bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2770: Antitumor activity of heat shock protein 90 (HSP90) inhibitor AT13387 in head and neck squamous cell carcinoma
Authors: Truong Kristy , Gouveia Christopher , Coupar Jamie , Smyth Tomoko , Lyons John , Chen Zhong , Waes Carter Van 
Published: August 2012

Abstract
Heat shock protein 90 (HSP90) has been shown to be overexpressed in a wide range of cancers, and plays a critical role in tumor cell growth and survival by stabilizing aberrant signaling proteins and by interfering with apoptosis. Several natural and synthetic inhibitors of HSP90 have been shown to have antitumor effects, but single agent development has been limited by poor solubility, poor availability and off-target toxicities (hepatotoxicity, retinal toxicity). The aim of this study is to investigate the biological activity of the small-molecule HSP90 inhibitor, AT13387 (Astex Pharmaceuticals) for antitumor activity in head and neck squamous cell carcinoma (HNSCC). Human HNSCC cell lines, UMSCC −1 (wild-type p53) and −46 (mutant p53) were treated with AT13387. The inhibitory concentrations (IC[[Unsupported Character - Codename &shy;]]50) of AT13387 on HNSCC cell lines were determined using MTT proliferation assay. AT13387 (55 mg/kg two consecutive days every week) antitumor activity, toxicity and survival were evaluated in the UMSCC −1 and −46 xenograft model in BALB/c SCID mice. AT13387 inhibited the proliferation of both UMSCC cell lines in vitro with IC50 levels of 0.05-.10 µM by MTT assay. In vivo, AT13387, at 55 mg/kg showed significant antitumor effect and improved survival in both wtTP53 UMSCC-1 and mtTP53 UMSCC-46 xenograft models. The treatment was well-tolerated and no significant body weight loss observed. These data suggest that AT13387 may possess potent antitumor activity in human HNSCC, regardless of the p53 mutation status. The potential of AT13387 as a chemosensitizer for radiotherapy is being investigated. These preclinical data suggest that AT13387 holds promise as a potential chemotherapeutic agent for HNSCC clinical trials. (Supported by NIDCD project ZIA-DC-000073 and AT13387 provided to NCI by Astex Pharmaceuticals)
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 2770. doi:1538-7445.AM2012-2770
Abstract 2772: AT13387, an HSP90 inhibitor, is effective in both vemurafenib-sensitive and -resistant melanoma models
Authors: Rodriguez-Lopez Ana M. , Smyth Tomoko , Curry Jayne , Graham Brent , McMenamin Rachel , Lyons John , Thompson Neil , Wallis Nicola 
Published: August 2012

Abstract
Background: Mutations in BRAF are found in approximately 50% of melanomas. Vemurafenib, the selective mutant BRAF inhibitor, is an effective treatment in this disease but is limited by the onset of resistance. A number of mechanisms of resistance to RAF inhibitors have been described, including alternative mechanisms for activating the MEK-ERK and AKT pathways. HSP90 inhibitors affect clients in both these pathways and so it has been suggested that HSP90 inhibition is a potential mechanism for overcoming resistance to RAF inhibitors in melanoma. Results: AT13387 is a fragment-derived, potent HSP90 inhibitor, which is currently being evaluated in clinical trials. AT13387 inhibited cell proliferation in a range of melanoma cell lines, including cell lines with different mechanisms of resistance to vemurafenib (See Table). AT13387 treatment of melanoma cell lines resulted in the induction of HSP70, a marker of HSP90 inhibition, and depletion of HSP90 client proteins including BRAF and AKT. The levels of phospho-ERK, phospho-AKT and phospho-S6 were also depleted in both vemurafenib-sensitive (A375) and vemurafenib-resistant (A2058) lines indicating that the MEK-ERK and AKT signaling pathways were both inhibited. This demonstrates that vemurafenib resistance mediated by upregulation of the AKT pathway can be overcome by HSP90 inhibition. In vivo, AT13387 significantly inhibited growth of an A375 melanoma xenograft. Client proteins, including BRAF, CRAF and AKT were depleted in xenograft tissue and the MEK-ERK and AKT signaling pathways were again inhibited. Conclusions: These results demonstrate the activity of AT13387 in both vemurafenib-sensitive and -resistant models and show that HSP90 inhibition results in downregulation of signaling pathways that may be activated as a result of resistance to RAF inhibitors. These data support further clinical evaluation of AT13387 in melanoma.

