bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 659: Overexpression of TPX2 accelerates cell cycle progression in melanoma and is an indicator of response to Aurora A kinase inhibitors
Authors: Li Bin , Palma M. Dalla , Nathanson K. L. , Xu G. , Smalley K. , Herlyn M. 
Published: February 2011

Abstract
There is a tremendous need to identify more effective treatments for metastatic melanoma. In order to detect genetic changes in melanoma that might facilitate the development of novel therapies, we performed aCGH in melanoma cell lines and tumors and identified that Targeting Protein for Xklp2 (TPX2) was the most commonly amplified gene on 20q11.21, a region of frequent gain. Gene expression profiling studies also demonstrated overexpression of TPX2, suggesting a previously unknown role in the development of melanoma. TPX2 is a microtubule-associated protein that regulates bipolar spindle assembly and centrosome replication; the TPX2 - Aurora A interaction is essential for accurate segregation of chromosome and mitosis progression. We evaluated a potential role for TPX2 overexpression in melanoma using TPX2 overexpressing melanoma cell lines as a model. TPX2 overexpressing cell lines display accelerated cell cycle progression, increased CDK1/CDK2 activity, cyclin A/B1 levels, and constitutive activation and overexpression of Aurora A. We depleted TPX2 using shRNA to further dissect its role in melanoma. In unsynchronized cells, TPX2 depletion causes prolonged mitotic arrest accompanied by persistent activation of the spindle-assembly checkpoint (SAC) and caspase-3, and subsequent caspase-dependent cell death. In contrast, with G1/S synchronization, TPX2 depletion decreases S phase entry and delays S-G2-M phase transition followed by marked cell death. Accordingly, TPX2 depletion was associated with decreased CDK1 activity but not CDK2 activity, and activation of caspase and low activation of the SAC. Our data demonstrate that TPX2 overexpression is required for increased CDK1-cyclinB1 activity, thus accelerating cell cycle progression. Accordingly, TPX2-overexpressing melanoma cell lines are dependent on TPX2 for proliferation, whereas non-overexpressing cell lines and melanocytes are not. Additionally, TPX2-overexpressing cell lines are 3-10 time more sensitive to an Aurora A kinase inhibitor (VX680) than non-overexpressing cell line, suggesting that TPX2-activating Aurora A kinase could become a novel therapeutic target for treatment of melanoma with highly expressed TPX2, Finally, TPX2-IHC staining demonstrated that a significantly increased expression of TPX2 in primary and metastatic melanoma as compared to begin nevi, suggesting it is a marker of progression. Thus, we have identified TPX2 as a novel gene upregulated in melanoma. Overexpression of TPX2 may be a marker of tumors sensitive to Aurora A inhibitors allowing patient stratification for optimal therapeutic selection.
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 659.
Abstract 662: Molecular characterisation of ERG, ETV-1 and PTEN- gene loci identifies patients at low and high risk of death from prostate cancer
Authors: Reid Alison , Attard Gerhardt , Ambroisine Laurence , Fisher Gabrielle , Kovacs Gyula , Brewer Daniel , Clark Jeremy , Flohr Penny , Edwards Sandra , Berney Daniel M. , Foster Chris S. , Fletcher Anne , Gerald William L. , Moller Henrik , Reuter Victor E. , Scardino Peter T. , Cuzick Jack , De Bono Johann S. , Cooper Colin S. 
Published: February 2011

Abstract
Background: The discovery of ERG/ETV-1-gene rearrangements and PTEN-gene loss suggests their use in a mechanism-based prognostic classification of prostate cancer (PCa).
Purpose: To evaluate the potential clinical significance and natural history of different disease categories by combining ERG/ETV-1-gene rearrangements and PTEN-gene loss status.
Methods: We utilized fluorescence in situ hybridization (FISH) assays to detect PTEN-gene loss and ERG/ETV-1-gene rearrangements in 308 conservatively managed PCa patients with survival outcome data.
Results: ERG/ETV-1-gene rearrangements alone and PTEN-gene loss alone each failed to show a link to survival in multivariate analyses. However, there was a strong interaction between ERG/ETV-1-gene rearrangements and PTEN-gene loss (p&lt;0.001). The largest subgroup of patients (54%), lacking both PTEN-gene loss and ERG/ETV-1-gene rearrangements comprised a ‘good prognosis’ population exhibiting favourable cancer-specific survival (85.5% alive at 11 years). The presence of PTEN-gene loss in the absence of ERG/ETV-1-gene rearrangements identified a patient population (6%) with poorer cancer-specific survival that was highly significant (HR = 4.87, p&lt;0.001 in multivariate analysis, 13.7% survival at 11 years) when compared to the ‘good prognosis’ group. ERG/ETV-1-gene rearrangement and PTEN-gene loss status should now prospectively be incorporated into a predictive model to establish whether predictive performance is improved.
Conclusions: Our data suggest that FISH studies of PTEN-gene loss and ERG/ETV-1-gene rearrangements could be pursued for patient stratification, selection and hypothesis-generating sub-group analyses in future PCa clinical trials and potentially in patient management.
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 662.
Abstract 663: The comparative efficacy of the PARP inhibitors AG14361, ABT888 and AZD2281 in the treatment of triple negative and BRCA1 breast cancer
Authors: Velikodvorskaya Tatiana , Fatima Naheed , Fountain Renee Quick , De Soto Joseph A. 
Published: February 2011

