bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3754: Characterization of NMS-P285, a new highly selective and potent BRAF inhibitor
Authors: Pulici Maurizio , Amboldi Nadia , Pastori Wilma , Marchionni Chiara , Traquandi Gabriella , Cribioli Sabrina , Lupi Rosita , Modugno Michele , Casale Elena , Scolaro Alessandra , Felder Eduard , Donati Daniele , Isacchi Antonella , Pesenti Enrico , Galvani Arturo , Ciomei Marina 
Published: August 2012

Abstract
Aberrant activation of the MAPK-mediated pathway components, RAF-MEK-ERK, is frequently found in human cancers and clearly contributes to oncogenesis. In particular, one of the three isoforms of RAF, BRAF, presents activating somatic mutations in 60% of melanomas, 50% of thyroid cancers, 10% of colon and 20% ovarian carcinomas. The most common BRAF mutation, substitution of glutamic acid for valine at position 600 within the activation segment of the kinase domain, accounts for 90% of mutated BRAF cases, and results in elevated kinase activity with consequent enhanced promotion of cell survival and proliferation. BRAF selective inhibitors as vemurafenib and dabrafenib have recently shown excellent results in patients with advanced melanoma expressing BRAF V600E mutant form. Here we describe the in vitro and in vivo properties of a novel potent and selective BRAF inhibitor belonging to the arylthiazole class of compounds. This, NMS-P285, is a potent inhibitor of both wild-type and mutated BRAF, with no cross-reactivity in a panel of 61 kinases. This compound occupies the ATP-binding pocket of the activated form of the enzyme (DFG motif in), partly filling the kinase back pocket, (i.e. type I ½ inhibitors). NMS-P285 has an antiproliferative activity in the low nanomolar range only against cell lines bearing BRAF V600E or V600D mutations. Its mechanism of action is confirmed: a strong inhibition of MAPK pathway was observed in BRAF mutated cells whereas in non-BRAF mutated cells MEK activation was not observed. NMS-P285 possesses a favourable in vitro ADME profile and a very good preliminary PK in mouse. When orally administered to mice with BRAF mutated human xenograft tumors, NMS-P285 resulted more potent than both vemurafenib and dabrafenib demonstrating high antitumor activity with strong and persistent tumor regression observed in all mice. Mechanism of action was demonstrated also ex vivo in A375 bearing mice: MAPK pathway resulted to be completely inhibited up to 6 hours after a single treatment at 30 mg/kg. In conclusion, NMS-P285 is a candidate suitable for preclinical development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3754. doi:1538-7445.AM2012-3754
Abstract 3761: Efficacy of the ATP-competitive mTOR inhibitor AZD8055 in PTEN-wild type cancer cells
Authors: Dai Yao , Siemann Dietmar W. 
