bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B164: Role of endoplasmic reticulum stress in mechanism of action of antitumor quinols
Authors: Matthews Charles S. , McCarroll Andrew J. , Stevens Malcolm FG , Monks Anne , Bradshaw Tracey D. 
Published: June 2012

Abstract
The novel quinol PMX 290 is an experimental anti-tumor agent with potent activity against colon, renal and breast tumor cell lines in vitro (GI50 &lt; 200 nM). PMX 290 disrupts thioredoxin/ thioredoxin reductase redox regulation and inhibits HIF-1 signaling. A pro-drug of PMX 290 is currently under development at Pharminox Ltd, UK. Here we present data suggesting an additional mechanism of action for PMX 290 highlighting a role for the induction of endoplasmic reticulum stress.
Treatment of HCT116 colon or TK-10 renal carcinoma cells with PMX 290 leads to the induction of a distinct vacuolar phenotype 4 – 6h after addition of the compound. These perinuclear vacuoles were identified as swollen endoplasmic reticulum (ER) as their membranes stain positively with a fluorescent ER dye. Furthermore when a fluorescent analogue of PMX 290 is added to cells it co-localized with the ER dye.
Microarray data from HCT116 cells treated with PMX 290 demonstrated the induction of a panel of mRNAs for genes involved in ER stress. These included GADD34, TRIB3, DNAJB9, BiP and CHOP as well as several genes upregulated by ATF4. Uncharacteristically for a quinol there was no increase in thioredoxin reductase mRNA levels although other markers of oxidative stress were upregulated (e.g. heme oxygenase 1).
The gene array results suggest that the PERK-eIF2alpha ER stress pathway is activated by PMX 290. Upon activation by ER stress PERK phosphorylates eIF2alpha which switches off general translation and allows the expression of the transcription factor ATF4. This switch to reduced protein synthesis and expression of ATF4 transcribed chaperone proteins lowers the load on ER and increases protein folding efficiency thus alleviating ER stress. A transient increase in eIF2aplha phosphorylation and a concurrent increase in BiP levels were detected byWestern blot in response to PMX 290 in HCT116 cells. In conclusion, ER stress appears to play an important role in the anti-tumor activity of PMX 290 and represents a novel mechanism of action for this class of compound.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B164.
Abstract B168: ANG1005: Results of a phase I study in patients with advanced solid tumors and metastatic brain cancer
Authors: Kurzrock Razelle , Gabrail Nash , Moulder Stacy , Noles Cherie , Smith Carrie , Guo Zhong , Bouchard Danielle , Churchill Wendy , Bento Paula , Neale Ann , Castaigne Jean-Paul , Sarantopoulos John 
Published: June 2012

Abstract
ANG1005 is a new generation taxane created from Angiochem's Engineered Peptide Compound (EPiC) platform. Studies have shown that ANG1005 gains entry into the brain compartment by targeting the low-density lipoprotein receptor-related protein (LRP) which is one of the most highly expressed receptors on the surface of the BBB. Once inside the brain, ANG1005 enters tumor cells using the same receptor-mediated pathway through LRP, which is upregulated in various cancer cells including metastatic brain cancer cells. Metastatic brain cancer is the most common intracranial neoplasm in adults with an estimated incidence of 200 000 cases each year in the United States alone. To date, treatment options are limited and marginally effective. A multi-center, phase I, open-label, sequential cohort, dose escalation study of ANG1005 in patients with advanced solid tumors and brain metastases is ongoing in the US. Study objectives include characterization of safety and tolerability and identification of maximum tolerated dose (MTD). ANG1005 is administered by IV infusion once every 21 days (1 treatment cycle) without premedication. After evaluating doses of 30–700 mg/m2, 650 mg/m2 was identified as MTD. Data including adverse events and hematological parameters indicate that ANG1005 is safe and well tolerated. The most common events occurring at a severity ≥ Grade 2 according to CTCAE, version 3.0 at MTD (n=20) were neutropenia (95% of patients; Grade 4 in 75%), leucopenia (100%; Grade 4 in 40%), anemia (55%; no cases of Grade 4), thrombocytopenia (40%; no cases of Grade 4) and mucositis (25%; no cases of Grade 4); these events have been transient and manageable with standard treatments. Neurocognitive data have shown that ANG1005 does not cause cognitive impairment and tests for antibodies demonstrate that ANG1005 does not elicit antibody production even in patients who have received up to 6 cycles of treatment. Pharmacokinetic data indicate linear ANG1005 bioavailability. Disease control (≥ stable disease) assessed by CT/MRI in this heavily pre-treated group of patients was achieved in 70% at doses &gt; 300 mg/m2 including 7 patients who had previously progressed on taxane therapy. Partial response was observed in 30% of patients dosed &gt; 300 mg/m2. Tumor types that showed the best improvements were breast, non-small cell lung and ovarian cancers. Furthermore, partial and complete responses were achieved in metastatic locations including the brain (67% disease control), liver (70% disease control), lung (67% disease control) and lymph nodes (80% disease control). Clinical data gathered to date indicate that ANG1005 shows promise as a potential treatment option for patients with advanced solid tumors and brain metastases.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B168.
Abstract B174: The effect of histone deacetylase inhibition on BRCA1 expression: A potential novel mechanism for enhancing platinum sensitivity in breast and ovarian cancer
Authors: Weberpals Johanne I. , O'Brien Anna , Garbuio Kyla , Clark-Knowles Katherine , Dimitroulakos Jim 
Published: June 2012