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 2772. doi:1538-7445.AM2012-2772
Abstract 2773: HSP90 inhibitors target KRAS mutant human tumors through degradation of STK33
Authors: Azoitei Ninel , Hoffmann Christopher M. , Ellegast Jana M. , Ball Claudia R. , Obermayer Kerstin , Gößele Ulrike , Koch Britta , Faber Katrin , Genze Felicitas , Schrader Mark , Kestler Hans A. , Döhner Hartmut , Chiosis Gabriela , Glimm Hanno , Fröhling Stefan , Scholl Claudia 
Published: August 2012

Abstract
Mutations in the KRAS proto-oncogene occur in ∼30% of human cancers and are particularly prevalent in adenocarcinomas of the pancreas, lung, and colon. Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS have not met with success. We have recently shown that cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, supporting STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33, which remain to be elucidated, are not yet available. Using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex and BAG2, a member of the BAG family of molecular chaperone regulators, bind to and stabilize STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon cancer-initiating cells harboring mutant KRAS. Similar to HSP90 inhibition, short hairpin RNA-mediated suppression of BAG2 depleted STK33, whereas BAG2 overexpression rescued STK33 protein levels in the presence of HSP90 inhibitors, resulting in diminished apoptosis in KRAS mutant cancer cells. These findings (1) provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, (2) indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, (3) identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential, and (4) point to BAG2 as a candidate cancer drug target.
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 2773. doi:1538-7445.AM2012-2773
Abstract 2785: Discovery of a novel HDM2 inhibitor with potent in vivo anti-tumor activity
Authors: Wang Yaolin , Lipari Philip , Mirza Asra , Lin Yinghui , Zhang Rumin , Bogen Stephane , Bogen Stephane , Ma Yao , Hicklin Daniel J. , Seidel-Dugan Cynthia , Liu Suxing , Wang Xiaoying , Doll Ronald , Shipps Gerald , Bishop Walter Robert 
Published: August 2012

Abstract
HDM2 is a major negative regulator of the p53 tumor suppressor pathway. Aberrant HDM2 overexpression and gene amplification contributed to accelerated cancer development and growth. Several small molecule inhibitors of HDM2-p53 protein-protein interaction have been reported in recent years with anti-tumor activities in tumor xenograft models. Here we describe a novel and potent small molecule inhibitor of HDM-p53 inhibitor that binds selectively to HDM2 with high affinity compared to HDM4. Treatment of cancer cells with this HDM2 inhibitor results in activation of p53 pathway as demonstrated by study of pharmacodynamic biomarkers both in cell culture and in tumor xenograft in vivo. More importantly, cancer cells response to this HDM2 inhibitor is mechanism based and dependent on the presence of functional p53 status as shown in a profiling of a broad-panel of cancer cell lines. This inhibitor is very potent against cancer cell growth with IC50 below 200 nM for most cell lines tested in vitro. It is orally bioavailable and has single agent activity that results tumor regression in SJSA-1 osteosarcoma model or growth inhibition in A549 NSCLC and A2780 ovarian cancer xenograft models. In addition, combination of this HDM2 inhibitor with various chemotherapy agents results in added or synergistic anti-tumor response both in vitro and in vivo in several human cancer xenograft models with limited bone marrow toxicity at the efficacious dose.
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 2785. doi:1538-7445.AM2012-2785
Abstract 2900: Redox nanoparticle enhances effect of anticancer chemotherapy and suppresses cardio-toxicity
Authors: Nagasaki Yukio , Ozaki Yuki , Yoshitomi Toru 
Published: August 2012

