bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A28: Apoptosis induction with the MEK inhibitor AZD6244 and BH3 mimetic ABT-737 in melanoma.
Authors: Niglio Scot A. , Rosenberg Stephen , Jeong Byeong-Seon , Shin Seung-Shick , Mehnert Janice , White Eileen , Goydos James 
Published: June 2012

Abstract
Over sixty percent of patients with melanoma have the activating B-RAFV600E mutation leading to increased activation of the mitogen activated protein kinase (MAPK) pathway. The downstream effects of MAPK pathway activation are increased proliferation, invasiveness, and survival through the regulation of down-stream targets such as the pro-apoptotic protein BIM. Prior studies have shown that inhibiting MAPK kinase (MEK), downstream of constitutively active B-RAF, can up-regulate BIM, leading to increased apoptosis in melanoma cell lines. However, single agent MEK inhibition has had limited effectiveness in the clinical setting for late-stage melanoma patients, likely due to an inadequate induction of apoptosis. We hypothesized that combining the clinically relevant MEK inhibitor, AZD6244 (ARRY142886) with a BCL-2 inhibitor, ABT-737, would lead to increased apoptosis over single agent therapies in melanoma cells via BIM activation and pan-BCL-2 inhibition. We compared single treatments of AZD6244 and ABT737 to the combination of these agents in a panel of melanoma tumor cell lines chosen by mutational status in both a monolayer system and an anchorage independent system. The combination of AZD6244 and ABT-737 had a synergistic effect on decreasing cell viability and increasing apoptosis compared to single agent treatments regardless of B-RAF mutational status. Western blotting revealed dramatic increases in cleaved caspase 3 and PARP with combinational treatment compared to single agent therapy. These early pre-clinical experiments indicate that AZD6244 combined with ABT-737 may be an effective combination therapy for patients with late-stage melanoma. Currently, we have plans to conduct in vivo studies to translate these results into the clinic.
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 A28.
Abstract A31: Induction of autophagy's mechanism in laryngeal squamous cancer cells by Trisenox.
Authors: Pereira Debora Lima , dos Santos Ferreira Ana Carolina , da Cunha Vasconcelos Flavia , de Faria Giselle Pinto , Kwee Jolie Kiemlian 
Published: June 2012

Abstract
Introduction: A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents. Laryngeal cancer is one of the most common worldwide malignancies of head and neck. Despite extensive research into molecular changes in laryngeal carcinogenesis, reliable molecular markers with predictive and prognostic value are still lacking. Trisenox is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), but is not applied at the clinical practice yet. However, many studies have demonstrated their effects in solid tumors. Among the numerous mechanisms implicated in chemoresistance, glutathione (GSH) and associated enzymes play a pivotal function in hematopoietic and solid tumors. Several studies report that depletion of GSH by L-buthionine-sulfoximine (BSO) sensitizes tumor cells to chemotherapeutic-ROS inducers such as Cisplatin and Trisenox. Our previous studies showed the combination of Trisenox and BSO, an important GSH-inhibitor, was synergistic and reduced the Laryngeal Squamous Carcinoma Cell line Hep-2 cell viability up to 60%. However, the mechanism of Trisenox-death induction is poorly understood. Here we investigated the pathway involved in the cytotoxic effect mediated by the combined BSO and Trisenox treatment in Hep-2 lineage.
Materials and Methods: The Laryngeal Squamous Carcinoma Cell line Hep-2 were maintained in RPMI culture medium and previously incubated with BSO. After 24h, the cells were treated with 1.0 and 4.0μM Trisenox for 72h. Acridine Orange assay was used through flow cytometer and imunnofluorescence to evidence the autophagic vacuoles. To evaluate the autophagic induction, we used 3-Metil-Adenine (3-MA), a known autophagy-inhibitor, in combination with Trisenox and BSO.
Results: We observed that the BSO potentiates the Trisenox-autophagic induced acid vesicules formation assessed by acridine orange in both flow cytometer and immunofluorescence assays. In addition, previous treatment with 3-MA inhibited up to 20% of the cytotoxic effect of 1.0 and 4.0μM Trisenox.
Conclusion: This study showed that BSO enhances the Trisenox-cytotoxic effects in laryngeal tumor cells through autophagic mechanisms. Trisenox might represent an attractive basis for laryngeal squamous cancer treatment.
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 A31.
Abstract A36: An anticancer drug combination and regimen database for research and clinical optimization.
Authors: Fernandez Eric , Robertson Martin , Snell Chris , Fell David A. , Chassagnole Christophe , Jackson Robert C. 
Published: June 2012

