bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A162: Inhibition of MEK sensitizes paclitaxel-induced apoptosis of human colorectal cancer cells by down-regulation of GRP78
Authors: Mhaidat Nizar M. 
Published: June 2012

Abstract
Here we report that paclitaxel induces variable degrees of apoptosis of human colorectal cancer cells. Paclitaxel induces multiple arms of the endoplasmic reticulum (ER) stress response, including up-regulation of 78-kDa glucose-regulatory protein (GRP78) and eukaryotic initiation factor α (eIF2) phosphorylation. Inhibition of MEK/ERK pathway sensitized colorectal cancer cells to paclitaxel-induced apoptosis. Similar result was obtained by inhibition of GRP78 using small interfering RNA molecules. Knockdown of MEK resulted in a significant down-regulation of paclitaxel-induced up-regulation of GRP78 indicating that activation of GRP78 is a downstream event of MEK/ERK pathway activation. These results indicate that GRP78 might be a novel mechanism underlying resistance of colorectal cancer cells to microtubule-targeting drugs. Combination of compounds capable of suppressing GRP78 might be a golden approach for improving the effectiveness of taxanes.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A162.
Abstract A177: Cetuximab resistance associated with dimerization-independence of oncogenic EGFR mutants
Authors: Cho Jeonghee , Chen Liang , Sangji Naveen , Du Jinyan , Okabe Takafumi , Yonesaka Kimio , Francis Joshua M. , Flavin Richard J. , Yu Soyoung , Greulich Heidi E. , Johnson Bruce E. , Eck Michael J. , Jänne Pasi A. , Wong Kwok-Kin , Meyerson Matthew 
Published: June 2012

Abstract
Asymmetric dimerization of the kinase domain is a key mechanism for activation of the epidermal growth factor receptor (EGFR). Here, we show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. Consistent with these findings, tyrosine phosphorylation of the carboxyl-terminus is not required for mutant EGFR-mediated cellular transformation. These differences in dimerization requirements may have clinical implications: treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization-dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization-independent EGFR mutants. These data imply that disruption of dimerization is among the antitumor mechanisms of cetuximab. We therefore hypothesize that EGFR mutation status in lung cancers may serve as a marker for clinical response to cetuximab.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A177.
Abstract A18: The dual angiogenesis/heparanase inhibitor PG545, but not the tyrosine kinase inhibitor sorafenib, inhibits spontaneous metastasis in models of breast and lung cancer
Authors: Bytheway Ian , Hammond Edward , Handley Paul , Dredge Keith 
Published: June 2012

Abstract
PG545 is a fully synthetic heparan sulfate (HS) mimetic selected as the lead oncology candidate for formal preclinical development. PG545 inhibits key processes in tumor progression (a) neovascularization - by interfering with growth factor binding and (b) metastasis - presumably by inhibition of heparanase activity. PG545 was assessed for anti-angiogenic activity in vivo and for antitumor and anti-metastatic activity in the T41 breast cancer and the Lewis Lung Carcinoma (LL/2) models using the tyrosine kinase inhibitor sorafenib as an anti-angiogenic reference compound. Both PG545 (daily or twice weekly) and sorafenib (daily) significantly reduced CD31 staining in the AngioSponge™ model. Twice weekly treatment with 25 mg/kg PG545, but not daily treatment with 60mg/kg sorafenib, significantly inhibited solid tumor growth in the T41 model. Moreover, PG545 significantly inhibited spontaneous lung metastases in a dose-dependent manner, whereas sorafenib significantly increased the number of metastases. In the LL/2 model, once weekly treatment with PG545 at 20 mg/kg significantly reduced solid tumor growth to a similar extent as sorafenib while the 40mg/kg dose appeared more efficacious than sorafenib. A significant reduction in spontaneous lung metastases was again associated with PG545 following either a single injection or once weekly treatment while sorafenib had no appreciable effect on metastases. PG545 was well tolerated with no significant loss in bodyweight noted. Taken together, the data demonstrate that PG545 is an effective angiogenesis inhibitor with anti-metastatic activity - an envious property for an anti-cancer compound, allaying recently publicized concerns that angiogenesis inhibitors and even chemotherapeutic agents may have the potential to aggravate metastatic development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A18.
Abstract A203: Heterogeneous nuclear ribonucleoprotein K (hnRNP K) binds to the vascular endothelial growth factor (VEGF) promoter and plays a role in its transcriptional control
Authors: Uribe Diana J. , Guo Kexiao , Shin Yoon-Joo , Hurley Laurence , Sun Daekyu 
Published: June 2012

