bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2427: Molecular and pharmacokinetic studies of dicycloplatin, a new platinum analogue, suggest it is a promising chemotherapeutic agent.
Authors: Yang Xuqing , Song Qinhua , Mueller Michael D. , Yu Jing Jie 
Published: August 2014

Abstract
Dicycloplatin (DCP), a new platinum compound recently approved by the Chinese FDA, is a platinum-based supramolecule. The host-part (carboplatin) and a guest-part (cyclobutane-1,1-dicarboxylic acid or CBDC) are linked by hydrogen bonds. DCP has a stable chemical structure and good water solubility. Pharmacokinetic studies show that the prototype DCP concentration 2-h after administration is still high (17.1 μg/ml), after 26.9 μg/ml at 0.5 hour. In comparison, 5.01 μg/ml of carboplatin prototype is obtained 2-h after administration. Preclinical in vitro and in vivo studies and a phase I clinical trial demonstrated that DCP possesses significant antitumor activity, with fewer adverse effects than carboplatin. Molecular investigation of DCP-treated ovarian cancer A2780 cells showed activation of several kinases, including Chk2, p53, BRCA1 and other downstream factors. The increase in activated p-Chk2, p-p53 and p-BRCA1 after 1-h DCP exposure at IC50 dose occurred in a time-dependent manner. Quantitative analysis of phosphorylated Chk2 and BRCA1 expression revealed that the amount of dicycloplatin-induced phosphorylation of the two factors doubled at 48-h and tripled for p53 at 24-h, compared to controls. We observed that the DCP-induced activation profile and cisplatin-activated mechanisms are similar. We conclude that dicycloplatin is a promising platinum chemotherapeutic compound.
Citation Format: Xuqing Yang, Qinhua Song, Michael D. Mueller, Jing Jie Yu. Molecular and pharmacokinetic studies of dicycloplatin, a new platinum analogue, suggest it is a promising chemotherapeutic agent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2427. doi:10.1158/1538-7445.AM2013-2427
Abstract 2428: Molecular determinants of dasatinib response in uterine carcinoma.
Authors: Huang Jie , Hu Wei , Bottsford-Miller Justin , Liu Tao , Zand Behrouz , Coleman Robert L. , Sood Anil K. 
Published: August 2014

Abstract
Despite the many attractive features of EphA2 as a therapeutic target in cancer, approaches to block it have lagged behind. Dasatinib is a multi-kinase inhibitor and may be useful for targeting EphA2. However, reliable predictive markers of response are needed. Additionally, the underlying mechanism deciding whether responsive or resistant to dasatinib and biological impact of EphA2 function in the context of EphA2 targeted therapy in cancer are not known.
We undertook a large number of studies to fully characterize the effects of dasatinib using in vitro (cell viability, RPPAs, gene expression, and confocal imaging) and in vivo uterine cancer models. Molecular markers for response prediction were identified by using RPPA and immunohistochemistry.
In vitro, the effects of dasatinib treatment varied among the different endometrial cancer cell lines tested, (IC50 values ranged from 30 nM to 17,792 nM), which was associated with varying levels of EphA2 and tyrosine phosphorylation and serine897 phosphorylation of EphA2, and with varying status of caveolin-1 (CAV-1), PTEN and RAS/MAPK . A set of markers that are essential for dasatinib response was identified, including EphA2, CAV-1, pAKTs473, BRAF/CRAF (MAPK pathway) and ppS6s240/244 (mTOR pathway). A novel mechanism for response was identified by which dasatinib can drive the BRAF and EphA2 to CAV-1 at the plasma membrane, resulting in breaking off the BRAF/CRAF heterodimer induced by dasatinib, and blocking compensatory activation of the MAPK pathway. In vivo data using orthotopic mouse models of uterine carcinoma were entirely concordant with our in vitro findings.
The efficacy of dasatinib therapy in uterine carcinoma depends on EphA2 phosphorylation at its S897 site and high CAV-1 levels are predictive of response to dasatinib. These findings may have clinical implications for ongoing dasatinib-based clinical trials.
Citation Format: Jie Huang, Wei Hu, Justin Bottsford-Miller, Tao Liu, Behrouz Zand, Robert L. Coleman, Anil K. Sood. Molecular determinants of dasatinib response in uterine carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2428. doi:10.1158/1538-7445.AM2013-2428
Abstract 243: ABCB5 is functionally required for melanoma growth.
Authors: Wilson Brian J. , Saab Karim R. , Schatton Tobias , Ma Jie , Murphy George F. , Gasser Martin , Waaga-Gasser Ana Maria , Frank Natasha Y. , Frank Markus H. 
Published: August 2014