Abstract
Introduction: Targeting BRCA1 expression has been shown to sensitize Breast-Cancer 1 (BRCA1)-expressing tumor cells to platinum-based chemotherapies. The improved outcome of (BRCA1)-deficient breast and ovarian cancer is believed to be linked to the impaired ability to repair chemotherapy-induced DNA damage. However, therapeutically relevant agents that target BRCA1 expression have yet to be identified. In this study, we explore the effect of histone deacetylase inhibition (HDACi) on BRCA1 expression and platinum sensitivity in a breast and ovarian cancer cell line model.
Experimental procedures: BRCA1 mRNA and protein expression was determined by Q-PCR and Western blot, respectively. The efficacy of the HDACi, M344, to potentiate the cytotoxicity of platinum-based chemotherapeutics was evaluated in a range of breast and ovarian tumor cell lines using the MTT cell viability assay and confirmed by flow cytometry. The effect on DNA damage was measured by immunofluorescence staining and flow cytometry for H2A.X foci, a hallmark for the presence of DNA double strand breaks.
Results: Baseline BRCA1 mRNA and protein expression was variable in three breast (MCF7, T47D and HCC1937) and three ovarian (A2780s, A2780cp a cisplatin-resistant variant and OVCAR4) cancer cell lines. Expression of BRCA1 protein decreased in response to the addition of the HDACi, M344, in the four cell lines that express detectable levels of BRCA1 by Western blot analysis. BRCA1 mRNA levels decreased with the addition of this HDACi in all the breast and ovarian cancer lines evaluated. Treatment with M344 also increased the sensitivity of these tumor cells to cisplatin and carboplatin treatment in the cell lines with high BRCA1 expression. Furthermore, expression of BRCA1 protein and mRNA decreased in cells treated with the combination of HDACi and cisplatin. A2780s cells subjected to combination platinum and HDACi treatment demonstrated increased levels of DNA damage as assessed by the presence of phosphorylated H2A.X foci in comparison to either treatment alone. Conclusion: This study supports a novel mechanism of BRCA1 targeting using an HDACi resulting in enhanced platinum sensitivity in breast and ovarian cancer cells. Further studies are needed to determine if a HDACi/platinum combination has potential clinical relevance in a subset of breast and ovarian cancer patients.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B174.
Abstract B178: Nanoscale quantification of phosphorylated and unphosphorylated ERK and MEK isoforms differentiates tumor and nontumor clinical specimens
Authors: Fan Alice C. , Dermody Jessica L. , Kong Christina , Zhang Nancy , Orban Mathias W. , Pai Reetesh , Xu Liwen , Varasteh Ben , Tran Mai , Sridhar Kunju , Lee Lowen , Greenberg Peter L. , Felsher Dean W. 
Published: June 2012

