bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C32: Gene expression analysis of myeloma cells resistant and sensitive to bortezomib.
Authors: Terui Yasuhito , Mishima Yuji , Tomida Akihiro , Hatake Kiyohiko 
Published: June 2012

Abstract
Purpose: The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM). Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To elucidate mechanisms of bortezomib resistance and find the way to overcome bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 multiple myeloma cell lines in response to bortezomib. Methods: The differential gene expression profiles of bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 multiple myeloma cell lines in response to bortezomib was performed using Affymetrix GeneChip. To confirm the results, real-time PCR and Western blot analysis were performed.
Results: At concentrations that effectively inhibited proteasome activity (maximum dose with 100nM), bortezomib induced cell death in bortezomib-sensitive IM-9 cells, but not in bortezomib-resistant IM-9. In comparison of differential gene expression profiles between bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 cells, we showed overexpression of KDM3A and KDM5B, which are associated with chromatin-mediated reversible drug-tolerant state, Moreover, CD200, CD69, and IGF1R, which are associated with cancer stem cells, were overexpressed in bortezomib-resistant IM-9.
Conclusion: Histone lysine-specific demethylase inhibitors as combination with bortezomib may be useful for overcoming bortezomib-resistance. Moreover, cancer stem cell antigen such as CD200, CD69, and IGF1R may also become molecular targets against bortezomib-resistance.
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 C32.
Abstract C34: Synergistic interaction between a novel histone deacetylase inhibitor and the proteasome inhibitor bortezomib in platinum-resistant ovarian carcinoma cells.
Authors: Gatti Laura , Benedetti Valentina , De Cesare Michelandrea , Corna Elisabetta , Cincinelli Raffaella , Zaffaroni Nadia , Zunino Franco , Perego Paola 
Published: June 2012

Abstract
Based on the ability of histone deacetylase inhibitors to modulate the expression of genes relevant for growth regulatory or apoptotic pathways, the purpose of the present study was to explore the interest of novel combination treatments for drug-resistant tumors. Thus, using cellular and biochemical pharmacology approaches, we examined the effect of the combination between the novel histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in ovarian carcinoma cell lines, including the parental IGROV-1 cell line and two platinum-resistant sublines. The IGROV-1/OHP and IGROV-1/Pt1 cells, selected for resistance to oxaliplatin and cisplatin respectively, are characterized by a mutant p53 gene. Using the combination index method and cell sensitivity assays, we found a synergistic interaction between ST2782 and bortezomib, more evident in the p53-mutant resistant sublines. Such an interaction was associated with increased apoptotic cell death, as shown by TUNEL assays. The treatment with ST2782 resulted in early induction of the pro-apoptotic protein Bax as well as in cleavage of caspase 3 and PARP only in the resistant cell lines, as supported by Western blot analyses. The inhibition of p53-transcriptional transactivation by pifithrin alpha in IGROV-1 cells enhanced the synergism between the two drugs. Conversely, knockdown of endogenous wild-type p53 in IGROV-1 cells following transfection of small interfering RNAs determined a considerable synergism reduction. These opposite effects support the relevance of the transactivation-deficient mutant p53 as a determinant of the synergism. Moreover, in vivo studies in IGROV-1/Pt1 xenografts indicated that tumor growth inhibition tended to be more marked in mice receiving the drug combination with respect to those treated with bortezomib alone. In conclusion, the present study supports the potential effectiveness of this combination in p53-mutant ovarian cancer models resistant to platinum compounds.
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 C34.
Abstract C35: Response of colorectal cancer cells to combination of EGFR mAbs with oxaliplatin is determined by the sequence of administration.
Authors: Elenius Klaus , Karrila Anna , Gustafsson Emil , Sundvall Maria 
Published: June 2012

