bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2615: Amplification and/or high expression of Myc family genes sensitizes tumor cells to aurora kinase inhibitors
Authors: Hook Kenneth E. , Pavlicek Adam , Garza Scott J. , Lira Maruja E. , Ching Keith , Kan Julie , Srinivasa Sreesha P. , Christensen James G. 
Published: February 2011

Abstract
The identification of patient populations predicted to derive clinical benefit from systemic treatment regimens is of critical importance for development of targeted therapies. Collective clinical data available for the Aurora kinase inhibitor class of targeted therapies has indicated that broad single agent clinical activity is not readily apparent. We screened a panel of established lung (mostly non-small cell) and colon cell lines for growth inhibitory sensitivity to PF-03814735, an Aurora family kinase inhibitor, revealing a potential correlation with Myc family amplification or expression. The Aurora kinases A and B have been shown to be functionally linked with Myc family oncoproteins in a number of tumor types. Myc family gene amplification events have been reported in about 30% of small cell lung cancer (SCLC) primary tumors and around 50% of cell lines established from SCLC. We next screened a panel of around 20 SCLC lines for sensitivity to PF-03814735 and its relationship to Myc family gene copy number and gene expression levels. Sensitivity to PF-03814735 in vitro was strongly correlated with amplification events in at least one of the Myc family genes (c-Myc, L-Myc, N-Myc) as well as mRNA expression levels of those genes. Myc family expression demonstrated a significant correlation with gene copy number. Follow up studies to evaluate antitumor efficacy in two SCLC xenograft models, H82 (c-Myc) and H69 (N-Myc), indicated significant tumor growth inhibition by PF-03814735. However, the SCLC models were not appreciably more sensitive to PF-03814735 than several non-Myc amplified tumors studied previously (HCT-116, COLO-205, MDA-MB-231) indicating that further study of optimal dose schedule and/or the molecular basis of sensitivity is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2615.
Abstract 265: EGFR positively regulates GBP1 expression to promote glioma cell invasion
Authors: Li Ming , Furnari Frank , Cavenee Webster 
Published: February 2011

Abstract
Glioma is the most common and deadly human brain tumor. Epidermal growth factor receptor (EGFR) amplification or constitutively active mutation (EGFRVIII) is one of the most frequent genetic lesions in gliomas. To identify target genes regulated by EGFR signaling, we performed expression array analysis and found that human guanylate binding protein-1 (GBP1), a large GTPase that is induced by inflammatory cytokines, is one of the predominant genes induced by EGFR/EGF or EGFR VIII kinase activity. Our results demonstrate that EGF/EGFR signaling could dramatically induce GBP1 expression at both the mRNA and protein level through the p38 MAPK signaling cascade that is distinct from Stat1 signaling used by interferon γ. Moreover, we identified IRF1 and YY1 as downstream transcriptional regulator for GBP1 enhancement by EGFR/p38 signaling. Interestingly, we show that GBP1 is required for EGFR-mediated matrix metallopeptidase-1 (MMP1) expression, and plays a role in glioma cell invasion in vitro. Overexpression of GBP1 enhances glioma cell invasion through MMP1 induction, which was independent of GBP1 GTPase activity. In contrast, siRNA-mediated knockdown of GBP1 inhibited MMP1 expression and in turn blocked cell invasion as well. Consistently, we found that GBP1 is overexpressed and positively correlated with EGFR/EGFRVIII and MMP1 expression in human glioma clinical samples and glioma cell lines, particularly in neural subtypes of GBM as demonstrated by TCGA database analysis. Therefore, Our results suggest that the dysregulation of EGFR-mediated GBP1 expression may contribute to glioma invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 265.
Abstract 267: The effect of amphiregulin knockdown on the expression of transformed phenotypes in triple-negative breast cancer
Authors: Baillo Andrea J. , Ethier Stephen P. 
Published: February 2011