Abstract
Physiomics and pharmacometrics have collaborated to design a new database of anti-cancer drugs and therapeutic treatment information aimed at researchers in oncology and clinicians. This database, accessible through the web, offers data on more than 130 anti-cancer drugs (small molecules and biologics) used in research and in the clinic. It contains information on drug combination as well as a several hundreds of cancer chemotherapy regimens routinely used in the clinic. These data are classified according to tumor type, species, or source (in vitro, in vivo or simulated). It will be constantly expanded and curated with the most recent information. Furthermore, it provides ways to standardize the expression and nomenclature of chemotherapy regimens unambiguously and uniformly is of paramount importance to improve efficacy, as well as to reduce medication errors. Individual drug information covers pharmacokinetic profiles, mechanism of action and of resistance, dose-response effect, dosing limits, therapeutic index, and immunosuppression data. Drug combinations are also referenced. The database covers synergy or antagonism, as well as a combination therapeutic index and cross-resistance information. Some drug combination having level of synergy depending on the drug schedule, drug sequence and administration timings are also referenced and thoroughly discussed.
The user can also browse and compare chemotherapeutic regimens, analyze the overall drug dose over a course of treatment, by tumor type, in animal and clinical models.
Advanced functions include the ability to do statistical analysis on drug usage and dosing in various contexts. It can also help determine which drug candidates are likely to be used in combination with a new chemical or biological entity, given the mechanism of action and other PK/PD data. Also, it will allow users to design new combinations and regimens, which obey dosing constraints, such as MLD and MTD.
Finally, data can be exported and used in spread sheets, modeling software or simulation packages.
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 A36.
Abstract A42: ALK and cMET expression in glioblastoma multiforme: Implications for therapeutic targeting.
Authors: Hudson Lori , Kulig Kimary , Young Debra , McLendon Roger , Abernethy Amy 
Published: June 2012

Abstract
Introduction: Mutations in the anaplastic lymphoma kinase (ALK) gene result in aberrant tyrosine kinase signaling and are implicated in a variety of human cancers. In vitro and xenograft studies implicate pleiotrophin (PTN) signaling via ALK in growth and progression of glioblastoma (GBM). In addition, expression levels of the proto-oncogene cMET correlate with glioma malignancy and grade, with its overexpression linked to shorter survival time and poorer treatment outcomes. Antibody targeting of ALK or cMET inhibits GBM growth in xenograft models, suggesting both as potential therapeutic targets. The relative expression, mutation frequency, and clinicopathological features correlated with ALK, cMET, or both in GBM is unknown. Here we describe our preliminary results of the prevalence of these biomarkers in GBM patient tumor samples.
Methods: GBM tumor samples were selected from patients seen at a single institution (DUMC) since 2010. Immunohistochemistry (IHC) was used for both cMET and ALK detection. Clone 5A4 was used for ALK and clone 8F11 for cMET (Novocastra). ALK positivity by IHC was defined as ≥10% focal or ≥ 25% overall staining. Positivity of cMET by IHC was defined as ≥ 25% overall staining.
Fluorescent in situ hybridization (FISH) for ALK employed a dual-color break-apart probe (Vysis, Abbott). Counting 100 cells, cases were classified as having an ALK gain or amplification as follows: Signal Scoring: ≤2 Intact; 3–5 Gain; &gt;5 Amplified and ≥10% Amp; ≥15% Gain; &lt;15% Intact. IHC and FISH assays were run on two separate blocks of tissue for all cases.
Results: As shown in the Table, cMET expression by IHC was detected in 65%, ALK expression by IHC in 25%, and ALK gene amplification or gain by FISH in 60% of cases. Thus, the majority of cases were positive for cMET or ALK by FISH, with 55% positive for both.
Conclusion: Our pilot results show cMET and ALK protein expression in a significant number of GBM samples, with 55% having concurrent ALK amplification/gain along with cMET expression. Consistent with preclinical models, these data suggest a role for cMET and/or ALK in the pathogenesis of GBM. With the advent of cMET and ALK inhibitors, our study provides important data on the prevalence of these biomarkers as possible drug targets in GBM. Our ongoing study will evaluate more cases and explore relationships between clinical characteristics and outcomes relative to ALK and/or cMET expression.

