bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A51: Quantitative assessment of VEGF combined with known clinical variables predicts outcome in patients with diffuse large B-cell lymphoma (DLBCL): Implications for guiding future treatment selection.
Authors: Donovan Michael J. , Puig Pere , Erill Nadina , Colomer Anna , Colomo Lluis , Campo Elias 
Published: June 2012

Abstract
Introduction: The pathogenesis of DLBCL is both complex and heterogeneous, and pathogenetic mechanisms remain largely unknown. A clinical index known as the international prognostic index (IPI) remains the ‘gold-standard’ for predicting response to therapy and overall survival; however, more recently, several groups have reported the utility of gene expression arrays to sub-classify patients and predict outcome. We sought to interrogate a series of biomarkers with multiplex quantitative immunofluorescence (QIF) to construct novel clinical algorithms which predict treatment response and overall survival (OS) post-treatment in a series of patients with DLBCL.
Methods: Clinical data including outcome and tissue microarray (TMA) cores for 149 patients were evaluated with QIF for association with response to standard chemotherapy and rituximab. Multiplex QIF with CRI Nuance imaging software for MUM1, Ki67, CD20, CD34, BCL2, BCL6, CD68, VEGF, HLA-DR, and NfKB. Kaplan-Meier survival function curves, hazard ratio and concordance index (CoI) were used to associate marker expression with OS and response to therapy.
Results: The cohort demographics for the 149 patients include a median age of 61 years; 43% female, 57% male and an IPI breakdown: Stage1 (30%), II (23%), III (25%) and IV (22%). Both low IPI and female gender were reliable predictors of good overall survival (p&lt;0.001, respectively). 67 of 149 patients had complete clinical and QIF data for subsequent analysis. Increasing tumoral-CD68 positive cells were associated with a poor objective response to treatment (complete/partial vs. none; p=0.019). For OS, increasing levels of VEGF, on a continuous scale, were predictive of poor OS (VEGF: HR 1.23, 95%CI [.98–1.54], p=0.010, CoI 0.34 and when a cut-point of 0.18 is applied, the significance of VEGF improves, p=0.005. By contrast only the BCL6 cut-point (&gt;3.84, p=0.003) was found to be significant in predicting poor OS. An expanded patient cohort will be needed to confirm both results, especially the BCL6 expression profiles. Optimal multivariate model to predict OS consisted of: Age, IPI index and VEGF levels (CoI 0.78, p=0.001), compared to a model with just age and IPI (CoI 0.72, p=0.02).
Conclusion: CD68, VEGF and BCL6 appear to be useful markers for understanding patterns of response and outcome for patients with DLBCL, post-treatment. A combined age, IPI and VEGF clinical algorithm may guide future treatment options for selected individuals.
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 A51.
Abstract A52: PTEN/PTENP1 transcripts expression and alterations in a large panel of human tumor xenograft in nude mice: Implication for resistance to targeted therapies involving EGFR/PI3K/PTEN pathways.
Authors: Vuaroqueaux Vincent , Ackermann Andreas , Krumbach Rebekka , Tillmann Hanns-Christian , Foucault Frederic , Schuler Julia , Metz Thomas , Fiebig Heinz-Herbert 
Published: June 2012