Abstract
Amphiregulin (AREG) and epidermal growth factor receptor (EGFR) co-expression leads to aggressive growth phenotypes observed in some triple negative breast tumors. In SUM-149 cells, a triple negative breast cancer cell line with an AREG/EGFR autocrine loop, we have shown that these cells are more invasive and motile than MCF10A cells grown with EGF and that altered signaling occurs when AREG is the stimulating ligand. To provide additional insight into the role of AREG in the SUM-149 cells, we have successfully knocked down AREG expression in the SUM-149 cells. Q-RT-PCR analysis showed an approximately 40-fold knock-down of AREG mRNA following stable transduction of the most effective shRNA vector. In these knock-down cells, secreted AREG was undetectable by ELISA, and cellular AREG was undetectable by western blot. Knock-down of AREG in SUM-149 cells resulted in a dramatic decrease in the growth rate of these cells, resulting in a doubling time of about half that of the parental SUM149 cell line. Soft agar assays comparing the anchorage-independent growth potential of SUM-149 cells with AREG knock-down SUM-149 cells demonstrated an approximately 50% decrease in soft agar colony forming ability. To examine the migration and invasion capacity of the AREG knock-down cells relative to parental cells, Matrigel invasion assays were carried out and showed that knocking down AREG resulted in a 40-fold decrease in the cells ability to invade the matrix. Our lab has previously shown that in SUM-149 cells, NF-κB DNA binding activity is initiated as a result of AREG activation of EGFR. NF-κB activity in the AREG knock-down cells was altered suggesting that AREG affects cellular signaling by altering transcription factors. Addressing the continued proliferation of the AREG knock-down cells, we examined the requirement for EGFR activation for growth of these cells. Phosphotyrosine western blot analysis demonstrated detectable EGFR activation in the AREG knock-down cells. Growth assays where these cells were treated with an EGFR tyrosine kinase inhibitor or with a neutralizing EGFR antibody demonstrated the dependency of EGFR for growth of these cells. Q-RT-PCR analysis for expression of all seven EGFR family ligands suggested that epigen or EGF may be factors contributing to the continued growth of these cells, in the absence of AREG. In summary, knock-down of AREG expression in SUM-149 cells has a dramatic affect on the cells ability to proliferate, invade, and form colonies in soft agar, which links this growth factor with the aggressive properties associated with the SUM-149 cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 267.
Abstract 2676: Unusual binding of TMP in two different sites in the binary complex with the Q35S/N64F double mutant of human dihydrofolate reductase
Authors: Cody Vivian , Piraino Jennifer , Pace James , Queener Sherry F. 
Published: February 2011

Abstract
In an effort to understand the role of specific active site residues in modulating the binding selectivity of inhibitors against dihydrofolate reductase (DHFR) from different species, a series of single and double mutants of DHFR were made at positions 35 and 64 of human (h) DHFR. To explore sequence differences between human and the pathogenic organisms Pneumocystis carinii (pc) and Pneumocystis jirovecii (pj) DHFR, the causative agent of Pneumocystis pneumonia (PcP) in patients with AIDS, kinetic data were measured for trimethoprim, used for treatment of AIDS-related pneumonia. Crystal structure data are reported for the Q35S/N64F double mutant of hDHFR as a binary complex with trimethoprim (TMP). These substitutions make the human enzyme resemble a cross between pjDHFR which has Ser/Ser at these positions and pcDHFR which has Lys/Phe at these sites. Kinetic data show enhanced affinity for the binding of TMP to this double mutant (Ki 604 nM) compared to wild type hDHFR (Ki 1757 nM). The Ki of TMP is 43 nM for pjDHFR and 222 nM for pcDHFR. Structural data for the binary complex of TMP with this double mutant of hDHFR revealed the unexpected binding of two copies of TMP; one bound in the normal binding site while the other occupies a shallow pocket different from that involved in binding the γ-glutamate of folate substrates or inhibitors. The trimethoxyphenyl ring of the second TMP makes a series of hydrophobic contacts with the trimethoxyphenyl ring of the first TMP and with the phenyl ring of residue F31 and the mutated F64 in this structure. Structural data for the binary complex of wild type hDHFR with TMP does not indicate such binding. The conformation of the two TMP in the double mutant complex differ significantly from each other and from that observed for the wild type hDHFR binary complex. Analysis of all DHFR TMP complexes reveals the bridge torsion angles fall into two broad ranges and the two TMP in the mutant hDHFR complex fall into the less populated group. These data suggest that the combination of hydrophobic contacts from the normal F31 in hDFHR and the mutant F64 provide a unique environment to create sufficient van der Waals contact energy to stabilize binding in this unusual site. Supported in part by NIH GM51670 (VC).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2676.
Abstract 2678: Molecular signature of drug action for microtubule stabilizing agents
Authors: Khrapunovich-Baine Marina , Menon Vilas , Fiser Andras , Angeletti Ruth Hogue , Horwitz Susan Band , Xiao Hui 
Published: February 2011