Abstract
The MAP Kinase pathway is commonly dysregulated in cancer. We have developed the use of a highly sensitive microfluidic nano-immunoassay system (NIA) to perform detailed analysis of ERK and MEK activation in hematopoietic and solid tumors. We recently reported use of NIA for measurement of proteins in as little as 4 nanoliters of lysate from preclinical and clinical lymphoma and leukemia specimens (Fan et al, Nature Medicine 2009). Now, we present results measuring specific isoforms of MAP Kinase proteins in cells sampled from patients with solid tumors and Myelodysplastic Syndrome (MDS). First, we developed tissue collection, handling and processing protocols to produce reliable NIA results in a small number of cells obtained by minimally invasive techniques. We collected over 100 blood buffy coat and fine needle aspirate (FNA) specimens from normal controls and patients with MDS or solid tumors. Using a single antibody that recognizes both the phosphorylated and unphosphorylated isoforms of ERK, we can determine not only relative levels of phosphorylated isoforms of ERK protein, but also calculate the percent phosphorylation of ERK in each clinical specimen. We have developed a similar method to quantify MEK isoforms. NIA revealed that adenocarcinoma, squamous cell carcinoma, renal cell carcinoma, and MDS samples could be distinguished from non-tumor specimens based upon different patterns of phosphorylated ERK isoforms. To determine if signaling changes can be detected by NIA upon treatment of cells with novel targeted therapies, human leukemic TF1 cells were treated with a polo-1 kinase (PLK-1) inhibitor, ON01910 (Onconova, Inc.). We found the surprising result that only 5% of ERK1 and ERK2 were found to be phosphorylated in the TF1 cell line, whereas 45% and 90% of MEK1 and MEK2 were phosphorylated, respectively. Additionally, NIA analysis revealed a 20% decrease in the percent of phosphorylated MEK2 after treatment with ON01910. Taken together, our studies demonstrate that NIA can be used to identify specific changes in MAPK signaling pathway that distinguish normal from malignant cells as well as quantitatively measure the response of malignant cells to a targeted therapeutic.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B178.
Abstract B179: An improved method for array comparative genomic hybridization of formalin fixed paraffin embedded surgical pathology specimens
Authors: Suuriniemi Miia , Killian Keith , Walker Robert , Edelman Daniel , Meltzer Paul 
Published: June 2012

Abstract
Array comparative genomic hybridization (aCGH) has been widely used on high quality DNA obtained from fresh tissue samples to investigate chromosomal abnormalities associated with different cancers. Formalin fixed paraffin embedded (FFPE) tissue samples are an ideal source for retrospective and prospective genomic profiling studies because they are abundant in the archives and are the most common derivative of clinical surgical pathology analyses. However, DNA degradation and cross linking due to tissue processing and storage conditions has limited their prior utility for molecular testing. Here, we report an improved and reliable method to isolate, purify, and label DNA from FFPE tissue samples for high resolution aCGH.
Samples (n=67) were obtained from FFPE tissue blocks of &gt;10yrs old and represented a variety of malignancies. Guided by hematoxylin and eosin stained sections, corresponding tissue block regions of maximal tumor cell density were targeted for extraction using a tissue microarray needle punch. Several changes to the Qiagen DNeasy kit, including buffers, temperatures, centrifugations, and elution conditions, were used to maximize DNA yield and produce a DNA derivative suitable for aCGH. Our method produced suitable DNA roughly 90% of the time, yet occasional impurities following Qiagen column purification persisted and manifested as a decreased 260/230 ratio, in which case we employed a simple additional column purification to render such samples usable. Non-enzymatic Universal Linkage System chemical labeling was used to directly couple fluorescent dyes with the sample and reference DNAs (1 ug each), which were then applied to an Agilent microarray. Data was analyzed in Nexus Copy Number software.
Average DNA yield was 1 ug per 0.6mm needle core. Our optional clean up step typically raised the 260/230 ratio from 1.5 to above 2. The majorities of samples (87%) were successfully labeled and produced good quality aCGH profiles with a median DLR score of 0.25 and signal-to-noise ratio of 17. We were also able to set up a threshold of the amount of label incorporation that reliably predicted the success of the aCGH. This will guide us in the future to test only samples expected to pass QC measures and thus not waste costly microarray components.
Our extraction and labeling method demonstrates the feasibility of successfully using DNA derived from FFPE tissue samples for aCGH, and brings this technique to the level of routine testing. Thus, our methodology removes many prior technical obstacles from aCGH based sample classification for diagnosis and clinical decision making using archival, current, and prospective FFPE specimens.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B179.
Abstract B193: Identification of selective inhibitors of ubiquitin specific proteases
Authors: Lopez Roman , Collura Vincent , Reverdy Céline , Planquette Cécile , Conrath Susan , Guedat Philippe , Delansorne Rémi , Daviet Laurent , Colland Frédéric 
Published: June 2012