Abstract
Melanoma remains a disease with relatively few beneficial treatments currently available, for late-stage patients. The ATP-binding cassette (ABC) transporter ABCB5 has recently been identified as a cell-surface marker for malignant melanoma initiating cells (MMICs; Schatton et al, Nature 2008), opening a new paradigm for investigation of this aggressive cancer. We have previously demonstrated that these ABCB5+ MMICs can evade the host immune system, and also express VEGFR-1, required for efficient tumor formation. However, the possibility that ABCB5 itself plays a functional role in melanoma tumorigenic growth and progression has not been investigated, until now.
To test whether ABCB5 plays a functional role in melanoma growth, or is solely a marker of the cancer stem-cell subset, we generated ABCB5-shRNA knockdown (ABCB5-KD) cell populations in melanoma model cell-lines. To distinguish a bona fide role in intrinsic tumorigenesis from immuno-modulatory effects we subcutaneously injected these cells, versus control cells, into highly immunocompromised NOD/SCID Il2rγ-/- mice and followed tumor progression. We observed a marked and significant downregulation in the ability of ABCB5-KD cells to maintain efficient tumor growth, implying a direct role for ABCB5 in melanoma progression.
To obtain mechanistic data to explain this phenotype we generated RNA from ABCB5-KD cells versus controls, and performed microarray analysis of global genomic changes in transcript levels of these cells. We then validated potential “ABCB5-pathway” genes, which also change in the reciprocal manner in an ABCB5 overexpression system that we have developed.
Our study links ABCB5 to a direct role in melanoma carcinogenesis, identifies genes and pathways of interest, and uncovers ABCB5 as a putative master-regulator of melanoma.
Citation Format: Brian J. Wilson, Karim R. Saab, Tobias Schatton, Jie Ma, George F. Murphy, Martin Gasser, Ana Maria Waaga-Gasser, Natasha Y. Frank, Markus H. Frank. ABCB5 is functionally required for melanoma growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 243. doi:10.1158/1538-7445.AM2013-243
Abstract 2431: IGF1R/IR axis is a novel treatment target in ER-negative breast cancer.
Authors: Kai Kazuharu , Kondo Kimie , Ueno Naoto 
Published: August 2014

Abstract
Background/Hypothesis: Insulin growth factor-1 receptor (IGF1R) and insulin receptor (IR) are overexpressed in a subpopulation of breast cancers (BCs). However, the clinical significance of IGF1R/IR is not fully understood, especially in ER-negative BC, which is aggressive and lacks molecularly targeted therapies. The objective of this study was to rationally develop treatment strategies for ER-negative BC with IGF1R/IR inhibitor. Method: We treated 6 ER-negative BC cell lines that express IGF1R/IR and have p53 mutations, a genetic hallmark of ER-negative BC, with KW2450, a dual tyrosine-kinase inhibitor against IGFR/IR. Western blot analysis was performed to confirm IGF1R, IR, or phosphor-IGFR/IR expression. To evaluate growth-inhibition effect, Cell-titer-blue assay and xenograft model were performed in vitro and in vivo. For apoptosis assay, Annexin V staining and western blotting of cleaved-caspase 8 and -PARP were performed. The amounts of intracellular reactive oxygen species (ROS) were measured as a candidate marker in predicting the efficacy of KW2450. Result: The values of IC50 are shown in the table. In cell-cycle analysis, all 6 cell lines treated with KW2450 accumulated in the G2/M phase and underwent cell death (sub-G1) in a dose-dependent manner. MCF7 and ZR15.1 cells, which have wild-type p53, had the same response to KW2450, which suggests that this phenotype is independent of p53 function. We attributed this cell death to apoptosis following apoptosis assay using one of the most sensitive cell lines, MDA-MB-468. We found that ROS accumulation correlated with a susceptibility to cell death at the dose of 0.5 μm, as shown below. In the xenograft model, we used SUM149 cells, a widely-used model, and saw a significant tumor growth-inhibitory effect at 20 or 40 mg/kg/day compared with vehicle control. Conclusion: ER-negative BCs that express IGF1R or IR are sensitive to KW2450. ROS accumulation with KW2450 treatment may be a good predictive marker of patient benefit from KW2450 treatment.
Molecular/genetic profiles and IC50s to KW-2450 in breast cancer cell lines, TN; triple-negative Cell line SUM149 MDA-MB-231 MDA-MB-468 BT-549 HCC70 SUM190 Subtype TN TN TN TN TN HER2+ p53 genotype M237I R280K R273H R249S R248Q Q317stop IC50 (μM) 0.23 0.35 0.27 0.28 0.26 1.72 % of dead cells 8.1 ± 0.2 7.3 ± 0.5 27.3 ± 0.9 NA NA NA % of ROS+ cells 3.6 ± 0.8 5.9 ± 0.4 62.5 ± 4.6 NA NA NA
Citation Format: Kazuharu Kai, Kimie Kondo, Naoto Ueno. IGF1R/IR axis is a novel treatment target in ER-negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2431. doi:10.1158/1538-7445.AM2013-2431
Abstract 2445: Cucurbitacin B suppresses breast cancer growth by inhibiting TGFβ-mediated integrin-HER2 signaling.
Authors: Gupta Parul , Srivastava Sanjay K. 
Published: August 2014