Abstract
Introduction: Most preclinical studies have used “in vitro” animal cell lines, “in vivo” allografts and/or gene knockdowns to predict the clinical efficacy of PARP1 and PARP1 & 2 inhibitors in the treatment of human breast cancer. It has been shown however that “in vitro” experiments with human breast cancer cell lines are more useful in predicting the clinical performance of cancer drugs than these other methods. In this study, the PARP1 inhibitor AG14361 and the PARP1 & 2 inhibitors AZD2281 and ABT888 were tested against a panel of 25 human breast cancer cell lines. Methods: The MTT assay was used to determine the IC50 inhibitory effect of the PARP inhibitors against the human breast cancer cell lines over a 72 hour period with each experiment being replicated at least 10 times. The MTT assay was validated for each cell line using direct counting via hemacytometer & trypan blue staining. Human to mouse xenografts were then challenged by PARP inhibitors. The IC50 results were then correlated with the PARP activity of each cell line. Results: The PARP1 inhibitor AG14361 was 5 and 8 fold more effective in inhibiting human breast cancer growth than ABT888 and AZD2281 respectively. The average IC50 values for AG14361, ABT888 and AZD2281 against BRCA1-/- human breast cancer cell lines were 20, 120, and 190 micromolar respectively. The average IC50 values for non-BRCA1 triple negative breast cancer were 24, 110 and 165 micromolar respectively. ANOVA analysis sustained the null hypothesis between BRCA1-/- breast cancer and non-BRCA1 triple negative breast cancer. Xenograft studies mirrored the “in vitro results”. These IC50 values are significantly higher than previously published preclinical data that utilized BRCA1 -/- animal cell lines and human BRCA1 gene knockdowns. This suggests that BRCA1 animal cell lines are more sensitive to PARP1 inhibitors and that human BRCA1 -/- gene knockdowns may be fundamentally different from naturally derived BRCA1-/- breast cancer cell lines. Conclusion: The PARP1 inhibitor was more effective than the PARP1 & 2 inhibitors in inhibiting breast cancer growth. Non-BRCA1 triple negative breast cancers were at least as sensitive to PARP inhibition as BRCA1 breast cancers.
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 663.
Abstract 668: Synergistic Bcr/Abl degradation effect is triggered by MB12066 with NQO2 inhibitors in chronic myelogenous leukemia
Authors: Kwon Hyun-Joo , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Shin So-Yeon , Jing Kaipeng , Song Kyoung-Sub , Park Jong-il , Yoon Wan-Hee , Lim Kyu , Hwang Byung-Doo , Kweon Gi-Ryang 
Published: February 2011

Abstract
Mutations of Bcr-Abl protein reduce the sensitivity of imatinib treatment for chronic myelogenous leukemia (CML). The resistance against imatinib treatment to CML patients needs to develop another target drug of Bcr-Abl through a novel mechanism. In present study, we investigated the effect of MB12066, small molecule related to quinone derivatives, on k562 cells (CML cell line) and the expression level of Bcr-Abl protein down regulated by MB12066. When k562cells were treated with MB12066, dose-and time-dependent Bcr-Abl degradation was detected, followed by decreasing of procaspase-3 and cleavage of PARP, which represent apoptotic stimuli. Quinone oxidoreductases [NAD(P)H: quinone Oxidoreductase 1(NQO1) and NRH: quinone oxidoreductase2 (NQO2)] are the major enzymes involved in the bioreduction of quinone-containing drugs. We found that MB12066 was a substrate of both NQO1 and NQO2 by examining recycling assay. For the functional study of NQO1 and NQO2 in Bcr-Abl degradation, we used inhibitors for each enzymes, dicumarol, quercetin and imatinib respectively. Interestingly, Bcr-Abl degradation was inhibited by dicumarol, but it was accelerated by quercetin and imatinib. Collectively, these results demonstrate that MB12066 destruct the Bcr-Abl through the NQO1 and NQO2 activity and it may show the possibility that combination therapy with NQO2 inhibitor may be beneficial for treating CML patients.
* H.J. Kwon and J.Y. Heo contributed equally to this work.
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 668.
Abstract 67: Selective cytotoxic targeting of von Hippel-Lindau-deficient renal cell carcinoma cells
Authors: Lai Edwin W. , Chan Denise A. , Hay Michael P. , Giaccia Amato J. 
Published: February 2011

