bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4394: Identification of molecular determinants of response to GSK1120212B, a potent and selective MEK inhibitor, as a single agent and in combination in RAS/RAF mutant non-small cell lung carcinoma cells
Authors: Liu Li , Hong Shi , Zhang Vivian , Gilmer Tona 
Published: June 2012

Abstract
MEK, a downstream effector for RAS, RAF and receptor tyrosine kinases, represents a promising target for treatment of RAS/RAF mutated Non Small Cell Lung Carcinoma (NSCLC). GSK1120212B is a highly potent and selective oral MEK inhibitor currently in phase II clinical trials. To identify markers of response to GSK1120212B and to generate hypotheses for effective combination therapies, we characterized baseline signaling pathways and gene expression profiles in a panel of 29 NSCLC lines with RAS/RAF mutations and determined their sensitivity to GSK1120212B, erlotinib (EGFR inhibitor), everolimus (mTOR inhibitor), docetaxel and the combination of GSK1120212B with these agents. Inhibition of cell growth and induction of apoptosis were determined after 72 and 24 hours of treatment, respectively. GSK1120212B potently inhibited cell growth (IC50≤ 50 nM) in 13/29 (45%) of the lines and induced apoptosis in 8/29 (28%) of cell lines. We also identified genes such as TGFA, EREG, LGALS3, CTNND1, ARHGEF3, KLF4, RPH3AL, STN2, TWIST2 and FOXC1 whose expression levels were highly associated with the response to GSK1120212B. Cell signaling analyzed at baseline demonstrated that sensitivity to GSK1120212B was associated with high levels of pMEK, low levels of pAKT/pFOXO3a and wild-type PTEN, and resistance was associated with high levels of pAKT/pFOXO3a or mutations of PTEN/PIK3CA/CTNNB1 in RAS/RAF mutant lines. These results suggest combination approaches for cell lines resistant to single agent GSK1120212B. Erlotinib or everolimus alone showed little activity in RAS/RAF mutant lines. The combination of GSK1120212B and erlotinib was synergistic and/or enhanced cell growth inhibition in 6 out of 10 RAS/RAF mutant lines tested, three of which had HER1 amplification or over-express TGFA and EREG. The combination of GSK1120212B and everolimus enhanced cell growth inhibition in 25/29 (86%) of cell lines and increased apoptosis in 12/28 (43%) of RAS/RAF mutant lines. Intriguingly, the RAS/RAF mutated lines that were sensitive to GSK1120212B alone as measured by induction of apoptosis were less responsive to docetaxel. Further, the combination of GSK1120212B and docetaxel was synergistic or increased apoptosis in 20/28 RAS/RAF mutated lines. Our results provide a strong rationale for testing GSK1120212B and these combinations in the clinic and warrant further investigation of the gene expression signatures and genetic mutations in patients to ultimately improve treatment outcome in RAS/RAF mutated NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4394. doi:10.1158/1538-7445.AM2011-4394
Abstract 4406: Multiple organic anion transporting polypeptides (OATPs) contribute to the in vitro and in vivo disposition of docetaxel
Authors: Ho Richard H. , Leake Brenda F. , Teft Wendy , Kim Richard B. 
