bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C229: BAL27862: A novel anticancer agent which dissociates microtubules and creates a distinct cellular phenotype
Authors: Bachmann Felix , Burger Karin , Pohlmann Jens , Kellenberger Laurenz , Lane Heidi 
Published: June 2012

Abstract
Background: BAL27862 is a synthetic small molecule potently inducing apoptosis in cancer cells due to tubulin depolymerization. BAL27862 has a broad in vitro anti-proliferative activity against a range of human tumor lines (low nM IC50s) and elicits significant antitumor responses in animal models of human cancer, including multidrug-resistant tumors, after oral or intravenous administration.
Materials and Methods: Anti-proliferative activity was analyzed with monolayer (crystal violet) or soft agar (clonogenic) assays. Effects on microtubules (MTs) were assessed by immunofluorescence (IF) or immunoblotting (IB) for -tubulin; centrosome maturation by IF for -tubulin.
Results: BAL27862 showed potent anti-proliferative activity in vitro on 8 NSCLC cell lines (IC50 range 8.5–17nM). Significant activity was also observed on 3 patient-derived NSCLC lines, highly resistant to paclitaxel (clonogenic IC50s: paclitaxel &gt;3.5 M; BAL27862 15nM, 29nM, 300nM). In all tumor histotypes analyzed, BAL27862 elicited a unique MT phenotype, distinct from that observed with conventional MT-targeting agents (paclitaxel, vinblastine, colchicine) or other mitotic inhibitors. In proliferating A549 NSCLC cells (anti-proliferative IC50: 16±2nM; MT depolymerization IC50: 10–20nM) BAL27862 caused a concentration-dependent effect on MTs. In interphase cells, at concentrations ≥15nM the MT network collapsed towards the MT-organizing center, with an absence of peripheral MTs. In dividing cells, an apparent fragmentation of the mitotic spindle occurred at 15nM, associated with the appearance of tiny MT asters. The asters decreased in size as concentrations increased (15–100nM), and were co-localized with condensed chromatin. A comparative titration (5–100nM) with the clinically used MT destabilizer vinblastine (VBL) indicated no phenotypic overlap. VBL-treated interphase cells had a mesh-like MT network with peripheral MTs intact, while in dividing cells aberrant, spindle-like structures were observed at concentrations ≥15nM. Using non-immortalized HS68 human fibroblasts, no obvious effects of BAL27862 (10–20nM) on centrosome number or size were observed, as defined by -tubulin staining; in contrast to an increase in size and decrease in apparent resolution of the centrosomes after treatment with VBL at the same concentrations. BAL27862 treatment also converted the abnormal spindle structures induced by the MT destabilizers VBL or colchicine into the distinct and dominant BAL27862 MT phenotype, further highlighting it's novel mechanism of MT disruption.
Conclusions: BAL27862 is a new tubulin-interacting agent with a novel mechanism of action leading to a unique MT phenotype. These observations, together with a broad antitumor activity targeting refractory tumors, strongly support further development of BAL27862 as an anticancer agent.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C229.
Abstract C230: MPC-6827 is safely combined with temozolomide for the treatment of patients with metastatic melanoma
Authors: Hamid Omid , Akerley Wallace , Stephenson Joseph , Yu Margaret K. , Evans Brent A. , Mather Gary , Swabb Edward A. , Hwu Wen-Jen 
Published: June 2012