Abstract
Regulated protein turnover is primarily controlled by the ubiquitin-proteasome system. The therapeutic efficacy of the proteasome inhibitor Bortezomib establishes this system as a valid anticancer therapeutic field. A promising alternative to targeting the proteasome itself lies upstream, at the level of the ubiquitin conjugation/deconjugation step to generate more specific anticancer agents. Ubiquitin-specific proteases (USP) are involved in the deubiquitination of specific target substrates regulating their stability, subcellular localization and/or activation status. USP represent a druggable target class due to their thiol-protease catalytic core which is amenable to pharmacological inhibition by small molecules. A genome-wide RNAi screen of the catalytically active human USPs in cancer-relevant cellular models and phenotypic assays allowed us to identify USP7/HAUSP and USP8/UBPY as promising cancer targets. Fluorescence-based screening assays using optimized USP substrates including various ubiquitin derivatives (ubiquitin precursor, branched ubiquitin chains) as well as specific, physiological substrates were developed. High-throughput screening performed on our chemically diverse library followed by different optimization programs resulted in the discovery of several series as novel USP inhibitors. Our progress made towards the specificity issue will be presented here with the identification of the first USP8- and USP7-specific series.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B193.
Abstract B202: A new curcumin analogue compound endowed with strong antitumor activity against neuroectoderma-derived cancers
Authors: Pisano Marina , Pagnan Gabriella , Dettori Maria Antonietta , Cossu Sara , Caffa Irene , Sassu Ilaria , Fabbri Davide , Emionite Laura , Cilli Michele , Pastorino Fabio , Palmieri Giuseppe , Delogu Giovanna , Ponzoni Mirco , Rozzo Carla 
Published: June 2012

Abstract
Sharing the common neuroectodermal origin, Malignant Melanoma (MM) and Neuroblastoma (NB) are tumors widely diffused among adult and children, respectively. Despite the current advances in treatment options, clinical prognosis of aggressive neuroectodermal cancers remains dismal. Chemotherapeutics currently in use are still unsatisfactory, therefore the search for novel therapies for such tumors is warranted. Curcumin, main component of curry spice, is one of the phytochemicals widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Moreover, it has been reported that curcumin exerts a good anti-proliferative activity on neuroectodermal tumor cells by inducing apoptosis. Recently, we have synthetized and tested in vitro various curcumin related compounds in order to select new antitumor agents displaying stronger and selective growth inhibition activity on both MM and NB cells. In this work, we have demonstrated that a new curcumin-related biphenyl compound, the α,β unsaturated keton (D6), was more effective in inhibiting tumor cells growth when compared to curcumin (D6 IC50 ∼1-2µM, vs curcumin IC50 ∼10-20µM). Normal fibroblasts proliferation was not affected by these treatments. Clonogenic assay, which measures the long-term effects of drugs on permanent cell growth arrest and cell death, showed a significant dose-dependent reduction in both MM and NB colony formation only after D6 treatment. Furthermore, TUNEL assay, Annexin V staining, caspases activation (such as caspases 3, 7, 9) and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin, but with a stronger and quicker extent. Besides, these apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release, meaning that also the intrinsic apoptotic route took place. As reported in literature, curcumin inhibited NFkB nuclear translocation in neuroectodermal tumor cells and, therefore, D6 showed the same inhibitory effects but at lower doses. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous MM and orthotopic NB xenograft models. In both experiments, D6 exibited significantly reduced tumor growth compared to both control and curcumin (MM: D6 vs control: P&lt;0.001 and D6 vs curcumin P&lt;0.01; NB: D6 vs both control and curcumin: P&lt;0.001).
Our data indicate the biphenyl curcumin-related compound D6 could be considered as a good candidate to develop new adjuvant therapies against tumors with neuroectodermal origin.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B202.
Abstract B203: Mitochondria-targeted superoxide spin-traps for treatment of cancers with high oxidative stress
Authors: Basu Hirak S. , Vallerga Anne , Clark Paul A. , Kuo John S. , Joseph Joy , Kalyanaraman Balaraman 
Published: June 2012