Abstract
Monoclonal antibodies (mAb) targeting EGFR (epidermal growth factor receptor), cetuximab (Erbitux) and panitumumab (Vectibix), have been approved for the therapy of metastatic colorectal cancer (mCRC). However, the majority of the patients are primarily resistant to EGFR mAbs or become resistant during the treatment. While activating mutations in KRAS have been reported to confer resistance to EGFR mAbs, some recent randomised controlled trials with EGFR mAbs combined to oxaliplatin-based regimens have failed to demonstrate clinical effect even in patients with KRAS wild-type mCRC. We have addressed the effects of EGFR mAbs on the growth of KRAS wild-type and KRAS mutant CRC cell lines in the absence and presence of oxaliplatin. Our observations indicate that while the KRAS mutant genotype is predictive for resistance to single agent EGFR mAbs, the combination of EGFR mAb plus oxaliplatin is not superior to oxaliplatin alone regardless of the KRAS status. However, sequential administration of oxaliplatin prior to EGFR mAb results in a clear additive effect whereas a sequence of EGFR mAb prior to oxaliplatin antagonizes the effect of oxaliplatin. The opposing effects of the two different sequences seem to be independent on both KRAS and BRAF mutation status.
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 C35.
Abstract C42: p16-enhanced the migration phenotypes in hepatocellular carcinoma cells is Rb-independent.
Authors: CHU HSIAO-CHIEN , Lin Ze-Shiang , Lewis Brian C , Chen Ya-Wen 
Published: June 2012

Abstract
The occurrence of tumor metastasis to the extra-hepatic region contributes to a poor prognosis of hepatocellular carcinoma (HCC). However, the molecular mechanisms of metastasis in HCC remain unclear. Our previous studies showed that concomitant loss of Ink4a/Arf locus accelerated tumor formation and metastasis in mice with liver specific Trp53 deletion, indicating roles of Ink4a/Arf locus in tumorigenesis and metastasis. In this study, we focus on the p16 (Ink4a), a well-known tumor suppressor in regulation of cell cycle. When re-introduction of p16 into Trp53 and Ink4a/Arf-null liver cancer cells, we unexpectedly observed that p16 could enhance cell migration in HCC cell lines, including murine and human orgins by transwell assay and ectopic p16 expression also increased colonization in the lungs via tail vein injection into immune-deficient mice. Interestingly, there was no significant change in expression of epithelial mesenchymal transition (EMT)-related proteins. We further demonstrated that activity of Cdc42 and Rac1 was increased in MM189 cell with p16 over-expression but activity of RhoA was partially decreased. By knockdown of small GTPase, Cdc42 GTPase was required for p16-enhanced cell migration, whereas the related RhoA GTPase inhibited p16-mediated migration. Analysis of p16 mutants indicated that the Cdk4 interacting domain was required for stimulation of HCC cell migration, knockdown of Cdk4 and Cdk6 showed that these proteins are dispensable for this phenomenon. We therefore hypothesized that p16-mediated migration is not involved in pRb-dependent pathways. To validate our hypothesis, knockdown of pRb did not impair p16-enhanced migration in HepG2 cells with ectopic p16 expression. Our study suggested that p16-enhanced migration is not mediated by pRb-dependent pathways and more studies needs to be performed to elucidate this.
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 C42.
Abstract C45: Validation of thromboxane A2 receptor (TP) as a target to block breast cancer metastasis.
Authors: Zhang Xuejing , Nie Daotai 
Published: June 2012