Published: August 2012

Abstract
Although the PI3K/Akt/mTOR pathway is frequently hyperactivated in human cancers due to the loss of function of the PTEN tumor suppressor, a proportion of cancer cells still carries wild type PTEN and thus the PI3K/Akt/mTOR pathway in these cells may remain unaltered. While it has been widely accepted that these cancer cells are less susceptible to the allosteric mTOR inhibitor rapamycin, it is unclear whether this is also the case for an ATP-competitive mTOR inhibitor. To address this question we evaluated the effects of the mTOR kinase inhibitor AZD8055 in a panel of wild type PTEN expressing cancer cells (6 cell lines of 4 tumor types). The phosphorylated Akt (S473) level was undetectable in most of these cells, suggesting the regular mTOR complex 1 (mTORC1) pathway and low mTOR complex 2 (mTORC2) activity. Cell proliferation was determined by WST-1 (MTT) assay and clonogenic survival was tested by colony formation assay. AZD8055 suppressed cell proliferation at the nanomolar level in a dose dependent manner, with IC50 values in a range of 6∼35 nM for different cell types. In contrast, rapamycin exhibited limited anti-proliferative effect, with less than 50% of inhibition observed even with higher doses in most cell lines. Similarly, clonogenic capacity was impaired by AZD8055 to a greater extent than was the case for rapamycin. To detect the mTOR pathway alterations by drug treatment, two cell lines with different expression levels of mTORC1 downstream pathways were selected: murine mammary tumor 4T1 cells (low phosphorylated S6 and high phosphorylated 4E-BP1) and human breast cancer MDA-MB-231 cells (normal phosphorylated S6 and moderate phosphorylated 4E-BP1). While the phospho-S6K (T389) and phospho-S6 (S235/236) pathway was potently inhibited by both agents, AZD8055 displayed more striking inhibition of the hierarchical 4E-BP1 phosphorylation (T37/46, T70 and S65) than rapamycin in both cells. In addition, both rapamycin and AZD8055 slightly increased Akt phosphorylation (T308 or S473), suggesting that the activation of the feedback loop controlled by S6K was functional. However, the PI3K inhibitor wortmannin did not sensitize cells to either agent, implying such feedback-dependent activation is dispensable for attenuating the drug response. Taken together, these findings indicate that AZD8055 significantly inhibits growth and survival of cancer cells that have wild type PTEN and normal PI3K/Akt/mTOR signaling, an observation mainly associated with the comprehensive activation of 4E-BP1. These data provide in vitro evidence in support of broadening the application of ATP-competitive mTOR inhibitors in cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3761. doi:1538-7445.AM2012-3761
Abstract 3766: Effects of a high-fat meal on the pharmacokinetics of orally administered GSK2118436 in patients with BRAF mutation-positive tumors
Authors: Grossmann Kenneth F. , Infante Jeffrey R. , LoRusso Patricia M. , Sharma Sunil , Blackman Samuel C. , Carson Stanley W. , Krachey Elizabeth C. , Nebot Noelia , Ouellet Daniele , Gordon Michael S. 
Published: August 2012

Abstract
GSK2118436 is a potent and selective small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF mutation-positive tumors. This study evaluated the effect of a high-fat meal on the pharmacokinetics (PK) of a single 150 mg oral dose of GSK2118436 administered to patients with BRAF-mutant solid tumors. This was an open-label, randomized, two-period crossover study. In a cohort of 14 patients, GSK2118436 was administered under fasted state or with a high-fat meal, with a 1-week washout between periods. Blood samples were collected up to 96 hours post-dose to characterize the PK of GSK2118436 and its circulating metabolites. PK parameters were calculated by non-compartmental methods (WinNonlin 5.2). Geometric mean ratios (fed/fasted) for the point estimate and 90% CIs were calculated for Cmax and AUC0-α, and median difference (90% CI) was calculated for tmax using the Hodges-Lehmann non-parametric method. The absence of a food effect can be concluded if the 90% CIs are contained between 0.8 and 1.25 for Cmax and AUC0-α. Following administration of a high-fat meal, median Cmax concentrations were delayed by 3.7 h (90% CI: 2.4-5.0) compared with the fasted state. A high-fat meal decreased the exposure to GSK2118436, with geometric mean ratios (90% CI) for Cmax and AUC0-α of 0.49 (0.35-0.69) and 0.69 (0.57-0.85), respectively. Metabolite exposures were decreased to a similar extent. Based on the data generated in this study, it appears that there is a food effect for GSK2118436, as the 90% CI are not contained within the acceptable boundaries of 0.8 and 1.25. In clinical studies GSK2118436 has been administered on an empty stomach, and results from this study are consistent with these recommendations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3766. doi:1538-7445.AM2012-3766