Abstract
Utilizing the self-assembled core-shell-type polymeric micelle technique, high-performance nanoparticles possessing stable nitroxide radicals in the core and reactive groups on the periphery were prepared (Nitroxide Radical-containing Nanoparticles; RNP). The average diameter of the nanoparticles was ca. 40 nm, and the nanoparticles emitted intense electron paramagnetic resonance (EPR) signals. Owing to the confinement of the nitroxide groups in the core of the nanoparticles, it reduces its toxicity, prolongs its blood circulation time. Under the low pH environment in vivo, it was confirmed that RNP disintegrated to expose the nitroxide radicals outside of the particle. It is sharp contrast against low-molecular-weight TEMPOL, which was reduced and excreted rapidly from the blood stream. Recently, we have reported that RNP is effectively worked to cerebral ischemia reperfusion injury. The RNP disintegrates in penumbra area due to the acidosis of ischemic region, followed by the scavenging reactive oxygen species (ROS) generated in this area. This strategy could be applied to other ischemic injuries such as renal and myocardial infarction. Quite recently, we have found that scavenging of ROS in tumor region by RNP improves efficiency of anticancer drug, doxorubicin (DOX). For example, RNP administration prior to the DOX-injection remarkably improved its efficiency. When RNP was administered via mice tail veil, it accumulated in tumor due to the enhancement permeation and retention (EPR) effect. The accumulated RNP scavenged excessive generated ROS in tumor, which suppressed activation of transcription factors such as NF-κB. Such suppression of inflammation related transcription factors might increase effectiveness of anticancer drug such as doxorubicin (DOX). The RNP pre-administration also reduced its side effect. Actually, 25mg/kg intravenous administrations of RNP before and after the DOX-injection (20mg/kg) reduced significantly the lactate dehydrogenase (LDH) and the creatine phosphokinase (CPK) activity. Thus, the nanoparticle anti-oxidant treatment is promising as a new adjuvant for anti-cancer chemotherapy without severe side effect by anticancer drug.
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 2900. doi:1538-7445.AM2012-2900
Abstract 2901: Development of mannose-polyethyleneglycol-modified liposomes for idiopathic thrombocytopenic purpura
Authors: Fujimura Tetsuo , Sugiyama Ikumi , Murai Kazunori , Ishida Yoji , Oku Naoto , Sadzuka Yasuyuki 
Published: August 2012

