bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B37: F14512, a polyamine-vectorized anticancer drug, triggers senescence cell death mechanism.
Authors: Brel Viviane , Annereau J-Philippe , Gomes Bruno , Vandenberghe Isabelle , Andre Karine , Marionneau Marie-Laure , Lacastaigneratte Laurence , Stennevin Aline , Rouquet Jerome , Latil Alain , Kruczynski Anna , Bailly Christian , Guilbaud Nicolas 
Published: June 2012

Abstract
Drugs specifically vectorized to cancer cells may offer a reinforced activity, resulting in an improved therapeutic index. In this context, F14512 exploits the Polyamines Transport System (PTS) to accumulate into cells and exhibits an enhanced anti-proliferative activity on a large panel of tumor cell lines as compared to etoposide. At the molecular level, the spermine tail of F14512 contributes to enhance the water solubility of the drug, and reinforces the activity of the drug toward its primary molecular target, topoisomerase II. This observation has encouraged the set up of a phase 1 clinical study with F14512 in patients with relapsed or refractory acute myeloid leukemia (AML).
In order to determine how these molecular properties translate at the cellular level, we have compared the kinetic of cell cycle modulation associated with the inhibition of cell proliferation. F14512 proved to be &gt;30-fold more cytotoxic than etoposide against A549 non-small cell lung cancer cells and triggers less but unrecoverable DNA damages and does not lead to a marked accumulation in the S-phase of the cell cycle, unlike etoposide. Interestingly, A549 cells treated with F14512 were less prone to undergo apoptosis (neither caspases-dependent, nor caspases-independent pathways) or autophagy but preferentially entered into senescence. Drug-induced senescence was characterized qualitatively and quantitatively by an increased -galactosidase activity, both by cytochemical staining and by flow cytometry. A morphological analysis by electron microscopy revealed the presence of numerous multi-lamellar and vesicular bodies and large electron-lucent vacuoles in F14512-treated cell samples. The mechanism of drug-induced cell death is thus distinct for F14512 as compared to etoposide, and this difference may account for their distinct pharmacological profiles and the superior activity of F14512 in vivo. The identification of such response markers for senescence are currently pursued on in vivo MX-1 models by following a transcriptomic analysis focused on cell death cascades including apoptosis and senescence. This study suggests that senescence markers should be considered as potential pharmacodynamic biomarkers of F14512 antitumor response, applicable in clinical trial.
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 B37.
Abstract B6: Aminopeptidase N-activated prodrug melphalan-flufenamide (J1) inhibits angiogenesis in vitro and in vivo.
Authors: Laitinen Sara , Wickstrom Malin , Fuchs Peder Fredlund , Gerwins Par , Larsson Rolf , Gullbo Joachim 
Published: June 2012

Abstract
Introduction: The membrane-bound metalloproteinase aminopeptidase N (APN) is involved in several different cellular processes associated with the malignant phenotype. Furthermore APN has also been reported to have a functional role in tumor angiogenesis and there appear to be a strong correlation between the expression of APN and the invasive capacity of a numerous tumor cell types. The melphalan-derived prodrug melphalan-flufenamide (previously designated J1) can be activated by APN suggesting possible anti-angiogenic properties.
Experimental: A series of experiments were performed to evaluate the effects of melphalan-flufenamide on angiogenesis; cytotoxicity on bovine endothelial cells, the TCS Cellworks AngioKit model with human endothelial cells co-cultured with fibroblasts, the chicken embryo chorioallantoic membrane assay, and finally in vivo in mice using the Cultrex DIVAA angio-reactor assay.
Results: Melphalan-flufenamide displayed high cytotoxic activity against endothelial cells, about hundred times more potent than the parental substance melphalan. This difference was also demonstrated in the more complex assays. Melphalan-flufenamide-treated AngioKit co-cultures showed significant superiority compared to melphalan regarding total tubule number, total tubule length, mean tubule length, and number of junctions. Finally mice were implanted subcutaneously with DIVAA angio-reactors, i.e. sterile tubes with a VEGF gel matrix, and treated with drugs. Melphalan-flufenamide was the most effective compound inhibiting in-growth of host micro-vessels in the tube, significantly better than melphalan and slightly better than the positive control bevacizumab.
Conclusion: APN is associated with several characteristics of the malignant phenotype, including angiogenesis. Melphalan-flufenamide is an APN-activated prodrug of melphalan, currently being evaluated in clinical trials. This study suggests that melphalan-flufenamide besides being an alkylating agent also demonstrates anti-angiogenic effects in different preclinical models in vitro and in vivo.
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 B6.
Abstract C122: Phase 1b relative bioavailability (BA) study of enteric coated tablet (ECT) in reference to powder in capsule (PIC) formulation of the investigational drug alisertib (MLN8237), an Aurora A Kinase (AAK) inhibitor, in patients with advanced nonhematologic malignancies.
Authors: Venkatakrishnan Karthik , Infante Jeffrey R. , Cohen Roger B. , Burris Howard A. , Zhou Xiaofei , Liu Hua , Fingert Howard , Dees E. Claire 
Published: June 2012