Published: June 2012

Abstract
Docetaxel is one of the most widely used antineoplastic agents and is approved for the treatment of breast, lung, ovarian, prostate, gastric, and head and neck cancers. It is a semisynthetic taxane derived from an extract of the needles of European yew tree (Taxus baccata). Docetaxel promotes the assembly of microtubules and stabilizes their formation by inhibiting depolymerization and cell death results from inhibition of normal microtubule processes. While it is known that docetaxel is a substrate of efflux transporters such as P-glycoprotein (P-gp), less is known regarding transporters that could mediate its cellular uptake. Accordingly, an array of drug uptake transporters, including organic anion, organic cation and bile acid transporters, were evaluated for radiolabeled docetaxel transport utilizing a recombinant vaccinia-based method in a heterologous cell system. Screening transport experiments and kinetic analysis in HeLa cells demonstrated that multiple organic anion transporting polypeptides (OATPs), including OATP1A2, OATP1B1, and OATP1B3, were capable of docetaxel transport in vitro. In addition, after intravenous administration, in vivo docetaxel transport experiments in Oatp1b2-/- mice (ortholog to hepatic OATP1B1/OATP1B3) revealed ∼5-fold higher plasma concentrations of docetaxel in Oatp1b2-/- mice versus their wild-type counterparts. The liver to plasma ratio of docetaxel was ∼3-fold increased in wild-type mice versus Oatp1b2-/- mice. Furthermore, the pharmacokinetic profile of docetaxel is characterized by substantial interindividual variability, with an up to tenfold difference in drug clearance, even in patients with normal hepatic function. A panel of single nucleotide polymorphisms (SNPs) in OATPs was assessed for docetaxel transport. Multiple SNPs in SLCO1A2, 1B1 and 1B3 were associated with impaired docetaxel transport in vitro. In conclusion, multiple OATPs were capable of transporting docetaxel in vitro and in vivo, suggesting these transporters are important to docetaxel disposition. A number of OATP variants were associated with significantly impaired docetaxel transport, which may have important toxicological and therapeutic ramifications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4406. doi:10.1158/1538-7445.AM2011-4406
Abstract 4439: A reversibly self-crosslinking nano-carrier system for efficient anticancer drug delivery
Authors: Li Yuanpei , Xiao Kai , Luo Juntao , Xiao Wenwu , Lee Joyce , Lam Kit S. 
Published: June 2012

Abstract
It is known that the intracellular concentration of glutathione (GSH) is substantially higher than that in the cellular exterior (∼10 mM vs ∼2 μM) and many types of tumor cells have an elevated GSH level compared to normal cells. This dramatic variation of the GSH concentration provides an opportunity for designing tumor specific drug delivery systems. Most of the chemotherapeutic drugs used in clinic suffer from severe dose-limiting side effects. In order to enhance the therapeutic efficacy and minimum the side effect of these drugs, we developed a stable and efficient nano-carrier drug delivery system based on the disulfide crosslinked micelles comprise of poly (ethylene glycol) (PEG) and dendritic oligmers of cholic acids and cysteines. Various poorly water-soluble anticancer drugs can be efficiently incorporated inside these polymeric nano-carriers. The nano-carriers are stabilized by disulfide bridges in the core to avoid premature release of the loaded drugs during circulation. After reaching the tumor sites via enhanced permeability and retention (EPR) effect, the nano-carriers will disassemble to release the core-loaded drugs upon the cleavage of disulfide bridges under reductive conditions following the intracellular uptake or triggered by additional reducing agents. The crosslinked nano-carriers were spherical with a uniform size of 30 ± 5 nm, and can load paclitaxel (PTX) in the core with drug loading content up to 35% (w/w). Cross-linking of the nano-carriers within the core reduced their critical aggregate concentration and greatly enhanced their stability in non-reductive physiological conditions. The release of PTX from the crosslinked nano-carriers was significantly slower than that from non-crosslinked nano-carriers and can be gradually facilitated in a reducing environment. The fluorescence intensity of BODIPY 650/665 (near infrared dye) labeled disulfide crosslinked nano-carriers sustained up to 24 hours within the blood stream of nude mice while that of non-crosslinked nano-carriers decreased faster and fell into the background level within 8 hours post injection. Targeted drug delivery to tumor site with these crosslinked nano-carriers was demonstrated by near infrared fluorescence imaging in nude mice bearing ovarian cancer xenograft. The nano-formulation of PTX was found to be less toxic than its free drug form in nude mice. We further demonstrated the crosslinked nano-formulation of PTX was more efficacious than both free drug and non-crosslinked nano-formulation of PTX in ovarian cancer xenograft model. This new class of nano-therapeutics shows great promise in the future cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4439. doi:10.1158/1538-7445.AM2011-4439
Abstract 4452: Controlled release complex of cisplatin for mesothelioma: gamma-PGA/Cisplatin complex formulation
Authors: Lee Chunman , Sasai Masao , Sawa Yoshiki 
Published: June 2012

Abstract
Cisplatin is the standard anti-tumor drug for mesothelioma, and other malignant tumors, however acute renal failure due to renal tubule injury is often induced as its adverse event. Hence, the dose of cisplatin is limited by the patient's renal function.