Abstract
The receptor of thromboxane A2 (TXA2), TP, is a seven transmembrane, G-protein-coupled receptor. Increased expression of TP at RNA level was found to correlate with a poor prognosis in breast cancer patients but it is unknown how TP expression and activities are involved in breast cancer progression. Here we report that TP is expressed in metastatic breast cancer cells at both RNA and protein levels. Treatment of breast cancer MDA-MB-231 cells by U46619, a TP agonist, induced cell body contraction. The U46619-induced contraction was blocked by SQ29548, a high-affinity TP antagonist. Further studies found that small GTPase RhoA was activated by TP activation and that pretreatment of MDA-MB-231 cells with Y27632, a Rho kinase (ROCK) inhibitor, blocked U46619-induced cell contraction. The requirement of RhoA activation in U46619 induced cell contraction was further confirmed by the ability of dominant negative RhoA to block cell contraction induced by U46619. MDA-MB-231 cells with TP knockdown displayed a reduced percentage of contraction under the treatment of U46619 and TXA2 agonist I-BOP as well as attenuated invasion ability. When injected into mice, MDA-MB-231 cells with TP depleted did not present significant changes in primary tumor formation or growth. However, TP depletion reduced the ability of MDA-MB-231 cells to metastasize to the lung and the liver in an experimental metastasis model. We further demonstrated that TP depletion reduced the lung colonization ability of MDA-MB-231 cells by blocking active extravasation. Taken together, TP is expressed in breast cancer and that activation of TP has profound effects on tumor cell cytoskeleton and contraction through activation of RhoA. Inhibition or depletion of TP reduces the metastatic dissemination of breast cancer cells in vivo by blocking the extravasation of tumor cells.
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 C45.
Abstract C5: Worse prognosis of KRAS c.35 G &gt; A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx).
Authors: Bruera Gemma , Cannita Katia , Giacomo Daniela Di , Lamy Aude , Troncone Giancarlo , Dal Mas Antonella , Coletti Gino , Frebourg Thierry , Sabourin Jean Christophe , Tosi Mario , Ficorella Corrado , Ricevuto Enrico 
Published: June 2012

Abstract
Introduction: Bevacizumab (BEV) addition to doublet chemotherapy significantly increases efficacy without differentially affecting prognosis in KRAS wild-type (wt) and mutant (m) MCRC. Present study evaluates clinical outcome of BEV added to triplet chemotherapy, FIr-B/FOx (Bruera G et al, BMC Cancer 2010, 10:567), according to KRAS genotype.
Methods: MCRCpatients (pts) were treated with first line FIr/FOx regimen including BEV and triplet chemotherapy (weekly alternating irinotecan or oxaliplatin associated to fluorouracil). Treatment schedule: weekly 12h-timed-flat-infusion/5-fluorouracil 900 mg/m2, days 1–2, 8–9, 15–16, 22–23; irinotecan 160 mg/m2 plus BEV 5 mg/kg, days 1,15; oxaliplatin, 80 mg/m2, days 8, 22; every 4 weeks. Tumoral samples were simultaneously screened for KRAS codon 12 and 13, and BRAF c.1799 T &gt; A mutations by SNaPshot multiplex assay (Di Fiore F, Br J Cancer 2007;96(8):1166–1169) and/or direct sequencing. Activity and efficacy were evaluated and compared using log-rank test.
Results: Forty-five MCRC pts were evaluated: 25 KRAS wt (56%), 20 KRAS m (44%). After 30 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wt 88% (C.I. × 14), 14 months, 38 months; KRAS m 80% (C.I. × 19), 12 months, 21 months. PFS and OS were not significantly different. Among KRAS m pts, ORR, PFS and OS at 19 months median follow-up in c.35 G &gt; A (13 pts) were 69% (C.I. × 26), 9 months, 11 months, respectively. OS of c.35 G &gt; A KRAS m was significantly worse compared to KRAS wt (p = 0.003) and to other than c.35 G &gt; A mutant pts (p = 0.022).
Conclusions: First line FIr-B/FOx intensive regimen adding BEV to triplet chemotherapy can further increase activity and efficacy without significantly affecting different clinical outcome in KRAS wt and m MCRC pts. For the first time in MCRC pts treated with BEV-containing chemotherapy, present study shows a significant interaction between the most prevalent c.35 G &gt; A KRAS mutation and worse prognosis compared to KRAS wt pts and to other than c.35 G &gt; A KRAS exon 2 mutations, depending from different biological aggressiveness and sensitivity to BEV addition to triplet chemotherapy.
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 C5.
Abstract C58: Humanization and characterization of an anti-ErbB-3 murine monoclonal antibody.
Authors: Sala Gianluca , Traini Sara , Risio Annalisa Di , Vianale Giovina , Tinari Nicola , Natali Piergiorgio , Muraro Raffaella , Iacobelli Stefano 
Published: June 2012