Abstract
Many human malignancies such as prostate cancer (CaP) and primary brain tumor (GBM) exhibit high oxidative stress. Developing a successful therapeutic drug to treat advanced metastatic CaP and GBM is a major unmet medical need. It has been demonstrated that in certain chemo- and/or radiation resistant cancer cells with high oxidative stress, cells depend on reactive oxygen species (ROS) for survival and proliferation. Therefore, reducing ROS can be a successful strategy for developing chemotherapeutic drugs for use against chemo- and/or radiation-resistant tumors. The mitochondria are a major source of superoxide and other ROS. We focused on targeting spin-trapping nitroxide analogs at the mitochondrial interstitial space with appropriate linker length in order to remove the superoxide in order to reduce the cellular ROS levels without interfering with the mitochondrial electron transport chain. Our lead compound in this new class of drugs is Mito-tempol-C10. The drug successfully blocked ROS production in human CaP and GBM cell lines as determined by DCF dye oxidation assay. It exhibited marked growth inhibitory effect against androgen-dependent as well as androgen-independent cultured human CaP cells (IC50 &lt; 1 µM) and similar growth inhibitory activity against several human GBM cells lines as well as cultured primary brain tumor stem cells as determined by DNA fluorescence measurement assay. Preliminary pharmacokinetic (PK) study show that the drug has serum half-life of approximately 45 minutes, but is retained by the tumor and other animal tissue for more than 24 hours. The drug is tolerated by ICR white mice, nude mice and NOD-SCID mice at a dose of 15 mg/kg i.p. given once every week for four weeks without any overt systemic toxicity. Preliminary efficacy study at this treatment condition showed marked effect on the growth of intracranially implanted, radiation-resistant U-87 MG human GBM cells in NOD-SCID mice and a small, but significant effect on the growth of androgen-independent PC-3 human prostate cancer cell xenografts growing on the flanks of nude mice. These results confirm that mitochondria-targeted spin-traps that reduce cellular ROS can be therapeutically effective in treatment of advanced, hard-to-treat human tumors with high oxidative stress.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B203.
Abstract B205: Evaluation of circulating CD34+ cells following treatment with anti-EGFL7 in preclinical models of efficacy
Authors: Huseni Mahrukh , Kadel Edward , Desai Rupal , Kan David , Cheng Jason , Yu Shang-Fan , Singh Mallika , Raja Rajiv , Ye Weilan , Hegde Priti 
Published: June 2012

Abstract
A significant existing challenge for anti-angiogenic therapy is that there are no validated biomarkers to either monitor dosing, response to therapy or escape from therapy. This limitation is a more significant challenge when the therapy in question targets a novel pathway with a unique MOA. Some generalized biomarkers have been identified to follow administration of anti-angiogenic therapy, and included in this class are circulating endothelial cells or CECs. CECs are a well-established marker of on-going and active angiogenesis1. In this report we describe the utility of measuring CECs in response to targeting a novel angiogenic protein, EGFL7. EGFL7 is an extracellular matrix protein that is highly expressed in endothelial cells of angiogenic vessels, including embryonic, tumor and injured vasculature. Inhibition of EGFL7 activity by anti-EGFL7 results in a reduction of tumor microvascular density and tumor growth in genetically engineered models of cancer such as RIP-T Ags. In order to identify a circulating biomarker for this response, we first explored the effect of anti-EGFL7 treatment on circulating CD34+ cells in preclinical tumor models, particularly in RIP-T Ag and MDA - MB-231. Analysis of circulating CD34+ cells showed a statistically significant decrease in circulating CD31−/CD34+/CD45dim cells in the blood of tumorbearing mice treated with anti-EGFL7. In order to characterize their molecular profiles, we isolated the two subpopulations of CD34+ cells - CD31−/CD34+/CD45dim and CD31+/CD34dim/CD45dim cells - from healthy adult human peripheral blood by flow cytometry. Subsequent microarray analysis of the two populations indicated that the gene expression profile of CD31+/CD34dim/CD45dim was indicative of terminally differentiated circulating endothelial cells (CEC), whereas the profile of CD31−/CD34+/CD45dim was suggestive of circulating progenitor cells (CPC.) Further evaluation by RT-PCR confirmed expression of EGFL7 in both CECs and CPCs. Additionally, we compared the prevalence of CD31+/CD34dim/CD45dim cells in whole blood from healthy adult and treatment naive NSCLC whole blood and confirmed that CD34+ cells could be used to follow administration of anti-EGFL7 in humans.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B205.