Abstract
Background: PTEN alterations are major determinants of resistance to several new targeted therapies involving EGFR/PI3K/PTEN pathways. Recent findings also suggested implication of its associated PTENP1 pseudogene. PTEN can be altered at the gene or transcriptional level. PTEN expression is often higher in stroma than in tumor cells complicating readouts of assayed tumor samples. Taking advantage of the stroma of xenografted human tumors in nude mice being produced by the host, we characterized specific PTEN/PTENP1 tumor cell transcript expression levels and mutational status in a large panel of tumor models.
Materials and Methods: A total of 192 patient-derived xenografts of 23 different histotypes were investigated. Human and murine PTEN, PTENP1 mRNA levels as well as PTEN gene copy numbers were quantified by quantitative polymerase chain reaction using species specific assays; PTEN transcript was analyzed by sequencing. Results were analyzed by tumor type and compared to sensitivity to cetuximab.
Results: PTEN transcript alterations were observed in 32 of the 192 tumor xenografts (17%) and were shown to be due to loss of PTEN gene for 9, to loss of transcript expression for 4 and to frameshift or substitution-missense mutations for 14 and 7 samples, respectively. PTEN expression levels and alteration frequency were both associated with specific histotypes. Melanoma and breast cancer showed most PTEN alterations (6/11 and 6/16 respectively). PTENP1 pseudogene was shown to be well expressed in only 61% of tumor xenografts, whereby expression levels depended on the tumor type. No or low PTENP1 expression was found in tumor models having a PTEN alterations. Finally, in a tumor panel consisting of colon, non-small cell lung, gastric and head and neck cancer we found that none of the PTEN altered tumors analyzed were sensitive to cetuximab in vivo.
Conclusion: This study confirmed the multiplicity of PTEN alterations occurring in cancer. PTEN expression levels and alterations were associated with PTENP1 expression levels and depended on tumor types. PTEN alterations were shown to be associated with tumor resistance to cetuximab and their impact on other targeted therapies involving EGFR/PI3K/PTEN pathways should be evaluated.
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 A52.
Abstract A85: Mutant P53 as a potential target of chemopreventive isothiocyanates.
Authors: Wang Xiantao , DiPasqua Anthony , Mi Lixin , Greenspan Emily , Tomita York , Chung Fung-Lung 
Published: June 2012

Abstract
Studies in animals and humans support isothiocyanates (ITCs) as a promising class of cancer chemopreventive agents. It is believed that apoptosis induction and cell cycle arrest are important mechanisms underlying their chemopreventive effects. While several signaling pathways have been shown to be associated with their activities, little is known about the molecular targets of ITCs until recent years. Evidence obtained in this study supports a role of mutant p53 as a potential target of ITCs. We showed ITCs can selectively deplete mutant p53, but not the wild type, in various human cancer cells in a structure-dependent manner, as phenethyl ITC (PEITC) and benyl ITC (BITC) are potent mutant p53 depletors, whereas sulforaphane (SFN) is not. The SAR studies showed 2,2-diphenyl ITC, a synthetic compound, is the most potent mutant p53 depletor. We found the potencies of depletion coincide with their mutant p53 binding affinities, providing circumstantial evidence for a mechanism involving its direct binding by ITCs. The depletion of mutant p53 in cells by ITCs appears to involve protein aggregation. Nine pairs of isogenic cells with mutant p53 and shRNA knockdown were generated. Overall, cells with mutant p53 appear to grow faster than the corresponding cells with mutant p53 knockdown, consistent with its role in gain-of-function. However, no significant difference was noted in PEITC-induced apoptosis between the cell pairs examined so far, suggesting targets other than mutant p53 in these cancer cells may also be involved. DNA array studies using PEITC-treated SW480 colon cancer cells provide potential new lead targets. Furthermore, the role of mutant p53 depletion in preventing lung carcinogenesis by ITCs is also examined in mutant p53 transgenic animal models.
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 A85.
Abstract A9: Chronology of arterial hypertension and microalbuminuria associated with inhibiting treatments of vascular endothelium growth factor receptor in patients with cancer.
Authors: Pradera Jose Fuentes , Salvador Javier , Grilo Antonio , Rodriguez Maria , Lopez Amelia , Bernabe Reyes , Fernandez Eva , Gallego Inmaculada , Morales David 
Published: June 2012

Abstract
Purpose: Angiogenesis plays a major role in cancer. Drugs blocking the growth factor receptor in the vascular endothelium constitute a fundamental treatment in several cancers. Hypertension (HBP) and proteinuria associated with these treatments is frequent and presents in an oscillating and irregular way and is generally controlled by scarcely reliable means. Methods: We started a prospective study with the determination of microalbuminuria (MAL) in 24 hours orine samples and the execution of pre- and post-treatment 24 h-ambulatory blood pressure monitoring (ABPM) and selfmeasured of BP every 12 hours at home, during 60 days, in patients with cancer under treatment with either bevacizumab or sunitinib with a view to identifying the variations in MAL, ABPM and the onset of HBP at an early stage. For ABPM, a validated recording device was used; a recording was made prior to the start of the anti-angiogenic treatment and 20 days (at least) after the first dose. An OMRON M6 tensiometer validated by the European HBP Society was used, with the ambulatory BP figures being collected at home as per standards. MAL was measured in 24h orine samples in mg/L and mg/gr creatinine. The primary goal is to find differences of at least 16 mmHg in the mean BP between the two ABPM readings. Results: N=21. Eighteen patients received bevacizumab and three sunitinib. Mean age 57.0 years (26–79). Three patients was known to be hypertensive. Differences of 4.9 and 3.9 mmHg were found between the mean systolic and diastolic BPs before and after treatment (p&lt;0.05). Conclusions: Our data revealed a statically significant increase of blood pressure in patients treated with antiangiongenics as determined by ABMP. The data point to a greater increase in nocturnal BP suggesting a non-dipper pattern. The self measured records shown an early onset HBP. Microalbuminuria trends to increase in this patients. All data will be shown at the meeting.
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 A9.
Abstract B105: Ganetespib, a unique resorcinolic Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile in preclinical models.
Authors: Ying Weiwen , Proia David A. , Zhou Dan , Inoue Takayo , Tatsuta Noriaki , Sang Jim , Ye Shuxia , Acquaviva Jaime , Ogawa Luisa Shin , Wada Yumiko , Chimmanamada Dinesh , Zhang Shijie , Koya Keizo 
Published: June 2012