Abstract
The vascular endothelial growth factor (VEGF) promoter is capable of forming secondary DNA structures, called G-quadruplex and i-motif, in its proximal promoter region (−85 to −50 from the transcription initiation site) that can mask transcription factor binding sites thereby inhibiting transcription. To understand this dynamic region and its implications in transcriptional control we studied protein-DNA interactions of this structurally versatile region, specifically those involving transcription factors. Our candidate transcription factor, heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a single-stranded DNA binding protein able to binding to cytosine-rich sequences such as the VEGF polypurine/polypyrimidine tract. We found that the cytosine-rich 24-bp oligomer has the potential of forming an i-motif at pH 6.5 and formed a complex with hnRNP K as shown by CD spectra analysis and electrophoretic mobility shift assay (EMSA), respectively. The binding of hnRNP K to the VEGF promoter was confirmed through chromatin immunoprecipitation (ChIP) assay, and its effect on transcriptional control was demonstrated through RT/PCR of hnRNP K siRNA KO and overexpression assays. We also observed through EMSA/Footprint that the hnRNP K protein changes the oligo conformation from an i-motif structure to a more unstructured linear conformation. In summary, this work is the first to show that hnRNP K serves a role in the transcriptional control of VEGF and that a bromine solution left to react to the protein-complex can be used to footprint its binding motif.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A203.
Abstract A205: Chk2 status (activation, proteomic, gene, and exon expression) and insights into the activity of its inhibitor PV1019 across the 60 cell lines from the NCI Screen
Authors: Zoppoli Gabriele M. , Connelly John W. , Reinhold William C. , Jobson Andrew G. , Solier Stephanie , Monks Anne , Shoemaker Robert H. , Pommier Yves 
Published: June 2012

Abstract
Chk2 is a multi-substrate kinase involved in the DNA damage response and genomic stability. Part of the ATM-Chk2-p53 axis, it is also activated in various malignant tumors, possibly in a “gene addiction” context. Chk2 inhibitors are in development as anticancer agents based on their selectivity for enhancing the activity of DNA targeting agents in p53-deficient tumors. Here we determined the activation of Chk2, its protein and gene expression levels, and the activity of PV1019 (a new and specific Chk2 inhibitor; see abstract by Jobson et al.) across the 60 lines of the NCI DTP screen. Chk2 expression data were obtained from five microarray platforms (Affymetrix HG-U95, U133, U133 Plus 2.0, HuEx 1.0, and Agilent WHG). Levels of total and activated Chk2 (i.e., phosphorylated on threonine 68) were analyzed by Western blotting. PV1019 was tested in duplicate, and GI50 was interpolated from five serial dilutions of the drug. Our analyses demonstrate that a number of cell lines have high endogenous Chk2 activation (ovarian OVCAR-3 and OVCAR-4, renal RFX-393, lung NCI-H322M and EKVX, melanoma UACC-62 and -257, leukemia RPMI-8226 and breast BT-549) whereas the wild-type p53 tumors all showed low Chk2 activation. Expression of total Chk2 protein and mRNA were generally positively correlated to each other and to the activity of PV1019. Exon array analyses across the NCI-60 suggest exon 3 splicing in approximately half of the cell lines and transcript interruption between exons 8 and 10 in the ovarian SKOV-3 cells, which could be related to the low level of Chk2 expression in this cell line. Together, these data demonstrate a complex phenotype, which underlies the susceptibility of tumor cell lines to Chk2 inhibitors. Such phenotype may relate to potential patient selection for the optimal use of Chk2 inhibitors as single agents or modulators of DNA targeting therapies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A205.
Abstract A206: Clinically relevant perspectives of the clonal nature of cancer
Authors: Barrett Michael T. , Savage Stephanie , Lenkiewicz Elizabeth , Kiefer Jeff , Chow Donald , Yin Holly , Ruiz Christian , Bubendorf Lukas , Mousses Spyro , Demeure Michael J. , Von Hoff Daniel 
Published: June 2012

