bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-235: BCL6 enables Ph+ acute lymphoblastic leukemia cells to survive BCR-ABL1 kinase inhibition
Authors: Duy Cihangir , Hurtz Christian , Koeffler Phillip H. , Melnick Ari M. , Müschen Markus 
Published: June 2012

Abstract
Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. Recent efforts focused on the development of more potent TKI that also inhibit mutant tyrosine kinases. However, even effective TKI typically fail to eradicate leukemia-initiating cells, which often cause recurrence of leukemia after initially successful treatment. Here we report on the discovery of a novel mechanism of drug-resistance, which is based on protective feedback signaling of leukemia cells in response to TKI-treatment. We identified BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukemia-initiating subclones.
BCL6 is a known proto-oncogene that is often translocated in diffuse large B cell lymphoma (DLBCL). In response to TKI-treatment, BCR-ABL1 acute lymphoblastic leukemia (ALL) cells upregulate BCL6 protein levels by ∼90-fold, i.e. to similar levels as in DLBCL. Upregulation of BCL6 in response to TKI-treatment represents a novel defense mechanism, which enables leukemia cells to survive TKI-treatment: Previous work suggested that TKI-mediated cell death is largely p53-independent. Here we demonstrate that BCL6 upregulation upon TKI-treatment leads to transcriptional inactivation of the p53 pathway. BCL6-deficient leukemia cells fail to inactivate p53 and are particularly sensitive to TKI-treatment. BCL6-/-leukemia cells are poised to undergo cellular senescence and fail to initiate leukemia in serial transplant recipients. A combination of TKI-treatment and a novel BCL6 peptide inhibitor markedly increased survival of NOD/SCID mice xenografted with patient-derived BCR-ABL1 ALL cells. We propose that dual targeting of oncogenic tyrosine kinases and BCL6-dependent feedback represents a novel strategy to eradicate drug-resistant and leukemia-initiating subclones in tyrosine kinase-driven leukemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-235. doi:10.1158/1538-7445.AM2011-LB-235
Abstract LB-237: Epigenetic antagonism between Polycomb and SWI/SNF complexes duringoncogenic transformation
Authors: Wilson Boris G. , Wang Xi , Shen Xiaohua , McKenna Elizabeth S. , Lemieux Madeleine E. , Cho Yoon-Jae , Koelhoffer Edward C. , Pomeroy Scott L. , Orkin Stuart H. , Roberts Charles W.M 
Published: June 2012

Abstract
While epigenetic alterations are widely present in cancers, in the context of genomic instability it has been difficult to determine the degree to which epigenetic alterations serve as primary drivers of tumorigenesis. Cancers initiated by mutation of the SNF5 chromatin remodeling subunit, despite being highly aggressive and lethal, are diploid and genomically stable, making them an ideal model for this purpose. SNF5 is a core subunit of the SWI/SNF chromatin complex and is mutated in the large majority of malignant rhabdoid tumors (MRT), highly lethal cancers that occur in kidney, brain, and soft tissues of young children. Inactivating mutations in SNF5 have also recently been found to occur in a variety of other cancers and mutations in other SWI/SNF subunits occur frequently in ovarian, endometrial, renal, and lung cancers. Given our findings of genomic stability, we hypothesize that the consequences of SNF5 loss are fundamentally epigenetic in nature; that characterization of the epigenetic changes present in our model systems, rather than in cancers with genome instability, will identify those epigenetic alterations capable of driving oncogenic transformation; and lastly that cancers carrying mutations in the SWI/SNF complex can be effectively treated with epigenetically targeted therapies.
Analysis of Drosophila mutants suggests that Polycomb and SWI/SNF complexes can serve antagonistic developmental roles. However, the relevance of this relationship to human disease is unclear. Here we have investigated functional relationships between these epigenetic regulators in oncogenic transformation. Mechanistically, we show that loss of the SNF5 tumor suppressor leads to elevated expression of the Polycomb gene EZH2 and that Polycomb targets are broadly H3K27-trimethylated and repressed in SNF5-deficient fibroblasts and cancers. Further, we show antagonism between SNF5 and EZH2 in the regulation of stem cell-associated programs and that Snf5 loss activates those programs. Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss. Collectively, we demonstrate that the rapid onset of tumor formation following SNF5 loss arises due to imbalanced epigenetic antagonism between the SWI/SNF complex and the Polycomb complex PRC2. Our work reveals essential roles for epigenetic modifications during tumor formation and demonstrates that inactivation of EZH2 can have therapeutic efficacy against cancer in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-237. doi:10.1158/1538-7445.AM2011-LB-237
Abstract LB-247: Mutation and functional analysis of PIK3CA and PIK3R1 in endometrial cancer
Authors: Cheung Lydia Wai Ting , Hennessy Bryan T. , Li Jie , Yu Shuangxing , Myers Andrea P. , Djordjevic Bojana , Lu Yiling , Stemke-Hale Katherine , Zhang Fan , Ju Zhenlin , Cantley Lewis C. , Scherer Steve E. , Liang Han , Lu Karen H. , Russell Broaddus R. , Mills Gordon B. 
Published: June 2012