Abstract
Targeted inhibition of the molecular chaperone heat shock protein 90 (Hsp90) results in the simultaneous blockade of multiple oncogenic signaling pathways and has thus emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (STA-9090) is a unique resorcinolic inhibitor of Hsp90 currently in clinical trials for a number of human cancers. Here we describe the key interaction of ganetespib with a number of amino acid residues in the ATP binding pocket of Hsp90 which results in high affinity binding. Ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematological tumor cell lines. By using a novel isotope-labeling scheme and LC-MS/MS detection technique, we have determined that Hsp90 occupancy by ganetespib in cancer cells is relatively fast under saturating conditions, reaching equilibrium within 5 minutes of ganetespib exposure. In vivo, ganetespib demonstrated strong single-agent activity in solid and hematological xenograft models, as evidenced by significant tumor growth inhibition and/or regression. Of note, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib efficiently distributed throughout tumor tissue, including hypoxic regions &gt;150 m from the microvasculature, to inhibit proliferation and induce apoptosis. Most importantly, ganetespib showed no evidence of cardiac or liver toxicity and exhibited minimal potential risk for CNS or ocular toxicities. Taken together, this preclinical activity profile suggests that ganetespib may have broad application for a variety of human malignancies and mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.
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 B105.
Abstract B127: Establishment and characterization of in vitro co-culture assays comprising tumor and fibroblast cells that more closely model the cell/stroma interactions of human tumors.
Authors: Eberlein Cath , Ross Sarah , Rooney Claire , Farren Matthew , Weir Hazel , Barry Simon 
Published: June 2012

Abstract
Human solid tumours are comprised of epithelial cells interacting with a surrounding stroma or microenvironment. The stroma consists of several cell types including immune cells, endothelial cells and fibroblasts as well as macromolecules constituting the extracellular matrix. It has become clear from both pre-clinical and clinical studies that the tumour stroma plays a critical role in tumour progression and response to therapeutics. TGF-b is one of a number of pivotal regulators of the tumour microenvironment. Among its roles, TGF-b drives the cross-talk between tumour cells and fibroblasts resulting in a cancer associated fibroblast phenotype. This activated CAF state is linked to increased progression and survival of tumour cells and response of tumours to therapeutics.
Modeling this cross-talk is challenging however we have developed in vitro assays using tumour cells from a range of tissue types, for example NSCLC, breast, pancreatic and prostate, co-cultured with normal human fibroblasts and assessed cell/cell and cell/extracellular matrix interactions using a range of end-points including -smooth muscle actin and fibronectin. We have further characterized the assays, for NSCLC cell lines, using pharmacologically active agents to modulate canonical and non-canonical TGF-beta signaling pathways and assessed the effects on tumour cell growth, fibroblast activation and secretion of key growth factors, cytokines and proteases. We have also used RNA expression profiling of a selection of genes to investigate signaling pathways activated in tumour and fibroblast co-cultures compared to when the cells are grown as monocultures.
We will describe the development of methods to establish and quantify the different end-points explored in tumour and fibroblast co-culture assays and show data using inhibitors to validate these methods with NSCLC cell lines. We will show data from further comparison of monocultures and co-cultures by analysis of RNA and protein in cell lysates and conditioned media samples.
The development of more complex in vitro assays with more than a single cell type allows greater insight into the various tumour-stromal interactions that take place in tumours in vivo. This allows early understanding and testing of agents which may provide therapeutic benefit in limiting tumour-stromal interactions and signalling in patients.
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 B127.
Abstract B138: Harnessing the glycolytic switch for therapy in a novel mouse model of anaplastic thyroid carcinoma.
Authors: Gabriela Valeria , Arciuch Antico , Russo Marika , Cristofano Antonio Di 
Published: June 2012