Abstract 377: Organic Anion Transporting Polypeptides (OATPs): A potential new molecular target for imaging/therapy of hormone dependent breast cancers
Authors: Banerjee Nilasha , Allen Christine , Bendayan Reina 
Published: August 2012

Abstract
The purpose of this research is to explore the potential of Organic Anion Transporting Polypeptides (OATPs), a family of membrane-associated uptake transporters, as a novel molecular target for imaging and treatment of breast cancers. It has been reported that some of the OATP isoforms (e.g. OATP1A2, OATP2B1) are over expressed (up to ten times) in breast cancer tissues as compared to surrounding normal tissues. Furthermore, estrone-3-sulpahte (E3S), a predominant source for tumour estrogen in post-menopausal patients with hormone dependent breast cancers has been characterized to be a substrate for many of the OATP isoforms. This suggests that the two- three times higher E3S concentration reported in malignant tissues, as compared to the surrounding normal tissues, could be due to higher expression and/or increased functional activity of OATPs in breast tumour tissues. By characterizing the differential expression and function of OATPs in breast epithelial cells and breast cancer cells, their potential as novel molecular targets can be established. In this study, the gene and protein expression of seven OATPs (i.e. OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, OATP3A1 and OATP4A1) that are known to recognize E3S as a substrate, were compared in normal breast epithelial cells (MCF10A), hormone dependent breast cancer cells (MCF7) and hormone independent breast cancer cells (MDA/LCC6-435, MDA-MB-231 and MDA-MB-468) by real time qPCR and immunoblotting. OATP mediated E3S uptake was also characterized by transport experiments. Six of the seven OATPs (except SLCO1C1) were found to be expressed in breast cancer cells at the transcript level. Expression of SLCO1A2, 1B1, 1B3, 2B1 and 3A1 was exclusive, similar or significantly higher (p&lt;0.001) in cancer cell lines compared to the normal breast epithelial cells (MCF10A). At the protein level, expression of all the OATP isoforms was observed to be either exclusive or higher in the cancer cell lines as compared to the MCF10A cells. Specificity of OATP mediated E3S uptake was observed only in the cancer cells with significantly higher total uptake in the MCF7 cells. Estimation of the transport kinetics (Km and Vmax) of E3S uptake by the breast cancer cell lines, demonstrated E3S transport efficiency to be 10 times greater in the hormone dependent breast cancer cells than in the hormone independent cells. Taken together, these data suggest that i) OATPs can be a potential molecular target for hormone dependent breast cancers in post menopausal patients and ii) E3S can be used a ligand for actively targeting hormone dependent breast cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 377. doi:1538-7445.AM2012-377
Abstract 3779: Novel oral gallium compounds as modulators of cancer-related accelerated bone loss
Authors: Warrell Raymond P. , Thottathil John K. 
Published: August 2012

Abstract
Accelerated bone loss is associated with a number of metabolic and neoplastic conditions. Estrogen-receptor modulation, bisphosphonates (BP), and RANKL-inhibitors (RLI) are useful for metabolic bone disease. Parenteral BPs and RLIs are also associated with skeletal morbidity, including osteonecrosis. No oral agent has yet proved suitable for treatment or prevention of adverse skeletal-related events (SREs) in cancer patients (pts) with bone metastases. Our prior work showed that low-dose gallium (G) nitrate administered by subcutaneous injection (SC) reduced markers of accelerated bone resorption in pts with bone metastases from various tumor types, as well as advanced Paget's disease. Moreover, extended therapy