Abstract
Purpose: MPC-6827 (4-arylaminoquinazoline) is a microtubule destabilizing agent with in vitro cytotoxic and in vivo vascular disrupting characteristics. We determined the dose-limiting toxicity (DLT) and the most tolerable doses of MPC-6827 in combination with daily administration of temozolomide.
Experimental Design: Metastatic melanoma patients were treated weekly with a 2-hour intravenous infusion of MPC-6827 for 6 or 3 consecutive weeks during 8- or 4-week cycles, respectively. Temozolomide was administered orally either at 75 mg/m2 daily during the first 6 weeks of an 8-week cycle or at 85 mg/m2 daily during the first 3 weeks of a 4-week cycle. Therapy was repeated every 56 days in the 8-week cycle and every 28 days in the 4-week cycle. Three pre-selected doses of MPC-6827 were tested: 2.1, 2.7, and 3.3 mg/m2. Patients in the 2.1 mg/m2 dose level were treated at 8-week cycles. Due to the inconveniences of 8-week cycles, patients enrolled in the 2.7 and 3.3 mg/m2 dose levels were treated at 4-week cycles. Patients were observed for DLTs during the first cycle. Plasma samples were obtained at various timepoints after MPC-6827 infusion to evaluate concentrations of MPC-6827 and temozolomide. A conventional “3+3” design was used for dose escalation.
Results: Twenty-two patients (median age, 59 years; range, 35–81; median number of prior therapies,2; range 1–5) with stage IV melanoma (3 M1b, 19 M1c) were enrolled, two patients are still receiving therapy. Twenty patients (91 %) had an ECOG score 0–1 and ten (45%) patients had brain metastases. Eight patients (36%) received temozolomide/dacarbazine therapy previously. Four patients (18%) experienced a grade 3 or greater MPC-6827-related SAE, which include an increased Troponin I level (n=1), cerebral hemorrhage (n=2), and cerebral infarction associated with a brain metastasis (n=1). One of the cerebral hemorrhages was deemed a DLT. Median MPC-6827 half-life ranged from 2.9–4.0 hours. Cmax and AUC increased proportionally with dose. The highest dose tested was 3.3 mg/m2 once weekly with temozolomide 85 mg/m2 daily for 3 weeks of a 4-week cycle. Employing modified RECIST criteria, two patients achieved partial response (durations of 6 and 4 months). Another nine patients achieved stable disease (duration range: 1 – 6 months).
Conclusion: The combination of MPC-6827 and temozolomide is safe and well tolerated in patients with refractory metastatic melanoma, including brain metastases. Responses are durable. A dose reduction of MPC-6827 is not required when combined with temozolomide. Incidences of cerebral hemorrhage, deep venous thrombosis and/or pulmonary emboli were similar to those in previous reports.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C230.
Abstract C246: nab®-paclitaxel targets tumor stroma and results, combined with gemcitabine, in high efficacy against pancreatic cancer models
Authors: Maitra Anirban , Rajeshkumar N.V. , Rudek Michelle , Garrido-Laguna Ignacio , Laheru Daniel , Iglesias Jose , Desai Neil , Von Hoff Daniel D. , Hidalgo Manuel 
Published: June 2012

Abstract
nab®-paclitaxel (Abraxane ™, Abraxis Bioscience, Los Angeles, CA) is an albumin-bound nano particle formulation of paclitaxel that may target SPARC (secreted protein acid-rich in cysteine). In a phase I/II study in patients with advanced pancreatic cancer, the combination of nab®-paclitaxel and gemcitabine resulted in impressive clinical activity with an objective response rate of 40%, 10.3 months median survival and 78 % of patients having a decrement of CA199 &gt; 50 % (Von Hoff et al, ASCO 2009). To gain insight into the mechanisms underlying the high efficacy of this combination, we treated 11 freshly generated pancreatic cancer xenografts from the Johns Hopkins PancXenoBank collection. nab®-paclitaxel, in combination with gemcitabine, doubled the response rate of either agent alone and resulted in a 57% response rate, mimicking the results obtained in the clinical trial. Tumors treated with nab®-paclitaxel showed a marked decrement in the otherwise abundant fibrotic stroma characteristic of pancreatic cancer and present in control and gemcitabine only treated animals. The elimination of the stroma resulted in marked cellular tumors and increased tumor vascularization and cell-vessel proximity. Consequently, the intratumoral concentration of gemcitabine increased by 3.7 fold in mice treated with nabR-paclitaxel and gemcitabine versus those receiving gemcitabine alone. We conclude that nab®-paclitaxel effectively eliminates pancreatic cancer stroma resulting in increased delivery of gemcitabine and high antitumor effects. Targeting tumor stroma appears a promising strategy in pancreatic cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C246.
Abstract C63: Biological characterization of GSK2126458, a novel and potent inhibitor of phosphoinositide 3-kinase and the mammalian target of rapamycin (mTOR)
Authors: Hardwicke Mary Ann , Lu Hong , Luo Lusong , Diamond Melody , Sung Chiu-Mei , Carson Jeffrey D. , Plant Ramona , Gardiner Christine , Wang Jamin , Oleykowski Catherine A. , Gontarek Richard , Van Aller Glenn , Gilbert Seth , Sutton David S. , Tummino Peter J. , Wooster Richard F. , Knight Steven D. , Jackson Jeffrey R. , Dhanak Dashyant , Auger Kurt R. 
Published: June 2012

