bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B78: A novel EWS/Fli1 target gene, Eya3, is upregulated in Ewing's sarcoma to mediate chemoresistance.
Authors: Robin Tyler P. , Kreuger Aaron , McKinsey Erin , Reaves Lisa , Jedlicka Paul , Zhao Rui , Ford Heide L. 
Published: June 2012

Abstract
Ewing's sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients' whose tumors have a poor histological response to initial chemotherapy have a poor overall prognosis. Importantly, childhood cancer survivors are faced with long-term chemotherapy-associated toxicities many years after they have been cured of their primary disease. Therefore, targeting molecules involved in resistance to chemotherapy should benefit patients with resistant disease and allow lower doses of toxic chemotherapies to be used in treatment regimens, thus improving outcomes for children suffering from Ewing's sarcoma on multiple fronts. The vast majority of Ewing's sarcomas harbor a characteristic translocation, t(11;22), encoding the EWS/Fli1 fusion protein. We have identified the DNA-repair protein and transcriptional cofactor, Eya3, as a downstream target of EWS/Fli1. Eya3 is highly expressed in Ewing's sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell of origin of Ewing's sarcoma. We demonstrate that EWS/Fli1 mediates upregulation of Eya3 via repression of miR-145 and miR-708, microRNAs that target the Eya3 3'UTR. Furthermore, replacement of miR-145 and miR-708 in a Ewing's sarcoma cell line decreases Eya3 levels. It was recently shown that Eya3 promotes DNA repair by dephosphorylating a critical tyrosine residue on H2AX in response to DNA damage, resulting in the recruitment of DNA repair factors to the sites of DNA damage. Thus we tested whether knockdown of Eya3 in Ewing's sarcoma cells would decrease cell survival and sensitize cells to DNA-damaging chemotherapeutics used in the treatment of Ewing's sarcoma: etoposide and doxorubicin. Indeed, Eya3 knockdown led to increased cell death and sensitization to chemotherapy, and, as expected, Eya3 knockdown cells contained more DNA damage following treatment with etoposide than their control counterparts. These data strongly suggest that Eya3 mediates chemoresistance in Ewing's sarcoma through its ability to enhance DNA repair. Because Eya3 mediates DNA repair and survival via its intrinsic phosphatase activity, and because the phosphatase activity of Eya is also known to play a role in metastasis of other cancers, we have begun to develop inhibitors targeting the Eya phosphatase activity and to demonstrate their efficacy both in vitro and in cell culture. In closing, Eya phosphatase inhibitors or synthetic mimics of the microRNAs targeting Eya3 have the potential to improve outcomes for Ewing's sarcoma patients by improving therapeutic efficacy and decreasing associated toxicities of conventional chemotherapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B78.
Abstract B85: In vivo radiosensitizer effect of the HDAC inhibitor S78454 on orthotopic human glioblastoma.
Authors: Martinez-Gala Judith , Moyal Elizabeth L. Cohen-Jonathan , Delmas Caroline , Lelievre Helene , Jacquet-Bescond Anne , Kraus-Berthier Laurence , Depil Stephane , Toulas Christine 
Published: June 2012

