bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A68: MCT-1 oncoprotein induces chromosomal aberrations through impairing centrosomal and mitotic-spindle checkpoints.
Authors: Chen Yen-An , Shih Hung-Ju , Chu Kang-Lin , Choy Chik-On , Wu Pei-Hsuan , Wu Meng-Hsun , Hsu Hsin-Ling 
Published: June 2012

Abstract
Centrosome amplification and chromosome abnormalities are frequently detected in neoplasia and during tumorigenesis; however, the mechanism underlying these defects is still unclear. We here identify that the translational regulator, MCT-1, is a novel proto-oncoprotein located at the spindle-organizing apparatus. Decrease of cellular MCT-1 level results in intercellular bridging, chromosome mis-congregation, cytokinesis delay, and post-mitotic apoptosis. MCT-1 induction alongside p53 deficiency (MCT-1-p53) synergistically deregulates mitotic checkpoint kinases and induces Cyclin E protein degradation. These are implicated with increased frequency of cytokinesis failure, multi-nucleation, and centrosome amplification in the subsequent cell cycle. Consistent with the incidences of polyploidy and aneuploidy are progressively induced by the continued cell cultivation and further promoted by the disruption of microtubule structure, array CGH analysis confirms that the pronounced chromosome amplifications and deletions occur on MCT-1-p53 cellular background. This is the first demonstration that MCT-1 plays an important role in the regulation of centrosome integrity and mitotic progression.
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 A68.
Abstract A69: Subtype-specific targeting of RAS signal transduction in pancreatic ductal adenocarcinoma.
Authors: Mirzoeva Olga K. , Collisson Eric A. , Schaefer Peter M. , Roy Ritu , Korn W. Michael 
Published: June 2012

Abstract
Pancreatic ductal adenocarcinoma (PDA), the fourth-leading cause of cancer related death in the US, remains an incurable disease. Among the most promising targets for new treatments for PDA is the KRAS oncogene since mutations in this gene are found in about 90% of all cases. Because attempts to target the KRAS protein itself have failed so far, inhibiting pathways down-stream of KRAS in particular the MAPK and PI3K pathways, represent promising targets. We discovered that inhibition of MEK, a major effector of KRAS signaling, leads to feedback activation of the pro-survival PI3K/AKT pathway through an EGFR-mediated mechanism. In agreement with this finding, many PDA cell lines show synergistic growth inhibition and induction of apoptosis when treated with combinations of MEK and EGFR inhibitors or MEK with PI3K inhibitors. We profiled gene expression patterns in an extensive panel of human PDAC cell lines and identified two subtypes with epithelial and mesenchymal features, respectively. The vast majority of cell lines demonstrating synergism in response to combinations of MEK inhibitors (CI1040 or PD0325901) with EGFR inhibitors (erlotinib) were of epithelial sub-type. In contrast, none of the mesenchymal-type PDA lines showed synergistic effects with respect to apoptosis or cell growth inhibition. Predictor analysis using the cell line mRNA expression data revealed a 13-gene signature predictive of sensitivity to the drug combination. We hypothesize that these predictors will allow for the development of patient selection strategies for clinical application of combinations of MEK- and EGFR inhibitors in PDA.
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 A69.
Abstract A7: The heparan sulfate mimetic PG545 as a monotherapy or in combination with the standard-of-care agents paclitaxel or carboplatin inhibits solid tumor progression in two murine models of ovarian cancer.
Authors: Dredge Keith S. , Hammond Edward , Handley Paul , Rowley Jessica , Peart Melissa , Brandt Ralf , Bytheway Ian 
Published: June 2012

Abstract
PG545 is a fully synthetic heparan sulfate (HS) mimetic currently being assessed by subcutaneous administration in Phase I clinical trials for advanced cancer patients. PG545 inhibits the enzymatic activity of heparanase, angiogenesis, solid tumor growth and spontaneous metastases in different tumor types. As a role for tumor angiogenesis emerged in the development of ovarian cancer, the number the clinical investigations using avascular therapies have increased in recent years. Moreover, given the fact that ovarian cancers can metastasize by multiple routes, the dual antiangiogenic and antimetastatic activity of PG545 may offer a promising approach to treat ovarian cancer patients. Standard treatment with PG545 involved a loading and maintenance dosing regimen of 20 mg/kg followed by weekly injections of 10 mg/kg as previously reported. In these studies the antitumor effect of weekly dosing with PG545, both as a monotherapy and in combination with standard-of-care agents, was investigated. In the first study, mice bearing A2780 tumors were treated with PG545 alone, paclitaxel alone (15 mg/kg, qw) or in combination of both compounds. Treatment with PG545 reduced tumor growth (TGI = 42%) compared to vehicle control and was more effective than paclitaxel alone (TGI = 11%). In combination, PG545 and paclitaxel significantly reduced tumor volume (TGI = 61%) compared to vehicle control. In a second model, mice bearing SKOV3 tumors received PG545, carboplatin (60 mg/kg) or in combination. Treatment with PG545 significantly inhibited tumor growth (TGI = 40%) compared to vehicle control, almost equivalent to the effect of carboplatin monotherapy (TGI = 41%). The combination regimen further impacted tumor growth, showing a significant effect by day 19 of treatment (TGI = 71% versus the vehicle control and the monotherapy groups). In conclusion, PG545 demonstrates antitumor activity as a monotherapy in ovarian cancer models which can be substantially enhanced using combination regimens with current standard-of-care agents such as paclitaxel and carboplatin.
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 A7.
Abstract A80: Modified dosing schedules with the EGFr inhibitors gefitinib and lapatinib in rodent models of mammary and urinary bladder cancer: Preventive and therapeutic effects.
Authors: Lubet Ronald , Bode Ann , Szabo Eva , Grubbs Clinton J. 
Published: June 2012