Abstract
Background: The investigational drug alisertib (MLN8237) is an orally available, selective AAK inhibitor. Early clinical studies used a PIC formulation; an ECT formulation was recently developed. Here we present relative BA results of ECT referenced to PIC designed to bridge transition to ECT in MLN8237 clinical development.
Methods: Eligible patients were age ≥18 years with advanced solid tumors and ECOG PS 0–1. Dose-escalation cohorts received alisertib 10 mg BID (N=1), and 20 mg BID (N=1), before formal relative BA evaluation at 40 mg BID, in a 7-day schedule followed by 14 days' rest (21-day cycles). Patients received MLN8237 40 mg BID as either ECT or PIC in a 2-cycle, 2-way cross-over design. Pharmacokinetic (PK) sampling was performed on Day 7 of cycles 1 and 2 to characterize steady-state PK of alisertib formulated as ECT or PIC for relative BA analysis. PK was also evaluated on Day 1 of ECT dosing.
Results: 22 patients were included (N=1 each at 10 and 20 mg BID; N=20 at 40 mg BID); 55% were male, 90% were white, and median age was 56 years. 14 patients were evaluable for relative BA analysis. Following BID oral dosing, absorption was fast (median Tmax ∼2.5 hours for ECT; ∼2 hours for PIC). Relative BA of ECT referenced to PIC was 90% (90% CI: 74.4, 108.8). Steady-state Cmax following ECT was 82% of that from PIC (90% CI: 69.9, 95.5). Mean accumulation ratio of ECT BID was ∼2.8-fold; mean peak-to-trough ratio was ∼2.5. The range of dose-normalized exposures following ECT was within the corresponding range observed with PIC, which has previously been associated with favorable pharmacodynamic effects (Dees et al. Abstract 3010; Cervantes et al. Abstract 3031, J Clin Oncol 2010;28:15s).
Conclusions: Systemic exposures following administration of ECT and PIC formulations of alisertib are generally similar, supporting transition from PIC to ECT in clinical development. Taken together with PK, pharmacodynamics, and antitumor activity from other trials, these data indicate that the ECT formulation of alisertib can provide exposures needed for clinically relevant bioactivity.
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 C122.
Abstract C184: A small molecule FAK inhibitor increases the cytotoxicity of 5-fluorouracil.
Authors: Melissa Heffler , Golubovskaya Vita M. , Cance William G. , Dunn Kelli M. Bullard 
Published: June 2012

Abstract
Introduction: Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that has been implicated in colon cancer progression. We have shown that SW620 colon cancer cells express both FAK and activated (phosphorylated) Y397 FAK. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that decreases cell viability and tumor growth in vivo. Because chemotherapy for colon cancer is based upon regimens containing 5-fluorouracil (5-FU), we hypothesized that combining Y15 with 5-FU would synergistically inhibit colon cancer cell viability and growth in vitro and in vivo.
Methods: SW620, SW480 and HCT116 colon cancer cells grown in culture were treated with Y15 and 5-FU alone and in combination. In vitro viability was assessed with an MTT assay. To test the in vivo affects of these agents, SW620 cells were injected into the flank of female nude mice. The mice were then treated with either Y15 (100mg/kg oral gavage), 5-FU (30mg/kg intraperitoneal injection), combination Y15+5-FU, or PBS control (30mg/kg intraperitoneal injection). Tumors were measured with calipers every 3 days and tumor volumes calculated.
Results: MTT assays demonstrated synergistic inhibition of cell viability with combination Y15+5-FU treatment. The viability of SW620 cells treated with 2microM of Y15 and 50microM of 5-FU was significantly less than that of cells treated with either agent alone (p&lt; 0.05). This trend persisted with dual treatment consisting of 2microM of Y15 and increasing doses of 5-FU (100microM, 200microM, 300microM, p&lt; 0.05). SW480 cells showed similar synergism, with the viability of cells treated with 4microM of Y15 and 50microM of 5-FU significantly less than that of cells treated with either agent alone (p&lt;0.05). Similarly, the viability of HCT116 cells treated with a combination of 500nM of Y15 and 200microM of 5-FU was significantly less than that of cells treated with either agent alone (p&lt;0.05). In vivo, oral gavage Y15 (100mg/kg) and 5-FU (30mg/kg) as single therapies did not inhibit tumor growth. However, mice treated with Y15+5-FU developed tumors that were significantly smaller than single treatment or control groups after 27 days of treatment (p&lt; 0.05).
Conclusions: The small molecule FAK inhibitor, Y15, increases the cytotoxic activity of 5-FU against colon cancer cells in vitro. In vivo, at a dose where neither agent decreases tumor growth, the combination of Y15 and 5-FU significantly inhibits tumor growth. These data suggest that Y15 augments the effect of 5-FU and suggests that the addition of this small molecule FAK inhibitor may be a good therapeutic adjunct for treating colon 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 C184.
Abstract C81: Therapeutic potential of SHIP1 and SHIP2 inhibitors in cancer.
Authors: Kerr William G. , Brooks Robert , Park Mi-Young , Gumbleton Matthew , Iyer Sonia , Viernes Dennis , Chisholm John , Fuhler Gwenny Manel 
Published: June 2012