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 A42.
Abstract A60: Comprehensive protein-protein interactions analysis to verify the key cancer and stem cell maintains mechanism in hepatocellular carcinoma.
Authors: Mori Taisuke , Kanai Yae , Fujimori Shigeo , Miyamoto-Sato Etsuko 
Published: June 2012

Abstract
Groundbreaking work demonstrated that ectopic expression of four transcription factors/TF, Oct4, Klf4, Sox2, and c-Myc, or less number TF could reprogram somatic cells to induced pluripotent stem cells (iPSCs) were subsequently generated using not only genetic manipulation but also protein induction. This work showed that the proteins might have huge complexity protein-protein interaction. The idea that cancer cells possess the partially same as stem cell properties such as self-renewing, drug resistance, and progression by same mechanism. Here we focus on evaluating large-scale protein-protein interaction (PPIs) of interacting regions (IRs) data at the domain level for “stemmness” TF-related protein complexes using a high-throughput mRNA display screen: In Vitro Virus/IVV method; Miyamoto-Sato E. et al., PLoS ONE. 2010). As a result of these global protein-protein interactions analysis with “stemness” molecules showed 440 interactions, Oct4:70, Sox2:96, Nanog:89, Klf4:37, Lin28:76, c-Myc:62 respectively. Especially we find unique hub protein X that is interaction with Nanog, Sox2, Klf4 and more stemness proteins. Now we are working on a further analysis to reveal the function of the unique hub protein X. Together this work suggest a novel resource for the assessment of cancer and stemcell function in various contexts, notably in the self-renewal of stem cells and progression of 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 A60.
Abstract A61: Darinasparsin (Z101) inhibits prostate cancer stem cells via inhibition of hedgehog signaling.
Authors: Bertino Joseph R. , Bansal Nitu , Lewis John , Youssoufian Hagop 
Published: June 2012

Abstract
An orally available form of Darinasparsin (D) an organic arsenical, is currently in Phase I trials. The parenteral form of D has shown antitumor activity in Phase II studies, in particular in patients with T-Cell Lymphoma. We tested D in four prostate cancer cell lines and after a 72h exposure, IC50's ranged from 2.5 to 12 micromolar, Du 145 cells being the most sensitive. Given the reports that arsenic trioxide inhibited Hedgehog signaling (Kim et al, PNAS 107:13432,2110), we tested the effect of D on Hedgehog signaling in prostate stem cells, isolated by adherence to collagen I, expression of CD 44, and lack of expression of CD24. D showed potent inhibition of DU 145 prostate cells adhering to collagen, inhibited prostate spheroid growth (IC50:2uM) and prostate stem cell colony formation. Western analysis showed that D decreased levels of the transcription factor Gli2, a downstream effector of Hedgehog signaling. Combination studies with taxotere, a FDA approved drug for the treatment of patients with advanced prostate cancer, showed synergistic cell kill at high fixed doses of the drugs. In contrast the combination of D with cabazitaxel showed less than additive effects. These studies encourage additional preclinical studies and a clinical trial of D in patients with advanced prostate cancer, alone and in combination with taxotere.
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 A61.
Abstract A8: LY2228820 dimesylate, a p38-MAPK inhibitor, modulates angiogenic endothelial cord formation in vitro and in vivo.
Authors: Tate Courtney , Blosser Wayne , Wyss Lisa , Pratt Susan , Stewart Julie , Stancato Louis 
Published: June 2012

Abstract
LY2228820 dimesylate is a highly selective small molecule inhibitor of p38-mitogen-activated protein kinase (p38-MAPK) that is currently under clinical investigation for human malignancies. p38-MAPK is implicated in a wide range of biological processes, in particular those processes that support tumorigenesis. One such process, angiogenesis, is required for tumor growth and metastasis, and many new cancer therapies are therefore directed against the tumor vasculature. p38-MAPK is activated in endothelial cells upon growth factor stimulation and is involved in the secretion of growth factors and cytokines, but the role this activation plays in angiogenesis is not well defined. Using an in vitro co-culture endothelial cord formation assay (a surrogate of angiogenesis), we investigated the role of p38-MAPK in growth factor and tumor-driven angiogenesis by pharmacological inhibition of p38-MAPK using LY2228820 dimesylate and by shRNA gene knockdown. Inhibition of p38-MAPK by LY2228820 dimesylate led to a significant decrease in growth factor (VEGF, FGF, EGF) and IL-6 induced endothelial cord formation and an even more dramatic decrease in tumor-driven cord formation from a variety of tumor cell lines representing a range of histologies. Inhibition of p38-MAPK in tumor cells led to decreased cytokine secretion of VEGF, EGF, IL-6, IL-8, and other proangiogenic factors. Small molecule inhibitor results were substantiated by similar results obtained using p38-MAPK specific shRNA. Consequently, it appears that p38-MAPK plays a role in endothelial cell angiogenesis and tumor cell cytokine secretion. LY2228820 dimesylate effects on an in vivo angiogenesis Matrigel plug assay revealed a significant decrease in hemoglobin content (a measure of functional neoangiogenesis) which correlated with decreased pericyte coverage of the vessels. These results implicate p38-MAPK in tumor angiogenesis, and suggest that in vivo inhibition of p38-MAPK may lead to increased vascular permeability and/or induction of vascular normalization.
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 A8.
Abstract B116: Imaging of primary tumor and metastases in mice using near-infrared fluorescent-labeled phosphatidylserine-targeting antibodies.
Authors: Gong Jian , Archer Rich , Peacock Matthew , Hughes Christopher , Freimark Bruce 
Published: June 2012