Abstract
Glioblastoma is an aggressive primary brain tumor with poor outcome, despite a treatment associating surgery and radiotherapy combined with temozolomide. Recent data have shown an in vitro synergy of the HDAC inhibitor S78454 (also called PCI-24781) with ionizing radiation, via inhibition of homologous recombinational (HR) repair of DNA double-strand breaks. We propose in this study to investigate the in vivo radiosensitizer effect of S78454 on human glioblastoma model.
For this, we generated orthotopic U87 human glioblastoma xenografts in nude mice. Intra-peritoneal (i.p.). S 78454 treatment was performed daily starting 10 days after the engraftment. Irradiation was performed in one daily 2 Gy localized fraction during 4 days followed by a second similar 4 days treatment performed after 3 days off (for a total dose of 16 Gy administrated on 11 days). Survival experiments were conducted in mice bearing xenografts in the four different groups of treatment (vehicle, S 78454 alone, radiation alone, S 78454 + radiation). Mice bearing orthotopic xenografts were sacrificed at the onset of neurological signs. Survival curves were then performed.
We first determined the S78454 dosing schedule to obtain a pharmacodynamic effect of the compound in the xenograft. Inhibition of RAD 51 expression, histone H3 and tubulin acetylation in the tumor were obtained 24 hours after daily i.p. treatment with 50mg/kg S78454. These results allowed us to define the schedule treatment combining S78454 with radiotherapy : mice were treated with S78454 50 mg/kg/d i.p., daily from Days 10 to14 and then from Days 17 to 21; one 2 Gy fraction radiotherapy was performed daily from Days 11 to14 and Days 18 to 21.
In these conditions of treatment, S78454 was well tolerated Survival of the mice treated with S78454 alone was not significantly increased while the survival of the mice treated with irradiation alone was significantly increased compared to the control group (P&lt;0.05). In contrast, the survival of the mice treated with the combined treatment was significantly increased compared to the group of animals treated with irradiation alone (P&lt;0.05) and to the group treated with S78454 alone (P&lt;0.01). Effect of S78454 on angiogenesis will be presented. Our results demonstrate that the HDAC inhibitor S78454 radiosensitizes human glioblastoma in vivo and strongly suggest that S78454 may be an interesting drug to combine with radiotherapy in clinical trials for patients with glioblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B85.
Abstract B86: Epigenetic regulation of TRAIL mediated by PRAME/EZH2 in cancer.
Authors: Mello Barbara P. , de Carvalho Daniel D. , Campos Antonio HJFM , Andrade Louise DB , Rocha Rafael M. , Binato Renata , Abdelhay Eliana , Carraro Dirce M. , Soares Fernando A. , Amarante-Mendes Gustavo P. 
Published: June 2012

Abstract
TRAIL, a member of the TNF ligand family, was shown to selectively kill oncogenically transformed cells and, therefore, to participate in the cell-mediated immunity against tumors. However, TRAIL is down-regulated in a variety of tumor-bearing patients. On the other hand, PRAME (preferentially expressed antigen of melanoma) is frequently overexpressed in a wide variety of malignant diseases. It was shown that PRAME can function as a repressor of retinoic acid receptor and this transcriptional repression depends on the formation of a complex with a member of the polycomb group, EZH2 (enhancer of zeste homolog 2). Interestingly, TRAIL expression can be positively regulated by retinoic acid. Data from our lab revealed that TRAIL is down-regulated and PRAME is up-regulated during the development of chronic myeloid leukemia (CML) and that their normal levels are restored after complete cytogenetic remission (CCR). Furthermore, there was a significant, negative correlation between the expression of PRAME and TRAIL in CML patients. Overexpression of BCR-ABL in the acute promyelocytic leukemia cell line HL-60 increased the levels of PRAME and decreased the levels of TRAIL. Knocking-down of either PRAME or EZH2 in K562 CML cell line resulted in a dramatic up-regulation of TRAIL. We concluded that PRAME up-regulation by BCR-ABL plays an important role in CML pathogenesis by repressing retinoic acid signaling pathway and, consequently, down-regulating TRAIL expression, a potent anti-cancer agent as an inducer of the extrinsic pathway of apoptosis. On the basis of these results, we performed bioinformatics analysis, using the Oncomine Research platform, for PRAME and TRAIL expression on solid tumors. We found several works in which PRAME and TRAIL expressions were negatively correlated. In particular, PRAME was up-regulated while TRAIL was down-regulated in kidney, lung, prostate and sarcoma compared to normal tissues. These expression patterns of PRAME and TRAIL were confirmed by real-time PCR in tumor cell lines of prostate, breast, colon and pharynx. At this moment, we are expanding the validation of bioinformatics data in a larger number of tumor cell lines as well as in tumor and normal tissues from patients with different forms of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B86.
Abstract B93: Gene fusions detected by whole transcriptome sequencing of lung adenocarcinoma.
Authors: Kohno Takashi , Ichikawa Hitoshi , Totoki Yasushi , Yasuda Kazuki , Hiramoto Masaki , Nammo Takao , Sakamoto Hiromi , Tsuta Kohji , Furuta Koh , Shimada Yoko , Iwakawa Reika , Chiku Suenori , Yamanaka Itaru , Watanabe Shunichi , Sekine Ikuo , Ogawa Seishi , Tsuda Hitoshi , Yoshida Teruhiko , Yokota Jun , Shibata Tatsuhiro 
Published: June 2012