Abstract
Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns (3,4,5) P3- protein kinase B (PKB/AKT) signaling pathway. The lipid phosphatases SHIP1 and SHIP2 have long been thought to act as tumor-suppressors by counteracting the survival signal induced by this pathway through hydrolysis or PtdIns (3,4,5) P3 to PtdIns (3,4) P2. However, a growing body of evidence suggests that PtdInd (3,4) P2 is capable of, and essential for, AKT activation, thus opening up a potential role for SHIP1/2 enzymes as proto-oncogenes. We have recently described a novel SHIP1 selective chemical inhibitor (3AC), which was capable of killing malignant hematological cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) cells, and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivo growth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors (1PIE, 2PIQ, 6PTQ), which efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns (3,4) P2. In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumors.
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 C81.
Abstract C87: Combination of chemotherapy and Akt inhibitor is synergistic in gastric cancer cell lines.
Authors: Almhanna Khaldoun , Cubitt Christopher , Zhang Shumin , Malafa Mokenge 
Published: June 2012

Abstract
Background: Molecularly-targeted agents failed to improve outcome in gastric cancer. MK-2206 (Merck & Co., Inc.) is an oral potent allosteric Akt inhibitor. In this study we evaluated the synergistic potential of MK-2206 in combination with selected chemotherapeutic agents (Carboplatinum, Paclitaxel) in human gastric cancer cell lines.
Materials and Methods: We evaluated effects of MK-2206 on cell growth and cell signaling using a panel of gastric cancer cell lines AGS, SNU-1 and SNY 16. The analysis of drug combinations was conducted by using CellTiter-Blue™ Cell Viability Assay which yielded the combination index (CI). MK-2206 and representative chemotherapy agent were further evaluated regarding their effects on Akt inhibition and downstream targets using western blots propped with the appropriate antibodies. We assessed the combination of MK-2206 and chemotherapy in three different treatment sequences.
Results: We demonstrated in vitro synergistic efficacy of MK-2206 when combined with carboplatinum and paclitaxel in the three cell lines examined. Efficacy was dose dependent. We assessed the combination of MK-2206 and carboplatin/paclitaxel in three different treatment sequences; Twenty-four hours of exposure to combination chemotherapy followed by a 48-hour exposure to MK-2206 resulted in the highest synergistic antiproliferative effect in all cell lines. On the other hand, the reverse sequence (MK-2206 followed by chemotherapy) and the concurrent treatment schedule were slightly synergistic or additive as well. The effects of MK-2206 on p-Akt and other downstream targets will be available at the meeting.
Conclusions: Our findings suggest that Akt inhibition augments the efficacy of existing gastric cancer therapeutics (carboplatinum and paclitaxel); thus, MK-2206 is a promising agent to treat gastric cancer patients who receive these cytotoxic agents. The altitude of synergy depended on the treatment sequence; a schedule of MK-2206 dosed before or concurrently with chemotherapy was not as effective as being dosed after chemotherapy. Further experiments addressing MK-2206's mechanism of action in combination with chemotherapy are ongoing.
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 C87.
Abstract C98: Evaluation of the PAXgene tissue system: Preservation of morphology and gene expression in human melanoma.
Authors: Hesse Peter , Wyrich Ralf , Voss Thorsten , Rainen Lynne , Groelz Daniel 
Published: June 2012