for 6-12 mos (0.5 mg/kg SC 2 wks on/2 wks off) produced substantial increases in total body calcium (measured by neutron activation analysis) in pts with myeloma receiving chemotherapy. However, inorganic G-compounds also exhibit low oral availability. Therefore, we synthesized a series of organic G-containing compounds to test their suitability as facilitators of long-term G administration. This work isolated several lead compounds that were then evaluated in animal studies. Methods: Isolated compounds were administered by oral gavage to dogs (Calvert Laboratories, Inc.), which then underwent serial blood sampling over 24 hrs. The objective was to achieve target plasma concentrations at specific times that had proved effective in acutely normalizing elevated blood calcium in human subjects with cancer-related hypercalcemia. Results: Various amino acid-like complexes yielded unpredictable results. Proline and carnosine showed only modest oral availability, compared with mandalate and histidine complexes that were superior. Among other organic bidentate G compounds, G4544(a) achieved a peak target, but time-to-peak (TTP) concentrations was delayed. G-4544(b), the same complex but with reduced nitrate content, improved TTP concentrations, but a follow-on study in human subjects failed to reproduce observations in dog (Proc. AACR 2010). To date, the complexes G4546 and G4547 yielded the best results, promptly achieving peak stable concentrations consistent with target objectives. Conclusion: The organic G compound, G4546, will be advanced into human clinical trials to determine its suitability for extended treatment of oncology patients who may develop accelerated bone loss.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3779. doi:1538-7445.AM2012-3779
Abstract 3787: Pharmacokinetics and pharmacodynamics of AV-203, a humanized anti-ERBB3 antibody
Authors: Meetze Kristan , Tyler Steven M. , Fleet Christina , Vincent Sylvie , Gifford James , Gyuris Jeno 
Published: August 2012

Abstract
ERBB3 is widely expressed in human carcinomas, and its over expression is associated with poor prognosis in patients with various carcinomas, (i.e., breast, ovarian, prostate, colorectal, pancreatic, gastric, and head and neck cancers). The presence of ERBB3 correlates with local to distal metastasis in lung, gastric, and colorectal cancers as well as bone invasion in prostate cancer. Activation of ERBB3 is also implicated in the development of resistance to current cancer treatments. Due to its lack of kinase activity, the activation of the ERBB3 receptor is dependent on heterodimerization with active receptor tyrosine kinases (RTKs). The recruitment of ERBB3 into active, heterodimer complexes is mediated by its ligand Neuregulin-1 (NRG-1) or by amplified, over expressed RTKs in a ligand independent manner. Therefore, ERBB3 can crosstalk with most major receptors involved in cancer development and maintenance such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and c-MET. AV-203 is a potent, humanized anti-ERBB3 antibody that inhibits both ligand-dependent and independent activation of ERBB3 both in vitro and in vivo. Pharmacokinetics and pharmacodynamics of AV-203 were characterized in mice using the A549 non-small cell lung cancer xenograft model. AV-203 administered IV in mice exhibits acceptable pharmacokinetics supporting preclinical efficacy studies. AV-203 administered IV in A549 NSCLC xenograft tumor bearing mice had lower serum AUC than naïve mice, demonstrating that the presence of human ErbB3 may alter the PK parameters of AV-203. In evaluating pharmacodynamics in vivo, AV-203 was able to down regulate total ERBB3 and ERBB3 signaling in A549 tumors in a time-dependent manner. Inhibition of ERBB3 signaling correlated with significant dose-dependent tumor growth inhibition in the A549 xenograft model. Dose scheduling studies with the constant AV-203 dose of 2.5 mg/kg revealed that the most efficacious schedule is the more frequent dosing at Q3D. In comparing the total dose of 10 mg/kg per 14 day cycle, at varying dose per injection and frequency, AV-203 resulted in significant tumor growth inhibition at all dose schedules. These data conclude that the efficacy of AV-203 is driven by total drug exposure and that AV-203 is not dependent on Cmax for its antitumor activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3787. doi:1538-7445.AM2012-3787