Abstract
[Objective]Idiopathic thrombocytopenic purpura(ITP) among thrombocytopenia is an acquired autoimmune disease and is not clear on the cause of disease. ITP is produced antibodies to the platelet by immunological action and is thrombocytopenia with platelet phagocytosis by macrophages in the spleen. There is a few deaths by the thrombocytopenia, whereas its effective treatment has not been developed. Polyethyleneglycol(PEG) modification of liposome as drug carrier is known to provide blood circulation. The surface of macrophages is overexpressed mannose receptor. Namely, mannose-PEG-modified liposome contained cytotoxic agent is expected to accumulate in macrophage and show cytotoxic effect. The effect of novel therapy for ITP was examined on platelet count and tissue distribution of cytotoxic agent. [Methods]Doxorubicin(DOX) as cytotoxic agent, containing liposome(LDOX), PEG-modified LDOX(PEG-LDOX) and mannose-modified PEG-LDOX(Man-PEG-LDOX) were prepared by remote loading method. ITP model mouse was created by administration of anti-platelet antibodies. Each liposome was administered from the tail vein in the ITP model mouse. On 24hr after each liposome administration, the platelet count was measured and DOX concentration was determined in each tissue. [Results]ITP model mouse was reduced to 7.1% of normal platelet count by anti-platelet antibodies treatment. In LDOX and PEG-LDOX groups, the platelet count does not recover to normal level and DOX concentration in the spleen was low. In contrast, the platelet count in Man-PEG-LDOX group recovered to normal level. Furthermore, DOX concentration in the spleen after Man-PEG-LDOX treatment showed a 2.7-fold of that in LDOX group. [Discussion]To be effective splenectomy for ITP treatment, it is prospected that the accumulation of cytotoxic agent in the spleen is useful. As liposome with PEG-modification has been developed for avoiding the reticuloendotherial system cells such as liver and spleen, this liposome can not show accumulation in the spleen and cytotoxic effect on the macrophages. Thus, PEG-modified liposome is unable to suppress platelets reduction by macrophage phagocytosis. In contrast, after Man-PEG-LDOX administration, DOX concentration in the spleen significantly increased, and thus the platelet count was recovered by cytotoxic effect on the macrophages. Furthermore, DOX accumulations in the heart and other normal tissue in the Man-PEG-LDOX group were lower levels, and DOX induced adverse reaction was expected to be not observed. In conclusion, Man-PEG-LDOX is hoped to be effective as novel treatment for ITP.
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 2901. doi:1538-7445.AM2012-2901
Abstract 2902: Polymeric nanoparticles enhance the bioavailability of the chemopreventive compound SR13668 in beagle dogs
Authors: Banerjee Aryamitra A. , Shen Hao , Hautman Mathew , Anwer Jaseem , Kapetanovic Izet M. , Liu Ying , Lyubimov Alexander V. 
Published: August 2012

Abstract
Chemopreventive compound SR13668 showed promising anti-cancer activity in several in vitro and in vivo models of cancer, including breast, lung, prostate, and ovary and it was proposed that SR13668 works through the modulation of PI3K/Akt pathway. However, low oral bioavailability substantially limited its development as a chemopreventive agent. A novel nano-formulation of SR13668 encapsulated in poly(lactic-co-glycolic acid) (PLGA) was produced with the aim to enhance the oral bioavailability of SR13668 in beagle dogs. A single gavage administration of SR13668 was performed at 2.8 mg/kg as nano-formulation and also as SR13668 in 0.5 % methylcellulose in 4 male and 4 female dogs. Whole blood and plasma samples withdrawn from these animals at different time points over 24 hr period were analyzed using LC-MS/MS method to obtain the systemic drug levels and to evaluate the pharmacokinetic profile achieved. In plasma the group mean highest concentration occurred at the 4 hr time point in both males (29.6 ng/mL) and females (27.9 ng/mL) whereas in whole blood the mean group peak occurred at 4 hr in males (51.7 ng/mL) and 6 hr in females (61.9 ng/mL). The animals dosed with SR13668 in methylcellulose had all levels below limit of quantitation (1.1 ng/mL) in both plasma and whole blood for all time points. This study was the first attempt of using nano-formulation to improve oral bioavailability of the chemopreventive compound SR13668 in large animals. The systemic levels achieved were high for this poorly bioavailable compound in dogs but were not to the desired levels and further work is needed to improve bioavailability using nano-formulations. Potential improvements that are planned for the SR13668 nano-formulations include using a high through-put screening method to optimize the conditions further, use of polyethyleneglycol- poly(lactic-co-glycolic acid) (PEG-PLGA) for SR13668 encapsulation and comparison with poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEG-b-PCL) and PLGA results to possibly obtain better absorption with increased stability in the gut and also placement of negative charges on the nano-particles using poly-acrylic acid (PAA) to facilitate the particle penetrating the mucus layer to increase bioavailability.
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 2902. doi:1538-7445.AM2012-2902
Abstract 2903: Therapeutic targeting of leukemia and lymphoma with a neuropilin-1 binding pro-apoptotic peptide
Authors: Karjalainen Katja , Jaalouk Diana E. , Bueso-Ramos Carlos E. , Zurita Amado J. , Kuniyasu Akihiko , Eckhardt Bedrich L. , Marini Frank C. , Lichtiger Benjamin , O'Brien Susan , Kantarjian Hagob M. , Cortes Jorge E. , Koivunen Erkki , Arap Wadih , Pasqualini Renata 
Published: August 2012