Abstract
The EGFR inhibitors are approved for treatment of lung and pancreatic cancers (Erlotinib, Gefitinib) and Neu overexpressing breast cancer (Lapatinib) in humans; as well as preventing multiple cancers in animal models. However, the development of toxicities (Iressa, skin rashes; Lapatinib, diarrhea) limit their potential use in prevention; and perhaps even in an adjuvant setting. We examined whether alternative dosing regimens which might reduce toxicity would still achieve preventive and therapeutic efficacy. Female Sprague-Dawley rats were administered a single IV dose of methylnitrosourea (MNU) at 50 days of age. In a prevention study, MNU treated rats administered Gefitinib daily (10 mg/kg BW/day, 7×/week) or Gefitinib (70 mg/kg BW, 1×/week) beginning 5 days after MNU resulted in 94 and 75% reductions, respectively, in cancer multiplicity. Simultaneous measurements of tumor load (number of tumors × tumor weight) showed that both regimens resulted in greater than a 90% decrease. In the therapeutic study (initiating treatment when animals developed a small palpable cancer), both regimens were again highly effective. A prevention study was also performed with Lapatinib (75 mg/kg BW/day, 7×/week or 525 mg/kg BW, 1×/week). While the daily dose reduced cancer multiplicity 90%, the weekly dose caused a 70% reduction. Finally, we examined the effects of daily or weekly dosing with Iressa (100 mg/kg BW/day, 5×/week or 500 or 250 mg/kg BW, 1×/week) in an ER− mouse model (using MMTV/Neu; p53+/− mice). This study showed that while daily dosing with Iressa decreased tumor multiplicity approximately 80%, weekly dosing at either dose caused roughly a 50% decrease. These data show that even a significant alteration in the dosing of Gefitinib (EGFR 1) or Lapatinib (EGFR 2/1) still resulted in a large reduction in mammary cancers. We similarly tested Lapatinib (weekly, 525 mg; or daily, 75 mg/kg/day) in a delayed preventive/therapeutic setting in an OH-BBN model of urinary bladder cancer. We found that although daily dosing was most effective weekly dosing was still relatively effective. The important clinical question will be whether this altered dosing will diminish the toxicities associated with these agents. We cannot determine this in animal models since, at the effective doses employed, the typical toxicities observed in humans are not observed. Supported by NCI contract number HHSN261200433001C.
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 A80.
Abstract B108: The novel HDAC inhibitor PCI-24781 synergizes with tamoxifen in ER-positive breast cancer by concertedly downregulating AKT1 expression.
Authors: Thomas Scott , Raha Paromita , Thurn K. Ted , Chen Stephanie , Munster Pamela 
Published: June 2012