Abstract
Microtubule-stabilizing agents (MSAs) comprise a class of drugs that bind to polymerized microtubules (MTs), thereby inhibiting their dynamic properties and leading to arrest in mitosis. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling studies led to the identification of the binding site for Taxol in the β-tubulin subunit of the MT polymer, the effect of the drugs on MT conformation was only recently deciphered in our laboratory using hydrogen deuterium exchange (HDX) coupled to high-pressure liquid chromatography and mass spectrometry (HPLC-MS). We have also utilized this technique to determine the binding mode and conformational effects of discodermolide, another MSA with potential to become a useful anti-tumor drug. We found that in tubulin isolated from chicken erythrocytes, discodermolide bound to an overlapping binding site with Taxol, but had a distinct pose within the pocket, such that it oriented itself away from the M-loop and toward the N-terminal H1-S2 loop of β-tubulin. Evidence of conformational effects on the C-terminal H12 helix in the α-tubulin subunit and of complementary MT stabilization between Taxol and discodermolide was found. These results provide the molecular basis for the ability of the two drugs to modulate interactions with endogenous microtubule associated proteins (MAPs) and for the synergy observed between them in vivo. Preliminary analysis of the data with four other MSAs, epothilone B, ixabepilone, peloruside A, and laulimalide, suggests a very similar mode of MT stabilization by all the drugs in this class, with some drug-specific, and more importantly, binding-mode-specific MT-stabilizing effects. Careful examination and qualitative comparison of the conformational effects of all the aforementioned MSAs is currently in progress, and will allow us to determine a molecular signature for drug action that may correlate with the corresponding therapeutic benefits.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2678.
Abstract 2681A: Structure-guided design of potent and selective inhibitors of B-Raf kinase displaying on-mechanism in vivo activity
Authors: Kim Joseph L. , Smith Adrian L. , Carnahan Josette , Beltran Pedro J. , Whittington Douglas A. , Rose Mark J. , DeMorin Frenel , Doherty Elizabeth , Huang Qi , Ncube Mquele , Paras Nick A. , Petkus Jeffrey K. , Tasker Andrew S. , Lee Matthew R. , Babij Carol , Fernando Manory , Hess Kristen , Le Quynh , Epstein Linda F. , Yakowec Peter S. 
Published: February 2011

Abstract
The Ras-Raf-MAPK signaling pathway plays a central role in diverse cellular processes including differentiation, proliferation and survival. This pathway is activated in a large percentage of cancers as a result of mutations in Ras or in B-Raf Ser/Thr kinase. The activating mutation V600E in B-Raf is present in approximately 60% of melanomas and occurs with lower, yet still significant, frequency in human colon and thyroid cancers. Hence, V600EB-Raf has received considerable interest as a small-molecule drug discovery target within the pharmaceutical industry. A high-throughput screen of Amgen's internal kinase preferred library against a recombinant V600EB-Raf kinase domain enzyme identified a class of biarylamide compounds as potent inhibitors of this kinase, and potential starting points for medicinal chemistry efforts. However, these compounds suffered from poor kinase selectivity, particularly against tyrosine kinases from the Src-, VEGFR and PDGFR-families. Crystal structures of representative examples of this scaffold in B-Raf and other tyrosine kinases identified a unique pocket in B-Raf that could be accessed to achieve selective inhibitors of this enzyme. Consequently a novel series of isoquinoline-based compounds was derived which demonstrated potent inhibition against V600EB-Raf enzyme and inhibition of MAPK pathway signaling in cell lines harboring V600EB-Raf. Further optimization within this inhibitor class yielded compounds with favorable in vivo properties as demonstrated by robust inhibition of ERK phosphorylation in V600EB-Raf driven pharmacodynamic models. Crystallographic work supporting the optimization of this series of selective B-Raf inhibitors will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2681A.
Abstract 2698: The parametric response map as an imaging biomarker for identifying progression from pseudoprogression in glioma patients
Authors: Tsien Christina , Galban Craig J. , Chenevert Thomas L. , Johnson Timothy D. , Hamstra Daniel A. , Sundgren Pia C. , Junck Larry , Meyer Charles R. , Rehemtulla Alnawaz , Lawrence Theodore S. , Ross Brian D. 
Published: February 2011

Abstract
We assessed whether a new method of quantifying therapeutic-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high grade glioma. Patients from a prospective IRB-approved trial with high grade glioma received concurrent chemoradiation. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired prior and at week 3 mid-treatment. Pseudoprogression was defined as imaging changes 1-3 months after chemoradiation that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional MR parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. Median radiation dose was 72 Gy (range: 60-81). Of 27 patients, stable disease/partial response was noted in 13 and apparent progression in 14. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in 6 patients. Based upon PRM analysis, a significant portion of the tumor volume had reduced rCBV (PRMrCBV) at week 3 in patients with progressive disease compared to those with pseudoprogression (p&lt;0.01). In contrast, change in average percent rCBV or rCBF, MR tumor volume changes, age, extent of resection, and RTOG RPA classification did not distinguish progression from pseudoprogression. PRMrCBV at week 3 during chemoradiation is a potential early imaging biomarker of response that may be helpful in distinguishing pseudoprogression from true progression in glioma patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2698.
Abstract 2701: Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients
Authors: Shulman Katerina , Cohen Ilana , Barnett-Griness Ofra , Gruber Stephen B. , Lejbkowicz Flavio , Rennert Gad 
Published: February 2011