Abstract
A considerable proportion of lung adenocarcinoma (LADC) cases develop through activation of oncogenes, i.e., somatic mutations in either the EGFR (10–40%) or KRAS (10–20%) genes, or fusion of the ALK gene (5%) with the EML4 or KIF5B genes, in a mutually exclusive manner. Tyrosine kinase inhibitors that target EGFR and ALK proteins are particularly effective for treating LADCs carrying EGFR mutations and ALK fusions, respectively. In this study, whole transcriptome sequencing (RNA sequencing) of 30 Japanese LADCs and three adjacent non-cancerous lung tissues was performed to identify novel chimeric fusion transcripts that could be potential targets for therapy. Analysis of more than 2 × 107 paired-end reads obtained by RNA sequencing and subsequent validation by Sanger sequencing of the reverse transcription (RT)-PCR products identified EML4-ALK fusions in two cases and a few other gene fusions in each single case. The two EML4-ALK positive LADC cases were negative for EGFR and KRAS mutations and also negative for other gene fusions. Therefore, the authenticity of ALK fusions as a driver mutation was validated. The prevalence and oncogenic property of novel gene fusions identified are being studied.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B93.
Abstract C110: Mutation and chemosensitivity profile of a panel of 25 patient-derived melanoma xenografts.
Authors: Fiebig Heinz Herbert , Vuaroqueaux Vincent , Maier Armin , Kelter Gerhard , Schueler Julia B. , Krumbach Rebekka 
Published: June 2012

Abstract
Melanomas account for a notable proportion of cancers worldwide. The heterogeneity and biological characteristics of melanomas present unique therapeutic challenges. Recently a number of somatic mutations were determined, which influence the prognosis and thus therapeutic needs markedly. Here we present a panel of patient-derived melanoma xenografts, established by Oncotest from primary patient material. From 80 patient explants, growth in serial passage was observed in 43% of the cases. Molecular profiling included mutational analysis for BRAF, PI3Kalpha, KRAS, NRAS, TP53, CTNNB1, MET and JAK3 using OncoCarta™ and exon sequencing. The chemosensitivity profile was determined in vitro using 2D and 3D culture assays.
Clinically relevant BRAF mutations were the most prevalent mutation and were found in almost two thirds of the melanoma models. The second most common gene mutated was NRAS, with about one quarter of the models harbouring activating mutations of NRAS. PI3Kalpha mutations were rare, and for KRAS no mutations were detected. Most of the melanomas showed multiple mutations of the investigated genes. Chemosensitivity profiling included cytotoxic (e.g. cisplatin, carboplatin, vinblastine, vincristine, ifosfamide, paclitaxel, and docetaxel), as well as targeted drugs (e.g. sorafenib and PLX-4720). The compounds showed diverse patterns of selectivity and potency: Differential activity was determined e.g. for vinblastine, vincristine, paclitaxel, and docetaxel, but also for the BRAF inhibitor PLX-4720. PLX-4720 was most active in melanoma models carrying the BRAF mutation as determined in monolayer and soft agar assays. Activity of vincristine revealed a correlation of sensitivity with a BRAF wild type genotype and resistance with BRAF mutation. The latter result was also described recently for melanoma patients with BRAF mutations, showing a diminished duration of response to treatment with vincristine, dacarbazine, bleomycin, lomustine, and human leukocyte interferon.
A collection of 25 patient-derived melanoma models is presented. Their mutational status as well as their responsiveness towards many cytotoxic and targeted agents was analyzed. This extensive genotypic and phenotypic characterization makes them a valuable tool for hypothesis generation and testing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C110.
Abstract C113: Modeling cetuximab clinical trial by conducting in vivo efficacy evaluation in large panel CRC patient-derived xenograft (PDX) models.
Authors: Chen Dawei , Yang Mengmeng , Deng Jiangyun , Song Xiaoming , Cai Jie , Chen Taiping , Chen Yiyou , Li Henry 
Published: June 2012