Abstract
Integrins have recently been shown to play an important role in promotion of cell motility and survival in various cancers through cooperative signaling with EGFRs. Integrins transmit cell survival signals through ILK-Paxillin complex and further play role in activating AKT signaling. Curcubitacin B (CuB) is a steroidal class of chemical present in the plants belonging to cucurbitaceae family. CuB has shown cytotoxic potential in several cancers by causing G2/M cell cycle arrest and inhibition of JAK/STAT3 pathway. However, the exact mechanism of CuB and its role in metastasis and cell survival is not known. Our results show that CuB significantly suppressed the growth of MDA-MB-231, SKBR3, MCF-7, MDA-MB-231 (HER2) and MCF-7 (HER2), five different breast cancer cells in a concentration and time-dependent manner. CuB also induced apoptosis and down-regulated Integrin linked kinase 1(ILK1) expression. In addition, CuB down-regulated Integrin β4 (ITGB4) and Integrin α 6 (ITGA6) protein expression and suppressed the phosphorylation of AKT at Ser473, paxillin at Tyr118. Previous studies have shown that Transforming growth factor β (TGFβ) mediates crosstalk between ITGB4 and HER2, through Src kinase to enhance cell survival and motility. Interestingly we observed significant downregulation of Src, EGFR and HER2 in various breast cancer cells, suggesting that CuB suppresses cooperative signaling of Integrins and HER2. We also observed that TGFβ pretreatment imparted protection against CuB induced cytotoxic effects, indicating that CuB modulates TGFβ mediated Integrin signaling. Taken together our results indicate the anti-cancer effects of CuB in breast cancer cells by targeting ITGB4/ITGA6, Src, ILK and TGFβ. Further detailed mechanistic work is in progress. [Supported in part by R01 grants CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Parul Gupta, Sanjay K. Srivastava. Cucurbitacin B suppresses breast cancer growth by inhibiting TGFβ-mediated integrin-HER2 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2445. doi:10.1158/1538-7445.AM2013-2445
Abstract 2447: Activation of Chk1 critical for Piperine induced cell cycle arrest and apoptosis in melanoma cells.
Authors: Fofaria Neel M. , Srivastava Sanjay K. 
Published: August 2014