Abstract
Loss of the von Hippel-Lindau (VHL) tumor suppressor gene, an essential alteration in the development of renal cancer, can be targeted through a synthetic lethal manner. In our screen we identified a compound, STF-31536, which is selectively cytotoxic toward VHL-deficient renal cancer cells in a HIF-dependent manner. This compound did not induce apoptosis and inhibits glucose transport. These findings are significant since we have previously shown another compound STF-62247 was cytotoxic toward VHL-deficient cells and induced autophagy in a HIF-independent manner. We have also shown that STF-31536 induces cell death in vitro and in vivo, however the mechanism and target of this compound is currently unknown. In order to identify the target of STF-31536, we have coupled analogs of STF-31536 to an affinity resin. Activity of these analogs was confirmed by cytotoxicity assays. Selected affinity chromatography reagents coupled to resin were used for binding assays to determine direct drug-target interactions. The potential targets were purified and identified by gel electrophoresis after collecting fractions from the column. Renal cell carcinoma cells deficient in VHL are characterized by elevated expression of VEGF and glucose transporter 1 (Glut-1). Immunoblots for Glut-1 transporter in protein fractions eluted from the column show binding of STF-31536 to Glut-1. Therefore, we show loss of the von Hippel-Lindau (VHL) tumor suppressor gene can be targeted by this small molecule through a synthetic lethal manner by disrupting glucose transport.
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 67.
Abstract 670: Aurora kinase inhibitor VE 465 synergistically enhances cytotoxicity of carboplatin in ovarian cancer cells through induction of apoptosis and downregulation of histone 3
Authors: Fu Siqing , Li Yangfan , Shen De-yu , Zheng Hong , Kavanagh John J. , Bast Rebert C. , Sood Anil K. , Hu Wei 
Published: February 2011

Abstract
Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis and play a role in tumorigenesis and progression in human tumors, including ovarian cancer. Aurora A and Aurora B are frequently overexpressed in high-grade and low-grade ovarian cancers. Targeting aurora kinases has great potential for improving the efficacy of treatment of ovarian cancer. In this study, we investigated whether the Aurora kinase inhibitor VE 465 will enhance the antitumor activity of carboplatin in human ovarian cancer cells. Cell viability was tested using the MTT assay in seven established human epithelial ovarian cancer cell lines with varying p53 status. We found that VE 465 and carboplatin had a synergistic effect (defined by the combination index) in both platinum-sensitive and -resistant ovarian cancers and that the growth-inhibitory effect was accompanied by reduction in expression of histone 3 and an increase in apoptosis. Aurora kinase inhibition in combination with carboplatin chemotherapy is an attractive combination for further development.
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 670.
Abstract 671: Triggering of CD99 induces apoptosis of Ewing's sarcoma cells through activation of p53 functions
Authors: Guerzoni Clara , Terracciano Mario , Manara Maria Cristina , Picci Piero , Scotlandi Katia 
Published: February 2011