We developed the Cisplatin controlled release complex that released cisplatin steadily, and relieved the adverse event, and examined its characteristics.
1) Slow release of cisplatin from novel complex
Concentration of cisplatin penetrated from the dialysis membrane was measured by ICP atomic emission spectrometer.
- Approximately 4% of cisplatin was released by day1 (initial burst was very low), and 10% of cisplatin was released by day 15, while free cisplatin oozed out from dialysis membrane immediately.
2) Cytotoxicity of novel complex in vitro
Cytotoxicity to murine mesothelioma cell line was measured by MTT assay.
- Over 10 μg/mL of cisplatin, novel complex possessed cytotoxicity, but under 5 μg/mL of novel cisplatin complex did not inhibit the growth of the murine mesothelioma cell line.
3) Bio-distribution of novel cisplatin complex in mice
Novel cisplatin complex was administrated intra-peritoneal cavity, and the cisplatin concentration of each organ was measured at 1, 3, 5, 7 days after the administration.
- Cisplatin of the complex was kept the concentration in the blood after the initial peak concentration, while free cisplatin was disappeared immediately.
Furthermore, cisplatin was found in the concentrated amount in the liver, since novel complex was accumulated in the liver at the early phase as a storage of cisplatin, and cisplatin was released steadily into the bloodstream.
4) Acute toxicity test for mouse
50 mg/kg of novel cisplatin complex was administrated into the peritoneal cavity, and mice were observed.
- All mice were alive with 9 days after cisplatin complex administration.
5) The anti-tumor efficacy of novel cisplatin complex in mesothelioma bearing mice
Each 10 mg/kg of cisplatin formulation was administrated into the peritoneal cavity at five days after subcutaneous inoculation of murine mesothelioma cells.
- On 9 days after cisplatin formulation administration, novel cisplatin complex was more effective than free cisplatin.
Conclusions; We have demonstrated that novel cisplatin complex that releases cisplatin steadily into the bloodstream can be successfully used for the chemotherapy without severe adverse event, despite high dose administration. Although much additional study of this complex is required, the results in this study warrant additional development of this complex for potential investigation into its use in clinical tumor chemotherapy for mesothelioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4452. doi:10.1158/1538-7445.AM2011-4452
Abstract 4460: Aromatase inhibition by active tamoxifen metabolites
Authors: Lu Wenjie J. , Flockhart David A. 
Published: June 2012

Abstract
Introduction: The mechanism of tamoxifen action in the treatment of breast cancer is believed to be via active metabolites that act as potent antagonists at the estrogen receptors. Despite this, few data have been published that relate the concentrations of these metabolites to their expected clinical effects. Since anti-estrogenic clinical effects may be brought about not only by estrogen antagonism but also by reduced estrogen concentrations, we tested the direct effects of tamoxifen and its active metabolites on aromatase activity.
Methods: The activity of recombinant human aromatase was measured by following the generation of fluorescent metabolite from 7-methoxy-4-trifluoromethylcoumarin (MFC) in microsomal incubations in the presence and absence of multiple concentrations of tamoxifen, endoxifen, N-desmethyl-tamoxifen and 4-hydroxy-tamoxifen. Inhibition of aromatase was determined at enzyme concentrations set at 7.5 nM by measuring the percentage of enzyme activity remaining.
Results: With MFC concentrations at the Km (25 µM), the IC50s for endoxifen and N-desmethyl-tamoxifen were 6.1 µM and 20.7 µM respectively. At concentrations up to 50 µM, no appreciable inhibition by tamoxifen or 4-hydroxy-tamoxifen was observed. Detailed characterization of inhibition by endoxifen and N-desmethyl-tamoxifen across a range of substrate concentrations demonstrated non-competitive kinetics for both inhibitors. The Ki values for endoxifen and N-desmethyl-tamoxifen were 4.0 µM and 15.9 µM respectively. Preincubation of these tamoxifen metabolites with aromatase did not demonstrate any irreversible effect on enzyme activity.