Abstract
Introduction: PreAnalytiX has recently developed the PAXgene® Tissue System, a formalin-free tissue fixation method for simultaneous preservation of tissue morphology and biomolecules. In this study, PAXgene Tissue was used to stabilize human melanoma specimens. Mirrored samples of melanoma were fixed with either neutral buffered formalin or PAXgene Tissue, or snap frozen in liquid nitrogen (LN2) and were compared for preservation of morphology, antigenicity, RNA and noncoding small RNAs.
Materials and Methods: Three cases of melanoma were equally divided into two parts: one part was fixed with PAXgene Tissue reagents, the second part of cases 1 and 2 were fixed with formalin and the second part of case 3 was snap-frozen in LN2. Formalin and PAXgene Tissue fixed samples were processed and embedded in paraffin (resulting in FFPE and PFPE tissue respectively). Tissue sections were stained with H&E or immunohistochemically for Ki-67 and S100. RNA or total RNA including miRNA was purified from all samples and analyzed for purity, integrity and performance in RT-qPCR assays on a TaqMan® PCR Array for expression analysis of 32 different human endogenous control genes and in 26 different single assays specific for non-coding, small RNAs.
Summary of results: H&E morphology was well preserved in sections of FFPE and PFPE. After optimization of the heat induced epitope retrieval step for PFPE samples, antigen localization, staining intensities, and number of stained cells were equivalent in FFPE and PFPE tissue for Ki67 and S100. RNA purity was generally high with A260/A280 values &gt;1.9 for all samples. RNA integrity as measured on Agilent Bioanalyzer ranged from 7.7 to 9.5 for LN2 samples, between 3.7 to 6.7 for PFPE and 2.1 to 2.8 for FFPE samples. Correlation of gene expression results in qRT-PCR was high between RNA from PFPE and LN2 (R2 = 0.99). Correlation between mRNA from PFPE and FFPE tissue was much lower (R2 =0.86). In contrast, when all the results from 26 different single non-coding, small RNA specific qRT-PCR assays were compared, there was a high correlation between miRNAs from PFPE with LN2 (R2 = 0.99) as with PFPE and FFPE (R2 = 0.99).
Conclusion: The PAXgene Tissue System preserves morphology, antigenicity, RNA and miRNA profiles in human melanoma specimens enabling morphological and multimodal biomarker testing with one sample. Disclaimer: For research use only. Not for use in diagnostic procedures. No claim or representation is intended to provide information for the diagnosis, prevention, or treatment of disease.
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 C98.
Abstract CN07-02: Target discovery with Oncomine: Discovering new targets and positioning old targets by integrative analysis of 10,000s of tumor genomes and transcriptomes.
Authors: Rhodes Daniel R. , Anstett Matthew A. , Williams Paul D. , Wyngaard Peter 
Published: June 2012

Abstract
The identification of oncogenic protein kinases in cancer has prompted the development of several novel targeted therapies. In many cases, such therapies have elicited dramatic clinical responses in patients harboring genetic activation of the target. To identify novel targets and additional opportunities to apply existing targeted therapies, we undertook a systematic analysis of somatic mutations and DNA copy number alterations across 10,000+ of cancer patients from The Cancer Genome Atlas (TCGA), COSMIC and Oncomine™ databases. We applied multiple analysis strategies to filter genetic alterations for those most likely to exert a ‘driver’ oncogenic effect. For somatic mutation data, we prioritized likely oncogenes as those with frequent hotspot mutations and infrequent nonsense mutations. For copy number data, we prioritized likely oncogenes as those undergoing frequent, high-level focal amplifications resulting in concomitant over-expression in amplified cases. To identify additional opportunities to apply existing targeted therapies, we characterized 22 specific kinases that are targeted by approved or investigational therapies. Among the 22 kinases, nearly all showed evidence for recurrent hotspot mutations or high-level focal amplifications in at least a small fraction of tumors. This objective analysis confirmed well known associations between genetic alterations and particular cancer types, but also identified several novel associations, usually in small sub-populations, suggesting additional indications for existing therapies. In addition to this focused analysis, we also conducted a genome-wide survey of all genes with evidence for oncogenic alterations and the cancer types with most frequent alterations. While most of the top hits correspond to well-known oncogenes, several novel candidate oncogenes were prioritized.
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 CN07-02.