Abstract
Background: The signaling network downstream of the human epidermal growth factor receptors ErbB-1 and ErbB-2 have been extensively targeted by cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance which is often associated with reactivation of the ErbB-3/PI3K-Akt axis. This may be overcome by ErbB-3 ligands that abrogates receptor-mediated signaling.
Methods: the murine MP-RM-1 monoclonal antibody that specifically binds ErbB-3 ectodomain was chimerized by replacing the murine constant regions with the human constant regions and humanized by gratfing Complementarity Determining Regions from the murine into a human antibody framework using a computer assisted molecular modelling. Recombinant genes were placed into the pCDNA3.1 expression vector and transfected into Chinese Hamster Ovary-S cells. Antibodies were screened on the basis of their ability to inhibit Neuregulin-1 (NRG-1)-induced activation of the ErbB-3/PI3K-Akt axis in IR-8 human melanoma cells (Table 1). Four antibody variants, i.e., cMP-RM-1 #1, hMP-RM-1 #6, hMP-RM-1 #10, and hMP-RM-1 #20, were selected and further tested for their ability to promote ErbB-3 downregulation and to inhibit in vitro and in vivo growth of tumor cells.
Results: Four chimeric (c) and sixteen humanized (h) antibody variants were obtained. All variants showed to possess antigen binding affinity comparable to that of their parental antibody. Initial screening identified one chimeric (cMP-RM-1 #1) and three humanized (hMP-RM-1 #6, hMP-RM-1 #10, hMP-RM-1 #20) antibodies as the most effective in inhibiting ErbB-3/Akt phosphorylation and promotion of ErbB-3 downregulation. Further testing revealed the antibodies potently inhibited colony formation ability of tumor cells and halted growth of melanoma and ovarian cancer xenografts in nude mice. Treatment with the antibodies was associated with a decreased ErbB-3 and Akt phosphorylation and ErbB-3 expression in the excised tumor tissue.
Conclusions: This successful production of chimeric/humanized antibodies possessing antitumor activity in vitro and in vivo may provide novel candidates for ErbB-3-targeted therapy.

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 C58.
Abstract C59: Antibody targeting of CD24 efficiently retards growth of experimental carcinomas.
Authors: Salnikov Alexey V. , Bretz Niko , Perne Claudia , Fogel Mina , Keller Sascha , Schlange Thomas , Moldenhauer Gerhard , Altevogt Peter 
Published: June 2012

Abstract
It has been shown that CD24 drives lung metastasis formation of bladder cancer and might be a good candidate for mAb-dependent therapy. We tested whether mAb SWA11 to CD24 would be effective in preventing tumor growth in xenotransplanted mice. In an A549 lung carcinoma model cells were implanted s.c. into SCID/beige mice followed by multiple injections of mAb over 37 days. Therapy with anti-CD24 mAb SWA11 lead to substantially reduced tumor load. The final tumor mass of treated animals was significantly smaller compared to isotype-control mAb treated animals. Similar observations were made in therapy models of CD24-positive BxPC3 pancreatic adenocarcioma cells in NOD/SCID mice and SKOV-3ip ovarian carcinoma cells in CD1 mice. The therapeutic effects were associated with changes in tumor cell proliferation, apoptosis and angiogenesis. Surprisingly, we found that SWA11 mAb treatment significantly altered cytokine tumor microenvironment. Also the mAb treatment lead to the increased infiltration of tumor tissue with immune cells suggesting involvement of ADCC. Addition of SWA11 mAb to the gemcitabine treatment strongly potentiated its anti-cancer efficacy in A549 lung cancer model. Our data demonstrate that targeting of CD24 could be beneficial for the anti-cancer treatment using standard chemotherapy regimes.
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 C59.
Abstract C62: 5A2, a new IL-3Ra (CD123) monoclonal antibody for the treatment of AML.
Authors: Huang Liang , Wang Na , Wang Huaying , Cao Zhixiang , Chen Yiyou , Li Henry 
Published: June 2012