Abstract
Breast cancer continues to be the most frequently diagnosed malignancy in women, and is second only to lung cancer as the cause of cancer death. While aromatase inhibitors are more commonly used in postmenopausal women, tamoxifen remains the only approved hormonal therapy for premenopausal patients presenting with estrogen receptor (ER)-positive disease. However, the effectiveness of tamoxifen is limited, as many tumors develop resistance. As such, substantial effort has been made to improve and extend the effectiveness of tamoxifen. To this end, we have demonstrated that histone deacetylase (HDAC) inhibitors potentiate the anti-tumor activity of tamoxifen in preclinical models, and in an early phase trial durable responses were achieved in a heavily pre-treated patient cohort. Mechanistic studies have revealed that HDAC inhibition directs breast cancer cells into mitochondrial-mediated apoptosis in part by altering the balance of apoptotic gatekeepers (e.g. Bax, Bak, and Bcl-2). In the current study, we extend our mechanistic understanding of this combination in ER-positive cells using the novel hydroxamic acid type HDAC inhibitor PCI-24781. Early clinical evaluation suggests that PCI-24781 is a potent HDAC inhibitor and is well tolerated at doses exceeding those needed for preclinical synergy. Here we demonstrate that PCI-24781 and tamoxifen act individually to additively abrogate AKT cell signaling by down regulating AKT1 mRNA and protein expression. Furthermore, PCI-24781 represses ESR1 transcription and thus exerts its effect on AKT1 expression in part through the regulation of ER expression. Attenuated AKT signaling manifests in elevated GSK3α/β phosphorylation, Bim, and p21 and a reduction in cyclin D. Cells exhibit an induction of an array of pro-apoptotic drivers, mitochondrial release of cytochrome C, caspase activation, and cell death. These results suggest that HDACs regulate the response of AKT to tamoxifen and that the cooperative effects of HDAC inhibitors and tamoxifen lead to enhance cell death. Therefore, early introduction of an HDAC inhibitor into hormonal therapy in patients with ER-positive breast cancer may counter the emergence of tamoxifen resistance.
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 B108.
Abstract B139: Arginine deprivation with pegylated arginine deiminase regulates key metabolic genes in RNA and DNA synthesis in ASS1-deficient malignant mesothelioma cells: Clinical implications.
Authors: Delage Barbara , Luong Phuong , Phillips Melissa , Chmielewska-Kassassir Malgorzata , Cutts Rosalind , Chelala Claude , Ghazaly Essam , Jithesh P. V. , Fennell Dean , Lemoine Nicholas R. , Hawkes Geoffrey , Wozniak Lucyna , Joel Simon , Jackson Robert C. , Szlosarek Peter W. 
Published: June 2012

Abstract
Tumors deficient in argininosuccinate synthetase-1 (ASS1), a key enzyme involved in arginine synthesis, are auxotrophic for arginine and sensitive to amino acid deprivation. Currently, several trials are testing the arginine-depleting agent, pegylated arginine deiminase (ADI-PEG20) in patients with cancer, including a randomised phase II multicenter UK study in patients with ASS1-deficient mesothelioma (NCT01279967). Here, we sought to identify key pathways involved in the mechanism of action of ADI-PEG20 using a panel of ASS1-deficient malignant mesothelioma (MPM) cell lines as our model. Epithelioid (2591), biphasic (MSTO) and sarcomatoid (JU77) mesothelioma cells were exposed to ADI-PEG20 and analysed using Affymetrix gene expression profiling with validation of candidate genes by qPCR and western blotting, and metabolic studies by LC-MS and 1H-NMR. ADI-PEG20 modulated several metabolic genes involved in nucleotide synthesis in the MPM cell lines. We identified suppression of ribonucleotide reductase (M1 and M2 isoforms), thymidylate synthase and dihydrofolate reductase by 24hrs, the latter enzymes being known targets of pemetrexed, a multitargeted antifolate used in the first-line therapy of mesothelioma. Moreover, metabolic profiling revealed upregulation of several modified nucleosides, including ribothymidine and downregulation of the nucleotide, guanosine monophosphate. Lastly, in vitro studies confirmed potentiation between ADI-PEG20 and pemetrexed and sequential therapy led to reduced tumor growth in vivo. In conclusion, arginine depletion modulates several key enzymes involved in nucleotide synthesis, providing a rationale for combining ADI-PEG20 with pemetrexed-containing regimens in 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 B139.
Abstract B173: Inhibition of the Mdm2-p53 interaction by geraniin.
Authors: Tatsuda Daisuke , Iijima Masatomi , Kitayama Takashi , Momose Isao , Nomoto Akio 
Published: June 2012

Abstract
Damage by UV, IR, chemical agents and other stresses causes cell cycle arrest and induces DNA repair in eukaryotic cells while severe DNA damage invokes apoptosis. Cell cycle checkpoint signaling pathways are responsible for cell cycle arrest and decisions about cell survival or apoptosis. Because the cell cycle checkpoint signaling pathway also regulates cell survival and apoptosis in tumor cells, proteins related to this pathway are attractive targets for anti-tumor drugs. p53 is a transcription factor and participates in cell cycle checkpoint signaling pathways. Mdm2 has ubiquitin E3 ligase activity and binds to p53 to promote its degradation by the ubiquitin-proteasome pathway. Inhibition of this Mdm2-p53 interaction induces cell cycle arrest and apoptosis. To search for new anti-tumor compounds, we constructed an Mdm2-p53 interaction assay using the in vitro TR-FRET technique to screen for natural products that inhibit this interaction. Using TR-FRET, we found that geraniin from plant extracts inhibited the Mdm2-p53 interaction. This inhibition was stronger than that induced by the microorganism product altenusin (IC50 58 nM and 2100 nM for geraniin and altenusin, respectively). A luciferase reporter assay showed that geraniin induced activation of p53 transcriptional activity in colon cancer cells. Geraniin also increased protein expression levels of p53 and inhibited cell growth in glioblastoma cells.
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 B173.
Abstract B18: Champions Tumorgraft™ models demonstrate spontaneous metastases.
Authors: Albee Lee D. , Friedman Jay , Anderson Nathan , James Meredith , Bruckheimer Elizabeth M. 
Published: June 2012