Abstract
The phosphoinositide 3-kinase (PI3K) pathway is among the most commonly activated pathways in human cancer. The biological role of PI3K in growth and survival of cancer cells and the prevalence of activating mutations in human cancers are well documented and a significant proportion of tumors would be predicted to benefit from inhibition of this pathway. Here we report on the characterization of the pan-PI3K pyridylsulfonamide inhibitor GSK2126458: a very potent (PI3K app Ki = 19 pM), reversible, ATP-competitive inhibitor of wild-type PI3K and the ‘hotspot’ activating mutants of p110 found in human cancer. GSK2126458 demonstrated good selectivity for the PI3K family of enzymes including the mTORC1 and mTORC2 complexes, when evaluated in a large panel of protein kinases. Consistent with potent PI3K enzyme inhibition, GSK2126458 decreased the cellular levels of phosphorylated AKT, p70S6K, PRAS40 and ERK in a concentration and time dependent manner, the IC50 for pAKT in the HCC1954 breast carcinoma cell line was 2 nM. GSK2126458 induced the nuclear translocation of the FOXO3a transcription factor in a concentration dependent manner that mechanistically appeared bimodal. Growth inhibition was time and concentration dependent with a 3 day exposure resulting in a growth IC50 (gIC50) of 9 nM in HCC1954 cells with evidence of cell death. Cell death correlated with induction of caspase 3 and 7 activity suggesting apoptosis was the mechanism of cell death. GSK2126458 had a breadth of activity for potent cell growth inhibition and induction of cell death in a variety of human cancer cells. GSK2126458 demonstrated robust, dose dependent in vivo pharmacodynamic activity as measured by inhibition of phospho-AKT in advanced BT474 breast cancer cell xenograft tumors. Inhibition of AKT phosphorylation was rapid and lasted for several hours after a single oral administration of GSK2126458. Transient increases in plasma insulin and blood glucose were observed. Evaluation of in vivo tumor growth effects of GSK2126458 in xenograft models demonstrated dose dependent tumor growth delay in several models of diverse tumor lineage and tumor regression in a breast cancer xenograft. The biological profile of GSK2126458 supports the clinical advancement of this compound and GSK2126458 has entered Phase I human clinical trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C63.
Abstract A10: Combined blockade of VEGF and Ang2 promotes dramatic tumor necrosis and growth inhibition of colorectal cancer xenografts.
Authors: Lalani Alshad S. , Castanaro Carla , Kyle Alastair H. , Minchinton Andrew I. , Thurston Gavin , Daly Christopher 
Published: June 2012

Abstract
Background: VEGF and Angiopoietin-2 (Ang2) are secreted growth factors that are elevated in many human malignancies and function to regulate critical yet distinct aspects of tumor angiogenesis. While blockade of VEGF in combination with standard chemotherapy regimens has been demonstrated to improve survival in patients with metastatic colorectal cancer, the clinical benefit is transient, with most patients experiencing disease progression. We hypothesized that a combination treatment with agents that block the VEGF and Ang2 signaling pathways would provide more potent inhibition of tumor angiogenesis than single agent therapies, thereby resulting in more pronounced and/or durable effects on tumor growth.
Methods: We assessed the antitumor effects of aflibercept (VEGF Trap) as a single agent or in combination with REGN910, a fully-human monoclonal antibody that specifically binds and potently inhibits Ang2 (each agent dosed at 15 mg/kg q4dx3). We employed whole tissue section mapping and multiplexed immunostaining techniques in Colo205 human tumor xenografts to assess changes in vessel density (CD31), hypoxia (pimonidazole) and tumor cell death (TUNEL).
Results: The combination treatment of REGN910 plus aflibercept provided significantly greater tumor regression than single agent aflibercept treatment. No additive gross toxicities or body weight loss were observed following the combination treatment. Consistent with a more potent effect on tumor growth, the combination treatment caused a more pronounced decrease in tumor vessel density and a greater increase in tumor hypoxia at 24 hr post-treatment than either single agent. Finally, the combination treatment promoted much more dramatic tumor cell death at 72 hr than either single agent.
Conclusions: Combined inhibition of VEGF and Ang2 using aflibercept plus REGN910 provides much more pronounced antitumor effects than either single agent, suggesting that combining these agents in the clinic is an attractive strategy to extend the benefit of anti-VEGF therapies.
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 A10.
Abstract A193: Assessment of effect of low- and high-fat diet on E7050 pharmacokinetics and characterization of E7050 pharmacokinetics after 100 mg, 200 mg, and 400 mg single oral doses in healthy subjects.
Authors: Mistry Bipin , Nishioka Yuki , Fan Jean , Verbel David 
Published: June 2012