Discussion: Among tamoxifen and its three major metabolites, only endoxifen and N-desmethyl-tamoxifen were found to be potent inhibitors of aromatase. This enzyme is the major source of estrogen in humans, and changes in its activity may thus alter estrogen-regulated physiology. Inhibition by these tamoxifen metabolites may contribute to changes in serum and tissue estrogen concentrations, and may explain in part the variability in bone density, serum lipid concentration, severity of musculoskeletal pain and breast cancer recurrence observed in patients taking tamoxifen. Relationships between tamoxifen metabolite concentrations and clinical outcomes may be complex, and mechanisms that underlie the multiple clinical effects of tamoxifen include the possibility of aromatase inhibition by endoxifen and N-desmethyl-tamoxifen.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4460. doi:10.1158/1538-7445.AM2011-4460
Abstract 4471: Antitumor effects of 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) on thyroid cancer cell lines with BRAF V600E mutation
Authors: Yim Ji Hye , Choi Hyun Jeong , Kim Eui Young , Kim Tae Yong , Kim Won Bae , Jang Sejin , Shong Young Kee 
Published: June 2012

Abstract
Background : Anaplastic thyroid carcinoma is one of the most aggressive human cancers with a median survival of only 6 months. Local surgical tumor debulking and combined with radio-chemotherapy is conventionally used but low success rate urges the search for new therapeutic targets. 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of the 5’ AMP-activated protein kinase (AMPK), which plays a role in cellular energy homeostasis. Activated AMPK is inhibits the protein kinase mammalian target of rapamycin, thereby reducing protein translation and suppressing cell growth and cell cycle entry. Recently, AMPK was reported to be mediated by RAF-MEK-ERK pathway in melanoma cells harboring the B-RAF(V600E) mutation.
Methods: We investigated the anti-tumor effect of AICAR on the proliferation of thyroid cancer cell lines with BRAF(V600E) mutation or wild type BRAF. We were to see the effect of AICAR on cell proliferation, apoptosis and cell cycle of thyroid cancer cell and reveal the mechanism of these changes.
Methods: The proliferation of thyroid cancer cell lines with BRAF(V600E) mutations was more significantly inhibited by administration of AICAR in comparison with cell lines with wild type BRAF. The suppressive effect of AICAR on cell proliferation of BRAF(V600E) mutated thyroid cancer cell lines was related with increased phosphorylation of AMPK, S-phase cell cycle arrest, and increased apoptosis. Interestingly, the AICAR suppressed phosphorylation of ERK and p70S6K in B-RAF V600E mutated thyroid cancer cells compared to B-RAF wild type cells.
Conclusion: In BRAF(V600E) mutation harboring thyroid cancer cell lines, AICAR induced AMPK activation resulted in decrease of cell growth, apoptosis, and increased cell cycle arrest via down-regulation of ERK and p70S6K activity. These results suggest that regulation of AMPK activity may be a potential target for cancer therapy in thyroid cancer with BRAF V600E mutation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4471. doi:10.1158/1538-7445.AM2011-4471
Abstract 4491: AZD5363, a novel Akt inhibitor, delays prostate cancer progression by inhibiting androgen-receptor activity
Authors: Lamoureux Francois , Thomas Christian , Crafter Claire , Davies Barry , Gleave Martin E. , Zoubeidi Amina 
Published: June 2012

Abstract
Introduction and Objective: Despite initial response to androgen deprivation therapy, prostate cancer (PCa) inevitably progresses after 3 to 4 years to its castration-resistant state (CRPC). Consequently, there is an urgent need for novel therapeutic agents that can prevent or at least prolong the time to CRPC progression. The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a key role in tumor progression and therefore is an attractive pharmacological target. In this study, we assessed the anti-cancer effects of the novel and selective Akt inhibitor, AZD5363, in vitro and in vivo in PCa.