Abstract
Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short cell-internalizing peptide ligands that bind to specific cell surface receptors on malignant hematopoietic cells. Such targeting motifs could also serve as vehicles for preferential delivery of cytotoxic agents to leukemias and lymphomas. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence FF/YXLRS, which bound to human leukemia and lymphoma cell lines as well as to primary human acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) bone marrow specimens obtained from patients. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, the functional relevance of this internalizing receptor was evaluated in the context of disease progression via the targeted delivery of a pro-apoptotic peptidomimetic to leukemia and lymphoma cells, and a potent anti-leukemia cell effect was observed both with cell lines and patient samples when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D(KLAKLAK)2. Markedly, the pro-apoptotic peptide did not have an effect on purified mononuclear cells from normal bone marrow cells. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with ALL or AML compared to normal bone marrow specimens. Taken together, our results indicate that NRP-1 could, potentially, be used as a target for ligand-directed therapy in human leukemias and lymphomas - as well as in many human solid tumors, which are also know to over-express NRP-1 - and that the prototype CGFYWLRSC-GG-D(KLAKLAK)2 is a promising drug candidate in this setting.
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 2903. doi:1538-7445.AM2012-2903
Abstract 2904: EGFR-targeted gold liposome for molecular imaging and therapy on NSCLC cells
Authors: Yokoyama Tomohisa , Osato Yoichi , Miyazawa Keisuke , Miyasato Akime , Hayabe Hiroko , Nomura Masaharu , Gotoh Noriko , Itoi Takao , Tauchi Tetsuzo , Ikeda Norihiko , Ohyashiki Kazuma 
Published: August 2012

Abstract
Nanotechnologies are in development for monitoring drug delivery and therapeutic effect for cancer. However, tumor-targeted multifunctional nanoparticles for imaging of and therapy of lung cancer are not available. The Epidermal growth factor receptor (EGFR) is overexpressed in approximately 80% of non-small cell lung cancer (NSCLC) and is a target for novel therapeutics, however, the clinical results using EGFR inhibitors for NSCLC treatment had mixed results. These results indicate that EGFR expression or its mutational status is solely not a reliable marker to determine the outcome. Therefore, we have developed liposome (120nm) encapsulated with colloidal gold that are conjugated to therapeutic anti-EGFR antibodies (Katayama Chemical Industries Co. Ltd. Osaka, Japan) to determine the molecular specific imaging of NSCLC. The colloidal gold is used for optical imaging and the anti-EGFR antibody for therapy. In the present study, we investigated in vitro effect of these liposomes on EGFR-expressing (HCC827 and H1299) and EGFR-null (H520) NSCLC cells. EGFR-targeted liposome exhibited a strong antitumor effect on EGFR-expressing NSCLC cells. On the other hands, no significant growth inhibitory effects were observed on non-targeted liposome-treated cells. Intriguingly, treatment with EGFR-targeted liposome resulted in significantly higher cell death as compared with anti-EGFR antibody and liposome alone. Furthermore, reflected polarizing microscopy showed that the concentration of EGFR-targeted liposome bound to EGFR-expressing NSCLC cells increased, but EGFR-null cells did not. When EGFR was inhibited pharmacologically, the binding efficiency of EGFR-targeted liposome was attenuated on EGFR-expressing NSCLC cells. These findings indicate that EGFR-targeted liposome are selectively bound and delivered to EGFR expressing NSCLC cells but not the EGFR-null NSCLC cells. We are currently determining in vivo effect of EGFR-targeted liposome using subcutaneous HCC827 and H520 tumor models. Our findings demonstrated that EGFR-targeted liposome is a promising agent for therapy and molecular imaging of NSCLC.
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 2904. doi:1538-7445.AM2012-2904