Abstract
Purpose: E7050, an orally available c-MET tyrosyne kinase inhibitor is currently under evaluation for the treatment of advanced malignancies. The objectives of this study were to evaluate (1) effects of a standard high-fat and low-fat meal on the pharmacokinetics (PK) of 100 mg E7050; (2) E7050 PK following single doses of 100, 200 and 400 mg of E7050 in under fasted condition and (3) the safety of E7050 in healthy subjects.
Methods: This open label study consisted of two parts: Part A (Food Effect) and Part B (Rising dose PK). Part A was a randomized, single-dose, three-way crossover study with a 2-week wash out between treatments. In Part A, 18 subjects received a single dose of E7050 (100 mg) in a fasting state, following a high-fat meal or a low-fat meal. In Part B, 12 and 10 subjects sequentially received 200 and 400 mg E7050 doses, respectively in fasted state. Serial blood samples for E7050 PK analysis were taken up to 196 h post-dosing. Subjects were evaluated for adverse events (AEs).
Results: Study results are summarized in Table 1. Based on E7050 Cmax, AUC(0−t) and AUC(0−inf), the presence of food at the time of dosing reduces exposure by 21 to 28%. When administered with food (high-fat or low-fat), the lower 90% CI limit for E7050 is below 80% for Cmax and AUC. Thus the food effect is independent of the type of meal consumed. However, the magnitude of the observed food effect was modest and clinically insignificant. PK of E7050 was found to be linear following single doses of 100 to 400 mg E7050. In this study, a single dose of the 400-mg E7050 tablet was safe and well tolerated when administered under fed and fasted conditions. Most TEAEs were mild in severity; there were no treatment-related severe or serious AEs and no treatment-related AEs leading to study treatment withdrawal. There were no clinically significant changes in vital sign assessments, clinical laboratory analyzes or ECG parameters.
Conclusion: Consumption of a low- or high-fat meal had no clinically significant effect on E7050 PK and E7050 can be administered without regards to food. PK of E7050 was found to be linear following single doses of 100 to 400 mg E7050. This study demonstrated an acceptable safety/tolerability profile of E7050 in healthy subjects.

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 A193.
Abstract A78: Simvastatin synergistically potentiates tipifarnib cytotoxic and apoptotic effects and disrupts Ras membrane localization in human leukemia cells.
Authors: Ahmed Tamer , Hayslip John , Leggas Markos 
Published: June 2012