Abstract
Patient derived xenograft (PDX) models without in vitro manipulation mirror patients' histopathological and genetic profiles1,2. This has the potential to significantly improve the predictive power of preclinical cancer animal models, and more importantly to enable the identification of predictive biomarkers for targeted therapeutics.
In this study, we set out to mimic a small size clinical trial by testing cetuximab in a large cohort of CRC models. Among 19 CRC models tested, 7 models were found sensitive (37%) and 12 resistant (63%) to cetuximab. All 3 models with BRAF activating mutation are found resistant to cetuximab. Of the 11 models with KRAS activating mutation, the response profile is more complex, with 6 models resistant and 5 models responsive to cetuximab. It is interesting that 3 out of the 4 models with G13D mutation are sensitive to cetuximab. Of the 5 models which harbor neither KRAS nor BRAF mutation, 3 models are resistant, suggesting that other oncogenic drivers are involved. Interestingly, one of the resistant models harbors an EGFR R776H activating mutation.
The observation that KRAS mutations such as G13D and G12C are still sensitive to cetuximab, although contrary to the accepted dogma that CRC patient with mutant KRAS does not benefit from cetuximab3, is consistent with the recent findings in clinic4–7. Other KRAS mutations such as A146T and R61H were found in the resistant models, may imply that mutations besides codon 12 and 13 can play roles in the pathogenesis of CRC and the drug resistance. The overall resistant profile of models with BRAF mutation may also suggests another potential risk factor which warrants further investigation.
In summary, our results have demonstrated that large panel HuPrime® can be used to effectively evaluate investigational new drugs for efficacy prediction and to discover predictive biomarkers to guide patient stratification for clinical development.
References
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4. W. De Roock, V. De Vriendt, N. Normanno, F. Ciardiello, S. Tejpar, Lancet Oncol 12, 594, 2011.
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6. W. De Roock et al., Lancet Oncol 11, 753, 2010.
7. R. Kirk, Nat Rev Clin Oncol 8, 1 2011.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C113.
Abstract C120: Quantitative analysis of ERK phosphorylation by single cell phospho-specific flow cytometry in colon cancer cells as an input for pharmacokinetic/pharmacodynamic modeling of U0126 concentration.
Authors: Hwang Jee Won , Ahn Joong Bae , Rha Sun Young , Roh Jae Kyung , Chung Hyun Cheol , Bae Soo Kyung , Bae Soo Hyeon , Shin Sang Joon 
Published: June 2012

Abstract
Background: To evaluate intracellular levels of phosphorylated proteins in many signaling pathways, Western blot, immunohistochemical and immufluorescence have been generally used until now. However, to establish pharmacokinetics-pharmacodynamics modeling of various drugs including antitumor agents, precise quantitative measurements of intracellular level of phosphorylated signaling molecules are critically needed. Methods and Materials: In this study, we investigated the ability of single cell phospho-specific flow cytometry to detect dynamic change of intracellular level of phosphorylated-ERK (pERK) as a pharmacodynamic marker of MEK/ERK inhibitor U0126 in human colon cancer cell lines. We also measured the intracellular concentration of U0126 in the cell lines using High-performance liquid chromatography.
Results: The fluorescence intensity changes by pERK-specific single cell flow cytometry after U0126 treatment was corresponded to the pattern of results obtained by Western blot and immunofluorescence staining in dose- and time-dependent manner. In HCT116 and HT-29 human colon cancer cells, the basal fluorescence intensity of pERK was inhibited with a 0.2- to-0.8 fold decrease according to increasing concentration of U0126 (0.1 − 100 uM). We detected the rapid decrease of pERK activity within 15 min after U0126 treatment; this decrease was continued to 2 hours. And we observed the gradual recovery of pERK level closely basal status until 24 hours. The concentration of U0126 in the media was associated with decreased activity of pERK but the intracellular concentration of U0126 was not.
Conclusion: Our data obtained by single cell phospho-specific flow cytometry are more sensitive, rapid, and quantitative in parallel compared with western blot. This accuracy allowed us to acquire precise inputs in order to establish pharmacokinetics-pharmacodynamics modeling of various anti-tumor agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C120.
Abstract C121: A phase 1 QTc study of tivozanib in patients with advanced solid tumors.
Authors: Chadha Manpreet , Infante Jeffrey R. , Cotreau Monette M. , Jacobson Lindsey , Strahs Andrew L. , Slichenmyer William , Vargo Dennis L. , Moore Kathleen 
Published: June 2012

Abstract
Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Previous preclinical and clinical studies have shown that tivozanib displays strong antiangiogenic and antitumor effects. Preclinical and retrospective electrocardiogram (ECG) analyses did not suggest an effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the proarrhythmogenic potential of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors.
Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Patients with a repeated baseline QTcF &gt;480 ms were excluded. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20–30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessment of clinical laboratory tests, physical examinations, vital signs, and recording of adverse events.
Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received at least one dose of tivozanib were evaluable for the present study. Preliminary adverse event data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented.
Conclusions: Preliminary data suggest that tivozanib at 1.5 mg daily over a 21-day period does not cause clinically significant prolongation of QT/QTc over baseline. Data from this study suggest that the safety and PK profile of tivozanib was similar to that observed in previous studies, and that the findings are consistent with the ECG evaluation in a monkey telemetry study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C121.