Abstract
CD99 is a transmembrane 32 KDa protein, whose expression is constantly associated to Ewing's Sarcomas Family of Tumors (EWSFT), a class of child bone tumors with particular poor prognosis. The monoclonal antibody 0662, raised against CD99, triggers massive and rapid cell death of Ewing Sarcoma's cells in vitro and in vivo, through a non-canonical, non caspase-dependent apoptosis. To elucidate the underlying molecular mechanism, we evaluated by phosphor- and micro-arrays specific pathways triggered by CD99 engagement in 6647 Ewing Sarcoma cell line. Despite its role in physiological and cancer scenery has not been yet fully elucidated, CD99 appears to be sufficient to modulate many important processes involved in: I) adhesion; II) migration and metastasis; III) cell-cycle regulation and cell signaling; IV) apoptosis and death receptor signaling. These data are consistent with our previous analysis of 0662 effects in vivo and in vitro: anti-CD99 monoclonal antibody triggers, indeed, homotypic aggregation and a rapid death response of ES cells, thus resulting in growth inhibition and reduced metastatic/colony-forming potential. As pointed out by array studies and subsequent western blotting validations, upon 0662 treatment, the oncosuppressor protein p53 appears to be readily activated by phosphorilation on serine 15. We therefore evaluated p53 and MDM2 activation and sub-cellular localization upon CD99 engagement both in p53 WT (LAP35 and WE68) or mutated (6647 and TC-71) cell lines: WT (LAP35 and WE68) or mis-sense point mutated p53 (6647: S241F) cell lines display a higher sensitivity to 0662 if compared to p53 truncated cell lines (TC71). Consistently we demonstrated that whereas 0662 readily induces p53 canonical targets (p21, BAX) in p53 expressing cell lines, no increase in p21 levels is detectable in TC71 p53TRUNC cells. We also demonstrated that, upon 0662 treatment, decreased or delocalized MDM2 levels may account both for p53 activation and sustained IGF-IR signaling, since both p53 and IGF1-Rß are targeted by the ubiquitine ligase for degradation. Since most Ewing Sarcoma patients display unmodified p53 status, its functional inactivation -e.g. through MDM2/MDM4 overexpression- may account for gained tumor aggressiveness, or progressed disease. Nonetheless, involvement of TP53 might give reason for higher effectiveness we reported against local tumors and metastases in the combined employment of CD99 monoclonal antibodies with Doxorubicin and may support 0662 mAb treatment in association with other drugs targeting e.g. the p53 regulators MDM2-MDM4. (grants from EU project Eurobonet and Italian Association for Cancer Research)
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 671.
Abstract 677: Targeting the survivin splice variant 2β in taxane-resistant ovarian cancer
Authors: Vivas Pablo E. , Rodríguez-Aguayo Cristian , Han Hee-Dong , Shahzad Mian M. , Sood Anil K. , Lopez-Berestein Gabriel 
Published: February 2011

Abstract
Survivin, a protein highly expressed in human cancers is involved in both control of cell cycle progression and inhibition of apoptosis. Transcription of the survivin gene locus (BIRC-5) yields at least 5 alternative splice variants that have been designed survivn-WT, survivin-ΔEx3, survivin-2β, surivivn-3β, and survivin 2α. It has been shown that the survivin splice variants have different expression levels and subcellular localization patterns that could be associated with unique functional properties. Whereas the effects of survivin on apoptosis and mitosis have been extensively studied and explored therapeutically, the role of specific survivin splice variants in ovarian cancer has not been investigated. Our compelling studies indicate that, compared with their taxane-sensitive counterparts, taxane-resistant ovarian cancer cells express higher survivin mRNA (particularly the WT, ΔEx3 and 2β isoforms) levels. Studies have shown that survivin-2β has proapoptotic properties: whereas, forced expression of survivin-2β sensitized cells to taxane-induced apoptosis, small-interference RNA (siRNA)-based silencing of survivin-2β protected cells from cells from apoptotic cell death. We have observed opposite results: siRNA-based silencing of survivin-2β induced cell growth arrest and apoptosis of taxane-resistant ovarian cancer cells. Furthermore, liposomes-encapsulated siRNA targeting survivin-2β inhibited tumor growth in orthotopic murine models of ovarian cancer. The anti-tumor effect was further increased by combination with docetaxel. Finally, we found a significant association of survivin-2β expression with progression free survival in the 117 epithelial ovarian cancers obtained at primary debulking therapy. Further studies are necessary to clarify the role of survivin-2β in ovarian cancer. The key finding from our study is that survive-2β is present in a substantial proportion of ovarian cancers, and is predictive of decreased progression-free survival (PFS) of ovarian cancer patients. These studies also show the feasibility of survivin-2β-targeting siRNA liposomal as a clinically applicable therapeutic modality for taxane-resistant ovarian 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 677.
Abstract 680: Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL via up-regulating DR5 and eradicating MCL-1
Authors: Wang Wenge , Katz Sharyn I. , Abdulghani Junaid , Dicker David , El-Deiry Wafik S. 
Published: February 2011

Abstract
Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent tumor cell death. Structurally, quinacrine bears similar characteristics with DNA-intercalating agents. Indeed, quinacrine competes with Propidium Iodide and shows a high binding affinity to DNA. Interestingly, quinacrine is a fluorescent dye that can be visualized under a laser microscope. In live cells, quinacrine is mainly clustered in the cytoplasm with a faint fluorescent signal in the nucleus. If the cells are fixed with methanol, quinacrine accumulates predominantly in the nucleus. Treatment by quinacrine alone at concentrations of 10-20 μM for 1-2 days can not kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment of TRAIL significantly. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death in 3-4 hr. Western blotting shows the level of DR5, a pro-apoptotic death receptor of TRAIL, is increased while MCL-1, a member of the Bcl-2 family, is decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism of quinacrine sensitization of hepatocellular carcinoma cells and the potential for clinical application are being further explored.
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 680.