Methods: LNCaP and C4-2 cells were treated with AZD5363 and submitted to western blot, qRT-PCR and immunofluorescence analysis. AZD5363 was tested for its ability to modulate PSA transactivation by luciferase assay. Cell viability was assessed by crystal violet and cell cycle population by flow cytometry. For in vivo xenograft studies, LNCaP cells were inoculated s.c. in the flank region of athymic nude mice. Mice were castrated and randomly treated with AZD5363 or control by oral gavage. Tumor volume and serum prostate-specific antigen (PSA) were evaluated twice per week.
Results: Here we report that AZD5363 inhibits cell growth in a dose-dependent manner (IC50 ± 200nM) in both LNCaP and C4-2, induces cell apoptosis as measured with PARP cleavage expression, Caspase 3 activity, and increases sub-G1 population (20.2% and 22.2% at 500nM for LNCaP and C4-2 cells, respectively). Interestingly, AZD5363 significantly abrogates androgen-induced PSA transactivation at concentrations &gt; ∼100nM and down-regulates AR expression at concentrations &gt; ∼1μM. These biologic events were accompanied by inhibition of downstream PI3K/Akt signaling. Most important, targeting the Akt-pathway in vivo significantly reduces tumor volume and serum PSA-levels and thereby delays progression to CRPC.
Conclusions: This study reports as a preclinical proof-of-principle that targeting PI3K/Akt pathway with AZD5363 inhibits androgen-dependent PCa progression in vitro and in vivo, using the AR-axis as a pharmacodynamic tool.
This work was supported by AstraZeneca, the Deutsche Forschungsgemeinschaft (German Research Foundation; Grant number: TH 1482/2-1), the Canadian Institutes of Health Research and l'Association pour la Recherche sur le Cancer (France).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4491. doi:10.1158/1538-7445.AM2011-4491
Abstract 4493: Preclinical efficacy of AZD8055, an ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitor, in vitro in urothelial carcinoma of the bladder
Authors: Lin Kelly Y. , Gupta Gopal N. , Sourbier Carole , Williams Heinric , Guichard Sylvie , Linehan W. Marston , Srinivasan Ramaprasad 
Published: June 2012

Abstract
Mammalian target of rapamycin (mTOR) has been shown to play a key role in energy sensing, cell growth, and cell survival in many cancers. Although alterations of the PI3K/Akt/mTOR pathway are frequent in urothelial carcinoma (UC), the effects of pharmacologic targeting of this pathway have not been systematically evaluated. Selective inhibitors of the mTORC1 component of mTOR have modest activity in renal cell cancer and are currently being evaluated in patients with advanced bladder cancer. Since selective mTORC1 inhibition may lead to feedback activation of Akt through mTORC2, concomitant disruption of mTORC2 activity may result in more complete mTOR blockade and more potent antitumor activity than inhibition of mTORC1 alone. In this study, the efficacy of the dual mTORC1/mTORC2 inhibitor AZD8055 was compared with that of rapamycin in three UC cell lines UMUC-3, TCCSuP and HT-1376. Both AZD8055 and rapamycin were able to downregulate the mTORC1 substrate pS6; however, only AZD8055 was effective in downregulating p4E-BP1, a critical component of cap-dependent translation that is also regulated by mTORC1. AZD8055, but not rapamycin, potently suppressed mTORC2 signaling as evidenced by downregulation of pAKTs473. AZD8055 exhibited potent in vitro antitumor activity against all three bladder cancer cell lines, with IC50s of 15-40nM by the MTT assay, while rapamycin had minimal antitumor activity at these concentrations (IC50 not reached at 1uM). In vivo efficacy of AZD8055 is under evaluation in mouse xenograft models. These data demonstrate that AZD8055 is a potent inhibitor of mTORC2 and a more effective inhibitor of downstream mTORC1 targets than rapamycin. Combined mTORC1/2 kinase inhibition may be superior to selective mTORC1 inhibition, and is worthy of clinical evaluation in urothelial carcinoma of the bladder.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4493. doi:10.1158/1538-7445.AM2011-4493