Abstract
Purpose: Metastatic colorectal cancer is frequently treated with Irinotecan (CPT-11), a topoisomerase-I inhibitor. Irinotecan toxicity is relatively commonly observed. The gene UGT1A1 encodes an enzyme that catalyzes the glucuronidation of the active irinotecan metabolite SN-38 which is eliminated in the liver by metabolic alteration to an inactive form SN-38G. We retrospectively evaluated the association between UGT1A1 genetic variation, prevalence of severe toxicity and colorectal survival.
Patients and Methods: In the Molecular Epidemiology of Colorectal Cancer (MECC) Study we identified 213 patients with metastatic colorectal cancer treated by irinotecan-based chemotherapy (FOLFIRI, IFL). DNA extracted from blood was used for genotyping either by simple determination of TATA box sequence in patient DNA or by implementation of fragment analysis that detects the difference in the number of nucleotides in the specific region analyzed. The polymorphism UGT1A1*28 is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Data on side effects and survival were extracted from full follow-up oncology records.
Results: UGT1A1*28 genotypes 6/6, 6/7, 7/7 were detected in 41.8%, 46.5%, and 11.7% of the patients respectively. Observed grade 3-4 toxicity included: diarrhea 22.4%, leucopenia 9.3%, neutropenia 8.9%, neutropenic fever 3.7%, and mucositis 4%. No significant difference was observed in the rate of diarrhea in patients with UGT1A1*28 7/7 genotype (20%) as compared to these with the 6/6 genotype (27.5%). Hematological toxicity was significantly more common in patients with the 7/7 genotype. Neutropenic fever was observed in 24% of the 7/7 genotype but only in 2% of the 6/7 genotype and 0% of the 6/6 genotype. Oncological hospitalization rate was very high among the 7/7 group (45.8%) and significantly higher than among the 6/6 group (14.4%). The Median overall survival of patients with 7/7 was significantly lower (2.10 years) than that of patients with the 6/6 variant (4.13 years, p=0.002).
Conclusion: UGT1A1*28 7/7 genotype is strongly associated with severe toxicity (mainly neutropenic fever) and oncological hospitalizations and with lower survival. These data support the FDA recommendation and product labeling to tailor treatment plans for colorectal cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2701.
Abstract 2702: Renal cell carcinomas lack arginosuccinate synthetase expression and respond to pegylated arginine deiminase treatment
Authors: He Wei , Chen Jianhe , Zheng Yuhui , Dai Zaoming , He Yan , Wu Bor-Wen , Bomalaski John 
Published: February 2011

Abstract
Biomarkers may be predictive of benefit from therapy. As a result, there is increasing interest in determining new biomarkers and new agents that may target specific pathways that are abnormal in a certain cancer. Normal cells produce arginine internally via the urea cycle. However, certain cancer cells lack one of the urea cycle enzymes, argininosuccinate synthetase (ASS) and become dependent upon an exogenous supply of arginine for growth and survival. For these ASS-deficient cancers, preferential killing of tumor cells induced by arginine deprivation may be effective and safe. ADI-PEG20 is a microbial enzyme, arginine deiminase conjugated with polyethylene gycol. The primary mechanism of action of ADI-PEG20 is arginine deprivation. Thus cancers that are deficient in ASS expression and require arginine could benefit from ADI-PEG20. ADI-PEG20 has been in phase 2 clinical trials for the treatment of hepatocellular carcinoma and metastatic melanoma. Patients whose cancers were deficient in ASS expression have demonstrated medical benefit from ADI-PEG20. Thus at least in these cancers, lack of ASS expression could serve as a biomarker to predict clinical benefit from ADI-PEG20. Other investigators have noted that human renal cell carcinoma (RCC) tissue specimens lack expression of ASS. To confirm these observations and investigate the extent of ASS deficiency in RCC, we analyzed biopsy samples obtained from 31 patients for ASS expression by immunohistochemistry and found all to be ASS negative. We also established three primary RCC cell lines and tested them for response to ADI-PEG20 treatment. Dose dependent growth inhibition was observed after 48 hours for all three cell lines using the MTS proliferation assay. We further tested three ATCC RCC cell lines, 786-O, ACHN and Caki-1 using the MTS assay and observed similar growth inhibition after 48 hours. Cell cycle analysis using the three primary RCC lines revealed that G1 arrest was apparent in samples treated with ADI-PEG20. After 48 hours of ADI-PEG20 treatment, the percentage of cells in G1 increased from 33% to 62%. These results suggest that ADI-PEG20 can potentially be an effective therapeutic agent for the treatment of RCC. They also suggest the potential utility of ASS expression as a biomarker in identifying patients that are most likely to benefit from the ADI-PEG20 treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2702.