Abstract 3797: Hyperphosphorylation and desumoylation of RanGAP1·SUMO1
Authors: Oussenko Irina , Holland James F. , Reddy E. Premkumar , Ohnuma Takao 
Published: August 2012

Abstract
Previous work from our laboratory showed that tumor cells exposed to an anticancer mitotic inhibitor, regosertib (ON 01910.Na), resulted in G2/M arrest and hyperphosphorylation of RanGAP1·SUMO1 (HRGS). These findings suggest that regosertib may act either as an inhibitor of a RanGAP1·SUMO1 phosphatase or stimulant of a new kinase (Cancer Res 2011; 71; 4968-76). We further studied the relationship between dephosphorylation and deSUMOylation of HRGS. In the present study we used DU145 prostate cancer cell line. After exposure to one microM regosertib for 24 h, cells were collected and subjected, in equal portions, to lysis in different lysis buffers composed of basic lysis buffer and varied in supplemented inhibitors. Basic lysis buffer contained 10 mM Tris-HCl, pH 8.0; 150 mM NaCl; 1% Triton; 0.5% NP-40; 1 mM EGTA and 1 mM EDTA. Thus, prepared cell lysates were analyzed by Western blot for expression of phosphorylated and non-phosphorylated forms of RanGAP1, RanGAP1·SUMO1, PP1 and Cdc25C. Results: Roche protease inhibitor cocktail, PMSF (0.5 mM), NaF (1 mM) and Na3VO4 (1mM) as inhibitors added to the basic lysis buffer were unable to protect against loss of SUMO-group from RanGAP1·SUMO1 and, concomitantly, against de-phosphorylation of PP1 phosphatase at T-320. However, addition of N-ethylmaleimide (NEM, an inhibitor of deSUMOylation) as a single inhibitor supplement in the basic lysis buffer resulted in concentration-dependent (2.5 ∼ 40mM) inhibition of deSUMOylation of HRGS. Yet, even at lower NEM concentration RanGAP1, devoid of the SUMO-group, was still phosphorylated. This might be in correlation with our finding that even low concentration of NEM in the lysis buffer kept PP1 in phosphorylated state at T320 (which is inhibitory to PP1), preventing it from auto-dephosphorylation and re-activation. Also, neither regosertib (up to 100 microM) nor okadaic acid (OA, up to 1 microM), added to the basic lysis buffer as putative inhibitors, could prevent loss of SUMO group from HRGS and dephosphorylation of PP1 at T320. Regosertib in the lysis buffer did not prevent dephosphorylation of hyperphosphorylated Cdc25C (aka mitotic Cdc25C), while NEM and OA did (the latter implies that dephosphorylation was carried out by PP1 in the lysate). Conclusion: These data show that hyperphosphorylated RanGAP1·SUMO1 can be deSUMOylated, but remains phosphorylated. DeSUMOylation may be a prerequisite for RanGAP dephosphosphorylation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3797. doi:1538-7445.AM2012-3797
Abstract 3798: Cryptotanshinone inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3/ERK and small GTPase pathways
Authors: Luo Yan , Huang Shile 
Published: August 2012

Abstract
Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here we show that CPT inhibited the tube formation of mouse lymphatic endothelial cells (LECs) in a concentration- and time-dependent manner. This effect was in part associated with inhibition of VEGFR-3 expression, as overexpression of VEGFR-3 conferred resistance to CPT inhibitory effect on tube formation in LECs, whereas downregulation of VEGFR-3 mimicked the effect of CPT, blocking the tube formation. Further study revealed that CPT inhibited phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2), a downstream effector of VEGFR-3. Overexpression of VEGFR-3 attenuated CPT inhibition of ERK1/2 phosphorylation, whereas downregulation of VEGFR-3 inhibited ERK1/2 phosphorylation in LECs. Ectopic expression of constitutively active MKK1 resulted in activation of ERK1/2, and partially prevented CPT inhibition of LEC tube formation. In addition, we also found that CPT inhibited protein expression and activities of Cdc42 and Rac1, but not RhoA. Downregulation of Cdc42 or Rac1 inhibited LEC tube formation, mimicking the effect of CPT. However, expression of constitutively active Cdc42 and Rac1 concurrently, but not Cdc42 or Rac1 alone, rendered resistance to CPT inhibition of LEC tube formation. The results suggest that CPT inhibits LEC tube formation at least in part through inhibiting VEGFR-3-mediated ERK and the small GTPase signaling pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3798. doi:1538-7445.AM2012-3798