Abstract
The National Cancer Institute estimates that about 76,250 new cases of melanomas will be diagnosed in 2012 in the United States leading to at least 9810 related deaths. Therefore, novel strategies to control and treat melanoma are of prime importance. In this study, we determined the cytotoxic effects of Piperine, a major constituent of black (Piper nigrum Linn) and long pepper (Piper longum Linn), in melanoma cell lines. Piperine treatment inhibited the growth of SKMEL-28 and B16-F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine was correlated with the down-regulation of cyclin D1 and induction of p21. The growth arrest was associated with DNA damage as indicated by phosphorylation of H2A.X at Ser139, activation of ataxia telangiectasia and Rad3-related protein (ATR) and checkpoint kinase 1 (Chk1). The G1 arrest by piperine was also associated with the down-regulation of E2F1 and decreased phosphorylation of retinoblastoma protein (Rb), hence indicating the inhibition of the dynamic transcription complex. In addition, apoptosis induced by piperine was associated with down-regulation of XIAP and Bid (uncleaved) and cleavage of Caspase-3 and PARP. Pretreatment of SK-MEL-28 with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Silencing of Chk1 in SK-MEL28 cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine treatment showing the involvement of Chk1. Through immunofluorescence of Phospho Chk1 (Ser 256), we found significant activation of Chk1 in the cells that were treated with piperine hence, establishing the role of Chk1 activation. Furthermore, our results showed that piperine treatment caused ROS generation in melanoma cells. Blocking ROS generation by Tiron pre-treatment prevented the cells from piperine mediated cell cycle arrest. Moreover, western-blotting results showed that Tiron pre treatment prevented the activation of Chk1 hence, confirming the role played by Chk1 in piperine mediated cell cycle arrest. Taken together, our results demonstrate that piperine induced G1 phase cell cycle arrest by generating ROS and inducing DNA damage with activation of Chk1 being a critical event. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Neel M. Fofaria, Sanjay K. Srivastava. Activation of Chk1 critical for Piperine induced cell cycle arrest and apoptosis in melanoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2447. doi:10.1158/1538-7445.AM2013-2447
Abstract 245: Phenotypically diverse cancer cell subpopulations in a luminal-like breast cancer xenograft model are associated with different signaling pathways.
Authors: Skrbo Nirma , Andersen Kristin , Kristian Alexandr , Antberg Linn , Hjortland Geir Olav , Egenbråten Olav , James Peter , Mælandsmo Gunhild Mari , Sørlie Therese 
Published: August 2014

Abstract
High degree of intratumor cellular diversity represent a major challenge when attempting to cure cancer. The presence of tumor cell subpopulations with enhanced in vivo tumorigenic capacity (tumor initiating cells, TICs), and high resistance to conventional cancer therapy, compared with the “bulk” tumor cell populations, has for the last decade been the focus of many breast cancer research groups. The cellular heterogeneity of an orthotopic luminal-like breast cancer xenograft model was investigated using IHC, flow cytometry, whole genome expression profiling and mass spectrometry-based proteomics combined with in vivo tumorigenicity and targeted therapy assays. Epithelial cell adhesion molecule, EpCAM, highly specific for the human tumor epithelial cells, was used to separate human tumor cells from the mouse stromal compartment.
Further flow analysis of the EpCAM positive tumor cell population revealed diverse expression of several cell surface markers, including CD24 and SSEA-4 (stage specific embryonic antigen 4).
SSEA-4-/CD24-, SSEA-4+/CD24- and SSEA-4-/CD24+ populations were capable of initiating tumors in NOD SCID mice while SSEA-4+/CD24+ cells were non-tumorigenic. Tumors resulting from the SSEA-4+/CD24- subpopulation did not express CD24, while tumors arising from the SSEA-4-/CD24- and SSEA-4-/CD24+ populations, contained all four subpopulations.
As measured by whole genome expression analysis and mass spectrometry-based proteomics, the molecular differences were most pronounced between tumorigenic subpopulations and the non-tumorigenic subpopulation. While the mRNA expression data revealed a high degree of similarity among the four subpopulations, the proteomics data suggested that several signaling pathways might have distinct and different activity across the populations. The effects of targeted therapy against ER and WNT signaling on heterogeneity and tumorigenicity have been evaluated by in vivo experiments.
Citation Format: Nirma Skrbo, Kristin Andersen, Alexandr Kristian, Linn Antberg, Geir Olav Hjortland, Olav Egenbråten, Peter James, Gunhild Mari Mælandsmo, Therese Sørlie. Phenotypically diverse cancer cell subpopulations in a luminal-like breast cancer xenograft model are associated with different signaling pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 245. doi:10.1158/1538-7445.AM2013-245
Abstract 2450: Either pan class I PI3K inhibitor or PI3K alpha selective inhibitor sensitizes head and neck squamous cell carcinoma cells to Erlotinib, an EGFR TKI.
Authors: Gao Ming , Lu Yen-Shen , Hsiao Li-Ping , Chen Suz Wen , Cheng Ann-Lii 
Published: August 2014