Abstract
Most cancer cells exhibit a peculiar metabolic behavior, producing energy by aerobic glycolysis instead of oxidative phosphorylation (Warburg effect). Several oncogenes directly drive this switch modulating the levels and activity of, among others, Hexokinase II, Lactate Dehydrogenase A, Pyruvate Kinase M2, and Pyruvate Dehydrogenase Kinase 1.
Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. We have engineered the first mouse model of ATC by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. Expression of the Foxe1, Pax8, and Nkx2–1 transcription factors, as well as of the thyroid-specific genes Duox2, Tpo, Tg, Tshr, and Slc5a5 (Nis) is reduced to almost undetectable levels in the anaplastic tumors, resembling the significant deregulation found in human ATC. Strikingly, the undifferentiated areas of all the tumors analyzed lose the expression of the epithelial marker E-cadherin, acquire the expression of the mesenchymal marker Vimentin, and display high levels of phosphorylated Smad2, strongly suggesting that elevated Tgf-β signaling contributes to the establishment and maintenance of EMT (epithelial-mesenchymal transition). Furthermore, similar to the human tumors, [Pten, p53]thyr−/− cells and tumors undergo the glycolytic switch known as Warburg effect. They display an up-regulation in the expression of Hexokinase II, Pyruvate Kinase M2, and Hypoxia-inducible factor 1α, and an increase in the amount of lactate levels. ATCs show an increase in glucose uptake by positron emission tomography (PET) and established cell lines derived from these tumors exhibit a high sensitivity to the therapeutic use of glycolytic inhibitors such as 3-bromopyruvate and 2-deoxyglucose, which synergize with standard chemotherapy.
Taken together, this model represents a novel, powerful tool to understand the biology of human thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients. The elucidation of this process will lead to innovative targeted approaches to selectively disrupt tumor progression, while preserving normal metabolism in non mutated 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 B138.
Abstract B143: PKM2 metabolic activator slows lung cancer xenograft growth.
Authors: Parnell K. Mark , Foulks Jason M. , Clifford Adrianne , Bullough Jeremy , Luo Bai , Vollmer David , Liu Jihua , McCarthy Virgil , Shaffer Matthew , Senina Anna , Liu Xiao-Hui , Pearce Scott , Xu Yong , Saunders Michael , Ho Kan , McCullar Michael V. , Kanner Steven B. 
Published: June 2012

Abstract
Tumor cells primarily utilize aerobic glycolysis, rather than oxidative phosphorylation, to metabolize glucose (the Warburg effect). The M2 splice form of pyruvate kinase (PKM2), the enzyme catalyzing the rate-limiting final step of glycolysis, is highly upregulated in tumors. Unlike the M1 splice form (PKM1), a constitutively active tetramer found predominantly in non-cancerous tissues, PKM2 is an inactive dimer under normal physiological conditions. Tetramerization of PKM2 requires binding of the allosteric activator fructose-1,6-bisphosphate (FBP), an upstream glycolytic intermediate, resulting in a fully active enzyme. Inactivation of PKM2 by cancer cells may allow glycolytic intermediates to be diverted into other biosynthetic pathways necessary for biomass production. The finding that PKM2 rather than PKM1 expression enhances tumorigenicity suggests that activators of PKM2 may have anti-tumor properties. We have identified and developed a series of small molecule PKM2 activators that exhibit low nM activation activity in biochemical and cell-based assays that measure pyruvate and ATP production. The extent of activation of these compounds is equal to or greater than that of FBP in biochemical assays. In addition, preliminary studies show that PKM2 activators inhibit the growth of lung cancer cell lines in vitro. The current lead compound was tested in established subcutaneously implanted A549 lung adenocarcinoma xenografts, where we observed a statistically significant 54% decrease in tumor growth, with no observable toxicity. These data suggest that this class of PKM2 activators is effective as tumor cell metabolic regulators with anti-tumor activity for lung cancer and potentially other malignancies.
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 B143.