Abstract
It has been hypothesized and subsequently shown that tumors arise as a result of an acquired genomic instability and the subsequent evolution of clonal populations of neoplastic cells. Thus the pattern and behavior of distinct genomically aberrant clones may underlie multiple clinical phenotypes in a variety of cancers. A fundamental hypothesis of cancer genome studies is that genes and cellular networks targeted by selected aberrations represent vulnerabilities that can be exploited for effective personalized therapies. However, the heterogeneity of neoplastic cells and the presence of admixtures of genomically normal cells make it difficult to comprehensively define cancer genomes in patients in vivo. By applying single parameter and multi parameter DNA content based flow cytometry of nuclei to isolate clonal populations from solid tumor biopsies, and coupling this strategy with array CGH, we obtained high definition genomic profiles of clonal populations from pancreatic adenocarcinomas (PA), adrenal cortical carcinomas (ACC), and prostate carcinomas (PC). The genomes of clonal populations in these disparate cancers have distinct patient-specific sets of aberrations with clinical relevance. For example, our clonal analyses detected unique gene-specific homozygous deletions converging on NOTCH signaling and multiple focal amplicons that target cell migration in PA, distinguished divergent clones within single biopsies, and identified genomic aberrations specific to therapeutically sensitive and resistant clones arising during the evolution of androgen independent metastatic PC. Application of these technologies in combination with next generation sequencing allows for elucidation of the unique clonal identities of cancer genomes in patients in vivo, which in turn can help guide diagnoses and tailor approaches to treatment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A206.
Abstract A228: Noninvasive magnetic resonance spectroscopic PD markers of a minor-groove interstrand cross-linking agent (BN2629) in human colon carcinoma and melanoma xenografts
Authors: Chung Yuen-Li , Troy Helen , Stubbs Marion , Thurston David E. , Judson Ian R. , Leach Martin O. , Griffiths John R. 
Published: June 2012

Abstract
BN2629 (also known as SJG-136) is a novel pyrrolobenzodiazepine dimer analogue that binds covalently in the minor groove of DNA, inducing little or no distortion of the double helix. Hence, it evades the p53-mediated detection and up-regulation of nucleotide excision repair mechanisms but induces apoptosis. It has just completed Phase 1 clinical trials in the USA (NCI) and UK (CR-UK), and has been approved by the NCI for Phase II evaluation.
The aim of this work was to develop a robust and non-invasive surrogate marker for tumor response following BN2629 treatment. We carried out an in vivo 31phosphorus magnetic resonance spectroscopy (31P MRS) study of BN2629 (80 g/kg via ip for 3 days) and vehicle in HT29 human colon carcinoma and LOX IMVI melanoma xenograft models. In vitro 31P MRS were performed on tumor extracts.
Significant growth delays (p&lt;0.0001) were observed in both BN2629-treated HT29 and LOX IMVI xenografts when compared with controls. In vivo31P MRS of the HT29 xenografts showed an increase in the phosphomonoester/total phosphorus signals (PME/TotP) (p=0.04) and PME/ - NTP ratios (p&lt;0.02) after 3 days of BN2629 treatment. No significant changes were observed in the control group. In vitro 31P MRS of extracts from BN2629-treated HT29 tumors showed significant increases in phosphoethanolamine (PE; p&lt;0.01), glycerophosphocholine (GPC; p&lt;0.01) and glycerophosphoethanolamine (GPE; p&lt;0.03) when compared with controls.
In vivo 31P MRS of the LOX IMVI xenografts showed an increase in - NTP/TotP ratio ( -NTP/TotP) (p&lt;0.01) after 3 days of BN2629 treatment. No significant changes were observed in the control group. In vitro 31P MRS of extracts from BN2629-treated LOX IMVI tumors showed significant increases in GPC (p&lt;0.001), GPE (p&lt;0.01) and ATP (p=0.04) when compared with controls.
Treatment with BN2629 resulted in tumor growth delay and altered bioenergetic and phospholipid metabolism in vivo, which are consistent with metabolic changes observed following treatment with agents such as 5-FU [1] and cyclophosphamide [2]. The phospholipid changes may be associated with alteration in membrane turnover following treatment, and these changes may have potential as surrogate non-invasive markers for determining tumor response following treatment with BN2629.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A228.
Abstract A238: The effects of foretinib on MET phosphorylation, gene expression, cell proliferation and tumor growth in MET-amplified tumor cells in vitro and in vivo
Authors: Liu Li , Liu Yuan , Hong Shi , Greger James , Martin Anne-Marie , Gilmer Tona 
Published: June 2012

