins that is suggested to have a role as a preventive agent in cancer, obesity, diabetes, and cardiovascular disease. Here we identified Ras-GTPase-activating protein SH3-domain binding protein 1 (G3BP1) as an important and novel molecular target of EGCG in lung cancer. EGCG interacted with the G3BP1 with high binding affinity (Kd = 0.4 μmol/liter). We also showed that EGCG suppressed anchorage-independent growth of H1299 and CL13 lung cancer cells, which contain an abundance of the G3BP1 protein. EGCG was much less effective in suppressing anchorage-independent growth of H460 lung cancer cells in which G3BP1 levels are low. Knockdown shG3BP1-transfected H1299 cells exhibited substantially decreased proliferation and anchorage-independent growth. shG3BP1-H1299 cells were resistant to the inhibitory effect of EGCG on growth and colony formation compared to shMock-transfected H1299 cells. EGCG interfered with the interaction between G3BP1 and Ras-GTPase-activating protein (Ras-GAP) and further suppressed the activation of Ras. Additional results revealed that EGCG effectively attenuated G3BP1-downstream signaling, including extracellular signaling-regulated kinases, and MAPK kinase in wildtype H1299 and shMock-H1299 cells, but had little effect on H460 or shG3BP1- H1299 cells. Overall, these results strongly indicate that EGCG suppresses lung tumorigenesis through its binding with G3BP1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4509.
Abstract 4517: HDAC inhibitors suppress p53 expression through transcriptional repression: Implication for therapy against metastatic breast cancer
Authors: Zhao Lisa Y. , Li Qiang , Seto Edward , Liao Daiqing 
Published: February 2011

Abstract
Cancer specific mutations of the p53 tumor suppressor gene are the most prevalent genetic lesions that underpin breast cancer pathogenesis and progression. In most cases, mutations result in a single amino acid substitution in the DNA-binding domain of p53. Such missense mutant forms of p53 accumulate at high levels in tumor cells. Recent advances demonstrated that missense p53 mutants have a critical role in driving cancer metastasis. Thus elimination of mutant p53 can potentially prevent metastatic progression of breast cancer. Inhibitors of histone deacetylases (HDACi) have proven anticancer effects and vorinostat, an FDA approved HDACi, has been in clinical use for treating certain malignancies. HDACi shapes epigenetic landscapes by restoring histone acetylation that is often suppressed in breast and other cancer types. One consequence of the restoration of histone acetylation is reactivation of tumor suppressors and other genes. Other effects of HDACi include modulation of posttranslational acetylation of non-histone proteins, which can influence their biochemical functions, resulting in a net effect of enhanced cell cycle arrest and apoptosis. Interestingly, HDACi profoundly suppresses the expression levels of p53. We found that this suppression occurs irrespectively of the mutational status of p53, but surprisingly only in certain types of cancer cells such as breast cancer. We further showed that the expression of exogenous p53 under a heterologous promoter was not affected by HDACi. These results suggest that HDACi might downregulate p53 through gene repression. To further test this idea, we assessed the effects of HDACi treatment and ectopic expression of classical HDACs (Classes I, II and IV) on luciferase reporter gene under the control of the p53 promoter. Among the 11 classical HDACs, ectopic expression of HDAC7 and HDAC10 seem to upregulate the reporter gene. We are currently investigating how these HDACs interact with the p53 promoter and what transcription factors and corepressors are involved in regulating p53 expression. Additionally, we are studying roles of depleting mutant forms of p53 by HDACi in suppressing migration, invasion and metastasis of breast cancer cells and assessing the efficacy of HDACi in conjunction with p53 gene therapy for treating breast cancer in a mouse model. (This work was supported by Bankhead-Coley Cancer Research Program of the Florida Department of Health, Stop! Children's Cancer, Inc. and the NIH.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4517.
Abstract 452: The hypoxic response is differentially regulated in small cell lung carcinoma (SCLC) cells as compared to non-SCLC cells
Authors: Persson Matilda , Johansson Martin , Monsef Nastaran , Planck-Sturegård Maria , Påhlman Sven , Pettersson Helen M. 
Published: February 2011

Abstract
Here we study the adaptive capacity of small cell lung carcinoma (SCLC) cells to hypoxia and the importance of activation of hypoxia-inducible factor (HIF) transcription factors in these cells. SCLC is an extremely aggressive tumor form and the 5-year survival rate for these patients is only approximately 9-15%. Regions of hypoxia (∼1% oxygen) often appear in solid tumors and are associated with aggressive tumor behaviour and poor outcome in several tumor forms. Tumor cells adapt to a hypoxic environment by changing the transcription of genes involved in a variety of processes, like angiogenesis, cell survival, and metabolism. This adaptive response is primarily regulated by the transcription factors HIF-1α and HIF-2α, which become stable at low oxygen levels. Studies using among others neuroblastoma, breast carcinoma and lung adenocarcinoma cells have demonstrated that HIF-1α primarily mediates the acute hypoxic response, whereas HIF-2α dominates during the more chronic phase of hypoxia.
We investigated cell survival in a panel of SCLC cell lines cultured at different oxygen pressures. In these cells we also studied expression levels of well known hypoxia-driven genes using quantitative real-time PCR. Quantitative real-time PCR, Western blot and immunohistochemistry were used to characterise the expression of HIF transcription factors in SCLC cells as well as in SCLC specimens. In all experiments a panel of non-SCLC cells and neuroblastoma cells were included for comparison.
Since tumor hypoxia correlates with poor prognosis it is important to elucidate how tumor cells adapt in response to hypoxia. Our results show that SCLC cells survive well at hypoxia, although the proliferation is somewhat reduced with lower oxygen pressure. Even though the SCLC cells have a high adaptive capacity, only a moderate up-regulation was observed for the investigated hypoxia-regulated genes at 1% oxygen. In addition, the expression patterns of HIF-1α and HIF-2α differ in SCLC as compared to non-SCLC, indicating that a “typical” adaptive response to hypoxia does not occur in SCLC cells. Based on these results a gene expression profile of hypoxic SCLC cells using microarray analyses are performed to further characterise the hypoxic adaptive response.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 452.
Abstract 4526: Suppression of Alox5 gene is involved in DZNep induced apoptosis in multiple myeloma cells
Authors: Xie Zhigang , Bi Chonglei , Cheong Lip Lee , Chng Wee Joo 
Published: February 2011

Abstract
The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. It was found that DZNep effectively depletes EZH2 levels and inhibits trimethylation of lysine 27 on histone H3. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines(8226, H929, KMS11, KMS12BM, KMS18, MM1S, OPM-2 and U266). We then attempted to identify molecular mechanisms of sensitivity to DZNep. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by qRT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Furthermore, down-regulation of ALOX5 by RNA interference can also induce apoptosis in H929. Since it was reported ALOX5 can regulate IL-6 mRNA level, we also determined IL-6 and IL-6R expression by qRT-PCR. As expected, IL-6 and IL-6R mRNA levels were decreased (&gt;2-fold) in H929 upon DZNep treatment. May-Grunwald-Giemsa staining demonstrated that treatment with DZNep also dose dependently induced nuclear and cytoplasmic morphologic features of apoptosis in H929. These findings in vitro warrants further investigation of DZNep for the treatment of MM in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4526.