Abstract
Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on tumor vascular endothelial cells and tumor cells in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. Binding of antibodies targeting PS on the tumor endothelial cells and tumors leads to recruitment of immune cells and engagement of the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. In Phase II trials a chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors. In the present study, we demonstrate imaging of primary tumor and metastases using real-time, near infrared fluorescence imaging of antibodies that specifically target PS. Tumor formation, proliferation rate and location of metastases were monitored by bioluminescence imaging (BLI) and near-infrared optical imaging of PS exposure using a near infrared dye-labeled (NIR) PGN635 F(ab')2 antibody fragment. PGN635 binds PS through the interaction of beta-2-glycoprotein 1 (2GP1) in the same manner as bavituximab binding to 2GP1 in humans. Specific co-localization of BLI and NIR-labeled PGN635 F(ab')2 was observed in tumors compared to a NIR-labeled isotype control antibody. Chemotherapy was shown to enhance the binding of PS-targeting antibodies to both primary and metastatic tumors. These data provide a rationale to image PS expression as a way to localize primary tumors or metastases and to monitor induced PS expression during the course of chemotherapy.
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 B116.
Abstract B117: Early detection of a metabolic tumor response to p70S6 kinase/AKT inhibition by LYS6KAKT1 using in vivo choline proton magnetic resonance spectroscopy.
Authors: Zhu Mingming , Shannon Harlan E. , Trowbridge Melissa , Cockman Michael D. , Rothstein Emily C. , Geeganage Sandaruwan , Fischl Anthony S. 
Published: June 2012

Abstract
As part of a comprehensive drug discovery platform aimed at targeting the PI3K pathway, we have developed a potent small molecule dual inhibitor of p70 S6 kinase and AKT targeting two key nodes of the pathway. LYS6KAKT1 is a potent, highly selective ATP competitive inhibitor against p70S6 kinase and AKT with an IC50 of 6 nM and 14 nM respectively. LYS6KAKT1 inhibits phosphorylation of S6 ribosomal protein and phosphorylation of GSK3b in U87MG glioblastoma cells as well as phosphorylation of other downstream AKT substrates such as PRAS40 and FOXO (Geeganage et al, Abstract 62, 22nd Molecular Targets and Cancer Therapeutics, 16–19 November 2010). In vivo, LYS6KAKT1 demonstrate potent phospho-S6 inhibition in nude mice bearing glioblastoma cells, with an ED50 value of 3 mg/kg and an ED90 value of 8 mg/kg 4 hours after a single oral dose. Based on pre-clinical observations, LYS6KAKT1 is currently being evaluated in Phase I clinical studies for cancer. The purpose of this study was to investigate the effect of LYS6KAKT1 on tumor choline metabolites, a potential tumor response biomarker for PI3K pathway inhibition. Proton Magnetic Resonance Spectroscopy ([1H] MRS) was used to monitor the changes in tumor choline metabolites following treatment of U87MG xenografts in athymic nude mice. LYS6KAKT1 (12.5 or 25 mg/kg, PO, BID) significantly reduced total choline tumor metabolites after 7-days of dosing (p = 0.0006, n = 36). The total tumor choline metabolites, after 7 days of dosing, correlated significantly with relative changes in tumor volumes (r = 0.68, p &lt; 0.0001, N = 36). The present findings indicate that reductions in tumor choline metabolites as measured by [1H] MRS in U87MG xenografts correlate with efficacy as measured by reduction in tumor volume and delay in tumor growth. The present data also indicate that tumor choline metabolites may serve as a potential non-invasive tumor response biomarker for efficacy of LYS6KAKT1.
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 B117.