Abstract
The epidermal growth factor receptor (EGFR) is overexpressed in 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. EGFR is therefore a potential therapeutic target for HNSCC. However, most HNSCC patients do not respond well to small molecular EGFR inhibitors. One of the possible mechanisms of EGFR TKI resistance is compensatory collateral activation of PI3K/Akt pathway. This study sought to explore whether NVP-BKM120, a selective pan class I PI3 kinase inhibitor, and NVP-BYL719, a novel PI3 kinase alpha selective inhibitor, may reverse the resistance of HNSCC cells toward erlotinib, an EGFR TKI. Cells were treated with the PI3K inhibitors, either BKM120 or BYL719, alone, erlotinib alone, or in combination, and viability was measured at 72 hours with MTT assay. Combination effect was evaluated by median effect analysis. Synergism, indicated by a combination index (CI) value &lt;1, were seen in all five cell lines (SAS, HSC3, UMCC1, CA922 and FaDu) studied. By immunoblotting analysis, combination of Erlotinib and either PI3K inhibitor resulted in dowregulation of p-EGFR and p-AKT expression in SAS cells. When SAS and HSC3 cells were treated with erlotinib in combination with either BKM120 or BYL719, an additional increase in the subG1 population by flow cytometry analysis were observed, indicating an increase of apoptotic cell death. Our data suggest that additional PI3K blockade might be an effective strategy to overcome resistance of HNSCC cells toward EGFR TKIs, and the beneficial effect is similar between pan Class I PI3K inhibitor and PI3K alpha selective inhibitor. (The study was supported by the grant of DOH101-TD-B-111-001).
Citation Format: Ming Gao, Yen-Shen Lu, Li-Ping Hsiao, Suz Wen Chen, Ann-Lii Cheng. Either pan class I PI3K inhibitor or PI3K alpha selective inhibitor sensitizes head and neck squamous cell carcinoma cells to Erlotinib, an EGFR TKI. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2450. doi:10.1158/1538-7445.AM2013-2450
Abstract 2453: Optimizing a modular synthetic approach for producing SH7139, a new drug candidate for treating B-cell lymphomas.
Authors: Balhorn Monique , Hok Saphon , Balhorn Rod 
Published: August 2014

Abstract
The scale-up of synthetic methods for producing small molecule therapeutics can often prove to be problematic and expensive. Synthetic mechanisms can be inefficient and purification methods used to select specific isomers or remove reactants or other contaminants can often be difficult to scale. The modular approach we developed for creating small molecule targeting agents called SHALs (Selective High Affinity Ligands) as therapeutics and diagnostics for B-cell lymphoma circumvents many of these problems by using off the shelf components as “recognition elements” that collectively contribute to the molecules high affinity and selectivity and miniPEG and common amino acids to build up the scaffold using solid phase chemistry. Here we present the results of our efforts to scale up the synthesis of the first of these promising new drug candidates, SH7139, to provide the compounds needed for pre-IND animal testing and a pet dog lymphoma clinical trial. Working with AmbioPharm Inc,, a CRO with extensive expertise in the GMP synthesis of peptide pharmaceuticals, we recently completed small pilot production scale syntheses of SH7139 and several closely related analogs. The simple solid phase peptide-based chemistry used to synthesize the compounds coupled with preparative HPLC adapted well to scale-up and resulted in the production of highly purified compounds identical in structure (as determined by mass spectrometry and nuclear magnetic resonance spectroscopy) to the bench scale syntheses we performed in house. However, one unexpected and notable difference between the scaled-up synthetic products and their bench-scale synthesis counterparts was their solubility. SH7139 and two of its analogs, which are essentially insoluble in water and PBS when synthesized in house, were observed to be highly soluble (&gt;100mg/ml) when synthesized using the scale-up protocol. While the reason for this is still under investigation, microscopic analyses of the dried product suggest the solubility difference may relate to the lyophilization step used to produce the dried product. The majority of the insoluble SH7139 we produce in bench-scale syntheses is amorphous in form, while the soluble SH7139 produced by AmbioPharm appears to be in a semi-crystalline or glass-like state. This research was supported, in part, by NIH/NCI SBIR grant 1R43CA159843-01 to Rod Balhorn.
Citation Format: Monique Balhorn, Saphon Hok, Rod Balhorn. Optimizing a modular synthetic approach for producing SH7139, a new drug candidate for treating B-cell lymphomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2453. doi:10.1158/1538-7445.AM2013-2453