Abstract
Background: Tipifarnib, a farnesyl transferase inhibitor, was initially designed to prevent Ras farnesylation and its subsequent membrane localization, which is necessary for Ras mediated signaling. Although, the clinical effectiveness of tipifarnib as a single agent in solid tumors was limited, it was modest in hematologic malignancies. Alternative prenylation by geranylgeranyl transferase has been postulated as an escape mechanism by which Ras evades the effect of tipifarnib. Simvastatin, an anti-hyperlipidemic drug that inhibits 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, has been shown in several studies to induce apoptosis in cancer cells through blockade of the geranylgeranylation pathway of small GTPases. Thus, we hypothesized that simvastatin can augment the cytotoxic effect of tipifarnib by blocking the alternative Ras prenylation pathway. Our studies were carried out in a panel of leukemia cell lines. Methods: Studies were carried out using five cell lines of varied leukemic origin including HL60, K562, Molt4, Jurkat and HSB2. Cells were exposed to increasing drug concentrations for 72 hours either as a single or combination treatment with simvastatin and tipifarnib. Cell viability was measured using AlamarBlue (Invitrogen) and the combination index values were calculated based on the Chou-Talalay equations. Apoptosis was evaluated using Annexin V assay. Biochemical assays assessing the expression of caspases, c-PARP and Ras, in both membrane and cytosolic fractions, were also used. Results: The combination of tipifarnib with simvastatin was shown to induce a synergistic cytotoxic effect in all cell lines tested. Notably, our results showed that coadministarion of simvastatin and tipifarnib resulted in the induction of apoptosis through the activation of several apoptotic markers including Caspase 3, 7 and 9 as well as the upregulation of cleaved PARP. These effects were accompanied by disruption of Ras membrane localization and its sequestration into the cytosol.
Conclusions: These findings demonstrate that combining simvastatin with tipifarnib effectively disrupts Ras prenylation and induces apoptosis in human leukemia cell lines. These effects were observed with simvastatin and tipifarnib concentrations that can be achieved in the clinic. Thus, the effectiveness of this combination should be explored further in future clinical 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 A78.
Abstract A79: Evidence that the antitumor effects of AMPK activation and crosstalk with the Akt pathway are dependent on the genetic profiles of human breast cancer cell types.
Authors: El-Masry Omar S. 
Published: June 2012

Abstract
The prevalence of breast cancer and drawbacks of many current therapeutic modalities underline the need for novel therapies. Those based on signal transduction have the potential for fewer side effects due to inherent redundancy of pathways. The fuel sensing enzyme, AMP-activated protein kinase (AMPK), is activated by low energy levels. We (El-Masry et al, Oncology Letters, in press), and others, have identified that AMPK is involved in cell proliferation and growth and could be a potential therapeutic target in cancer. Pharmacological activation of AMPK in MCF-7 (p53wt, ER+), MDA-MB-231 (p53−, ER−) and T47D (p53−, ER+) human breast cancer cell lines using 5-Aminoimidazole-4-carboxamide ribotide (AICA-ribonucleotide) resulted in anti-proliferative effects, with T47D cells being the most sensitive. These effects correlated with changes in apoptosis, including mitochondrial membrane potential (assayed by fluorescence activated cell sorting (FACS)) and Bax translocation to the outer mitochondrial membrane (assayed by immunofluorescence) suggesting that the apoptotic signal was p53 independent. Caspase inhibition showed that the anti-proliferative effect of AMPK activation was mediated by caspase 9 in all cell types. Execution was by caspase 6 in MCF-7 cells and caspase 3 and 6 in MDA-MB-231 cells. T47D cells were less responsive to both caspase inhibition and PARP cleavage than MCF-7 and MDA-MB-231. AMPK activation also resulted in trans-activation of p21, although this was dependent on the basal level of p21 in the different cell types. Previously we reported differential effects on the same cell lines in terms of PI3K/Akt signaling. Our current studies on possible crosstalk between the AMPK and PI3K/Akt pathways show that, whilst AMPK activation led to inhibition of Akt phosphorylation, the effect of Akt inhibition on AMPK phophorylation was cell type dependent. Akt inhibition increased phosphorylation of AMPK in T47D cells, but not in MCF-7 or MDA-MB-231 cells. Inhibition of Akt also decreased proliferation of T47D and MCF-7 cells, without effect on MDA-MB-231 cells. The adipokine leptin inhibited AMPK phosphorylation in all cell lines. Blockade of either Akt or mTOR inhibited this effect of leptin in T47D cells, suggesting that was mediated, at least in part, by activation of Akt, but did not affect MCF-7 or MDA-MB-231 cells. These data demonstrate crosstalk between metabolic and survival signaling. This interactive signaling was cell type dependent. In conclusion, the potential therapeutic effects of AMPK and its interaction with survival pathways were found to be different depending on genetics of the breast cancers investigated.
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 A79.