Abstract
One of the challenges in oncology drug development is the lack of in vivo models that demonstrate the spontaneous metastatic process. Standard subcutaneous implantation of cell-line based xenografts models seldom results in the generation of spontaneous metastatic lesions. In general, experimental metastatic models are utilized which requires the intravenous injection of cells or orthotopic implantation of tumors cells to replicate metastases. These methods fail to capture the full process of metastases and only capture seeding in the distant location. Champions Oncology utilizes its innovative Champions Tumorgraft™ platform where primary human tumors are implanted into immunocompromised mice in a manner that preserves the biological properties of the original human tumor. As part of its extensive characterization, Champions has recently observed an increasing number of Champions Tumorgraft™ models demonstrating spontaneous metastatic lesions following subcutaneous (s.c.) implantation. The tumor types demonstrating spontaneous metastasis include breast, melanoma, colorectal, esophageal adenocarcinoma, and head and neck squamous cell carcinoma. Two Champions Tumorgraft models highlighted in this report are CTG-0033, a breast cancer model, and CTG-0213, a melanoma model. These Champions Tumorgraft models demonstrate frequent metastases to the liver and spleen following s.c. implantation. For model CTG-0033, metastases were seen in greater than 75% of the animals following implantation. The metastatic behavior of this Tumorgraft model also parallels the clinical disease progression. For instance, CTG-0033 was derived from a breast cancer patient who, following the development of the Tumorgraft model, developed extensive metastases. Given that treatment failures clinically are often due to recurrence of the tumor at metastatic locations, there is significant need for in vivo models that replicate the spontaneous metastatic process. Overall, numerous Champions Tumorgraft models implanted s.c. exhibit spontaneous metastatic behavior and are therefore ideal models for oncology drug development focused on inhibition of metastases.
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 B18.
Abstract B19: Innovative tools to evaluate genetic targets and the efficacy of novel cancer therapeutics.
Authors: Kissel Holger , Xu Yan , Tugusheva Marina , Seibler Jost , Jonkers Jos , Grass David , Buiakova Olesia 
Published: June 2012

Abstract
More predictive small animal models for compound and genetic target assessment are needed to improve development of more efficacious drugs. For assessment of novel cancer therapeutics we have developed an in vivo and ex vivo bioluminescent imaging platform to evaluate compound efficacy. In these mouse models orthotopic tumor grafts are being used that are more relevant with respect to host-tumor interactions, display metastatic potential and allow the evaluation of responses to novel therapeutics. These models closely mimic the progression of human disease and allow quantitative analysis and high throughput in vivo assessment of potential anti-tumor activity.
In addition we will present an oncology platform using mouse models for breast cancer. The Brca1/p53 breast cancer model resembles hormone receptor- and ERBB2-negative (“triple-negative”) mammary carcinomas and shows responses to therapies similar to humans, including the emergence of drug resistance. We will present an orthotopic allograft system using primary tumors from Brca1/p53 deficient mice to allow the generation of cohorts developing breast cancer. These grafted mice can readily be used for testing of novel therapeutics in a tumor model resembling human disease.
Finally, we will present a transgenic RNAi system that can be used for studying the loss-of-function of target genes. We will present how this system can be used to develop novel disease models and how potentially this model can be combined with disease models to study the genetic loss of a drug target in an established disease state.
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 B19.
Abstract B204: Engineered cysteine antibodies: Improved antibody-drug conjugate vehicles.
Authors: Sussman Django , Torrey Lindsay , Westendorf Lori , Zhang Xinqun , Okeley Nicole M. , Alley Stephen C. , Lyon Robert , Meyer David , Miyamoto Jamie B. , Benjamin Dennis R. 
Published: June 2012

Abstract
The use of monoclonal antibodies for the delivery of anticancer drugs to tumor cells is an emerging therapeutic modality and has been the subject of a great deal of investigation. In this study we have engineered antibody variants with an additional cysteine residue in the each heavy chain to provide a route towards homogenous two drugs per antibody loading while interfering with Fc gamma receptor binding. We have characterized the relationship between the site of drug conjugation and a number of key parameters including relative protein expression, conjugatability, drug-linker stability, effects on biophysical properties of the resulting antibody-drug conjugate (ADC), and in vitro cytotoxicity. We demonstrate that the site of conjugation affects many of these parameters and that Engineered Cysteine (EC) antibodies can be considered a viable next generation ADC approach.
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 B204.