Abstract
Acute myeloblast leukemia (AML) is a classic stem cell disease driven by leukemic stem cells (LSCs). LSCs in general are resistant to the existing therapies and the current treatment prognosis are rather poor. Targeting AML-LSCs has thus been suggested as a new potential approach to improve the current treatment. IL-3 receptor -chain (IL-3R, or CD123) has been shown over-expressed on leukemic blasts, progenitors and LSCs. CD123 signaling contributes to leukemic development. CD123 may thus represent a suitable target for monoclonal antibody based treatment approaches against AML.
We immunized mice with purified IL3RA ECD/Fc fusion protein and the IL3RA expressing plasmid respectively. From the immunized mice we generated 3 and 8 hybridoma cell lines that secreted monoclonal antibodies recognize to IL3RA ECD/Fc and CD123 expressed on TF-1 (a CD123 expressing AML cell line) and 8G9 (a CD123 stable-expressing CHO established by us). In particular, among the 11 positive cell lines, one of the antibodies, 5A2, was confirmed with antagonist property to block the binding of IL-3/IL3RA. We demonstrated that 5A2 dose-dependently suppresses the IL-3 induced proliferation of TF-1 cells. In addition, 5A2 can also efficiently internalize into TF-1 cells. These observations suggest that 5A2 can be a potential candidate for development as an antibody based therapy against AML. At present, we are in process of further characterizing 5A2 (including determination of Kd, epitope, cross-species reactivity, inhibition of ex vivo proliferation of patient leukemic cells, along with in vivo efficacy in a suitable animal model, etc.). We are also initiating humanization of 5A2 to identify clinical candidate. We plan to also report and discuss the progresses on some of these studies.
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 C62.
Abstract C67: Investigating PI3K/mTOR inhibition in a mouse model of colorectal cancer mutant for both Apc and Pten.
Authors: Raja Meera , Shaw Paul , Clarke Alan 
Published: June 2012

Abstract
This study evaluates the effect of dual PI3K and mTOR inhibition as a potential novel therapeutic strategy in a preclinical model of colorectal cancer.
Loss of Pten in the context of Apc loss in the murine intestine accelerates tumorigenesis through increased activation of Akt. Tumor bearing AhCreER Apcfl/+ Ptenfl/fl mice were exposed to acute doses of a PI3K/mTOR inhibitor to investigate the immediate biological effects on tumors. To investigate the therapeutic potential of PI3K/mTOR inhibition, mice were treated with the PI3K/mTOR inhibitor twice daily to a survival end point.
Short term exposure to the PI3K/mTOR inhibitor confirmed inhibition of the pathway in tumor tissue through reduction of phospho-AKT, phospho-mTOR and phospho-S6, however this did not induce apoptosis. Chronic exposure resulted in a significant increase in longevity of mice from a median survival of 100 days post induction to beyond 300 days post induction with 20% of mice alive at a year post induction. Tumor burden and grade analysis indicates that chronic PI3K/mTOR inhibition slows down the growth rate of tumors and prevents tumor progression but does not prevent initiation of microadenomas after 80 days of treatment. Resistant tumors which were exposed to a longer period of treatment were found to be larger and on average more aggressive. Currently, we are investigating the mechanisms of resistance to chronic PI3K/mTOR inhibition to identify genes which may be responsible for resistant tumor growth and thus identify new drug targets.
Simultaneous inhibition of the PI3K and mTOR signaling pathways effectively prolongs survival of mice with aggressive adenocarcinoma and prevents tumor progression. Here we provide evidence that dual PI3K and mTOR inhibition may be a rational therapeutic strategy for patients with similar tumor profiles.
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 C67.