Abstract
The MET receptor tyrosine kinase (RTK) is frequently deregulated in many types of cancer and is a promising target for cancer drug development. Foretinib is a multikinase inhibitor with potent activity against MET and is currently in phase II clinical trials. In these studies, we determined the anti-tumor activity of foretinib in MET-amplified tumor cells and the MKN45 gastric xenograft tumor model in nude mice. We also measured the effect of foretinib on MET phosphorylation by immunoprecipitation and western blot and evaluated gene expression by Affymetrix microarrays in these models. In vitro foretinib demonstrated the most potent cell growth inhibitory activity in MET-amplified tumor cell lines MKN45 (IC50 = 9 ± 2 nM), HS746T (IC50 = 8 ± 2 nM), SNU5 (IC50 = 2 ± 0.2 nM) and NCI-H1993 (IC50 = 69 ± 5 nM). Foretinib inhibited the phosphorylation of MET, suppressed the phosphorylation of AKT and ERK, and reduced the expression of cyclin D1 in a dose dependent manner in these cells. Furthermore, foretinib given orally showed durable and near complete inhibition of MET phosphorylation (&gt;90%) and dose dependent anti-tumor activity against MKN45 MET-amplified gastric xenograft tumors in nude mice. Tumor stasis and significant tumor growth delay were observed for foretinib dosed at 10 mg/kg and PF-02341066, a MET selective inhibitor, dosed at 50 mg/kg in the same study. In addition, foretinib or PF-02341066 showed similar gene alterations on both MKN45 cells and xenograft tumors. These genes are involved in RTK cross-talk and MET signaling pathways (e.g., HER2, HER3, MET, PIK3IP1, DUSP4, DUSP6), cell motility (e.g., CDH1, TIMP2, CLDN3, MMP1), cell proliferation (e.g., CCND1, TP53INP1, TYMS, CCNB1) and apoptosis (e.g., TNFSF10, CASP8). These results demonstrate that foretinib is a potent MET inhibitor with associated changes in gene expression which correlate with anti-tumor activity in MET-amplified tumor cells both in vitro and in vivo. This gene signature warrants further investigation for its relevance as a MET-inhibitor mediated pharmacodynamic marker.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A238.
Abstract A239: MPS1 (TTK) kinase inhibition selectively kills aneuploid cells
Authors: Rawjee Teeara , Rowlands Martin , McAndrew Craig , Stubbs Mark , Lord Christopher J. , Reis-Filho Jorge S. , Ashworth Alan , Aherne Wynne , Workman Paul , Blagg Julian , Linardopoulos Spyridon 
Published: June 2012

Abstract
Monopolar spindle 1 (MPS1, also known as TTK) is a dual-specificity, cell cycle-regulated kinase required for the establishment and maintenance of the spindle assembly checkpoint during mitosis. Meta-analysis on expression array datasets showed increased MPS1 expression strongly correlated with time to relapse from breast cancer and this was significantly associated with breast tumors of a basal-like phenotype. However, the issue of whether inhibition of MPS1 in human tumor cells compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of MPS1 can indeed reduce the viability of human tumor cells and that this effect is selective; aneuploid tumor cell lines are sensitive to MPS1 inhibition whereas non-cancerous cells remained resistant. To identify chemical inhibitors of MPS1, a high-throughput screen of a library of small molecules using the Homogeneous Time-Resolved Fluorescence (HTRF) assay was performed. This strategy successfully identified a hit compound that selectively reduces viability in human breast tumor cell lines. These results further validate MPS1 as a therapeutic target and identify a proof-of-principle small molecule inhibitor.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A239.
Abstract A243: SCH727965, a novel potent cyclin dependent kinase inhibitor, inhibits pancreatic tumor growth and Ras-mediated tumorigenic signaling
Authors: Mishra Anjali , Feldmann Georg , Garrido-Laguna Ignacio , Dadon Tikva , Strock Christopher J. , Bannerji Rajat , Hidalgo Manuel , Maitra Anirban , Nelkin Barry D. 
Published: June 2012

Abstract
We have previously shown activation of cyclin-dependent kinase 5 (CDK5), a kinase associated with neuronal migration, in human pancreatic cancer. Abrogation of CDK5 function using a dominant-negative protein, RNA interference, or pharmacological disruption significantly mitigated invasion, migration and anchorage independent growth in vitro, and orthotopic tumor formation and systemic metastases in vivo. CDK5 blockade resulted in inhibition of RalA, a key effector pathway downstream of oncogenic Ras, central to tumorigenesis in pancreatic cancer. Restitution of Ral function rescued the effects of CDK5 inhibition in pancreatic cancer cells. Thus, CDK5 is important for Ras signaling in pancreatic cancer, suggesting that CDK5 inhibition may be an effective therapeutic strategy in pancreatic cancer. To begin to explore the therapeutic potential of CDK5 inhibitors in pancreatic cancer, we have examined the effect of the semi-selective CDK5 inhibitor SCH727965 (Schering-Plough). SCH727965 is a potent inhibitor of CDK1, CDK2, CDK5 and CDK9, with in vitro IC50 values of 3, 1, 1 and 4 nM, respectively. In this study, we evaluated the effect of SCH727965 on pancreatic tumor growth and migration. MTT assay results demonstrated that the IC50 for 2 pancreatic tumor cell lines, MiaPaCa-2 and Panc1.98, was 12nM and 24nM respectively. Migration and anchorage independent growth were significantly more sensitive to SCH727965. Thus, Boyden chamber assay, wound-healing assay and soft agar assays indicated 50% inhibition of migration and soft agar growth inhibition at 5nM, and complete inhibition at 10nM drug concentration — concentrations at which the effects on anchorage dependent growth were relatively minor. Tumors from low passage pancreatic tumor xenografts, or from pancreatic cell line orthotopic xenografts, showed 40–75% reduction of tumor growth after treatment with SCH727965, with significant reduction of metastases. SCH727965 treatment resulted in inhibition of RalA activation. Ral activity could be restored by enforced RalA activation, via expression of Rgl2-CAAX, a constitutively active form of a RalGEF (Ral guanine exchange factor) gene.
Our results show that SCH727965 is very effective against pancreatic cancer growth and metastasis. These results also suggest that SCH727965 blocks pancreatic tumor growth, migration and metastasis, at least in part by inhibition of dysregulated Ras signaling, by inhibiting CDK5.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A243.
Abstract A248: Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multitargeted inhibitors targeting insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor tyrosine kinases
Authors: Wang Gary T. , Mantei Robert A. , Hubbard Robert D. , Wilsbacher Julie L. , Zhang Qian , Tucker Lora , Hu Xiaoming , Kovar Peter , Johson Erick F. , Osterling Donald J. , Bouska Jennifer , Wang Jieyi , Bell Randy L. , Davidsen Steven K. , Sheppard George S. 
Published: June 2012

Abstract
Insulin-like growth factor-1 receptor (IGF1R) and members of ErbB family (eg. EGFR, ErbB2) are receptor tyrosine kianses that play significant roles in cancer and have been pursued as drug targets for cancer therapy. There is substantial evidence for the existence of reciprocal cross-talk between IGF1R axis and ErbB axis of cellular signaling. Acquired resistance to EGFR inhibitors gefitinib and erlotinib or ErbB2 inhibitor trastuzumab has been linked to activation of IGF1R signaling through induced overexpression of IGF1R or loss of IGF binding- proteins. Additionally, synergy between IGF1R inhibition and ErbB inhibition has been demonstrated in cancer cell growth inhibition and in xenograft models. Thus, molecules targeting both IGF1R and ErbB-family might have superior anti-tumor efficacy. This poster describes the lead discovery, optimization and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR and ErbB2. The leading compound, A-923573, showed IGF1R IC50 of 12 nM, EGFR (L858R) IC50 of 31 nM and ErbB2 IC50 of 11 nM, potent activity in cellular functional assays and anti-proliferation assays, as well as in an in vivo pharmacodynamic assay.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A248.