Abstract
The phosphatidylinositol 3 kinase (PI3K) pathway is the most frequently activated pathway across multiple tumor lineages and this is a potential therapeutic target. As a critical step to accelerate therapeutic development in endometrial cancer, we performed a comprehensive analysis of mutation and function of PI3K pathway members in a set of 243 highly characterized endometrial tumors. Whole gene resequencing revealed the highest frequencies of mutation in the PI3K pathway of any tumor lineage including PTEN (44%), PIK3CA (40%; encoding the p110α catalytic subunit of PI3K) and PIK3R1 (20%; encoding the p85a regulatory subunit). Indeed, when complete protein loss is considered, almost 80% of endometrioid endometrial cancers demonstrate an aberration in the PI3K pathway. Remarkably, mutations in the PI3K pathway were not mutually exclusive and indeed co-existence of PIK3CA or PIK3R1 mutation with heterozygous PTEN mutation occurred at frequencies higher than predicted by the frequency of each lesion alone. High-throughput reverse-phase protein array suggested that the dominant signaling effects occurred with PTEN protein loss and that PIK3CA or PIK3R1 mutation functionally mimic PTEN protein loss as indicated by protein markers including phosphorylated Akt and stathmin. Thus it appears likely that co-mutations in the PI3K pathway are selected to compensate haploinsufficiency of PTEN due to PTEN heterozygous mutation. To determine the functional consequences of mutations in PIK3R1, we demonstrated that several somatic PIK3R1 mutations tested conferred cytokine-independent growth on interleukin-3-dependent Ba/F3 cells and induced Akt phosphorylation in endometrial cancer cell lines indicating that they were gain of function mutations likely acting as oncogenes. Strikingly two of the gain of function mutations (E160* and R348*) lacked the ability to bind to the p110 catalytic subunit and E160* failed to bind to both p110 and PTEN. We demonstrate that E160* disrupts a novel mechanism of pathway regulation wherein p85 binds and stabilizes PTEN. Together, the data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers representing a novel opportunity for implementation of targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-247. doi:10.1158/1538-7445.AM2011-LB-247
Abstract LB-25: Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling
Authors: Rubbi Liudmilla , Titz Björn , Brown Lauren , Glavan Erica , Komisopoulou Evangelia , Chen Sharon S. , Low Tracey , Tahmasian Martik , Skaggs Brian , Müschen Markus , Pellegrini Matteo , Graeber Thomas G. 
Published: June 2012

Abstract
In subtypes and late stages of leukemias driven by the tyrosine kinase fusion protein Bcr-Abl, signaling by the Src family kinases (SFKs) critically contributes to the leukemic phenotype. We performed global tyrosine phosphoprofiling using quantitative mass spectrometry of Bcr-Abl transformed cells in which the activities of the Src family kinases were perturbed to build a detailed context-dependent network of cancer signaling. Perturbation of the SFKs Lyn and Hck with genetics or inhibitors revealed Bcr-Abl downstream phosphorylation events either mediated by or independent of SFKs. We identified multiple negative feedback mechanisms within the network of signaling events affected by Bcr-Abl and SFKs, and found that Bcr-Abl attenuated these inhibitory mechanisms. The Csk binding protein Pag1 (also known as Cbp) and the tyrosine phosphatase Ptpn18 both mediated negative feedback to SFKs. We observed Bcr-Abl-mediated phosphorylation of the phosphatase Shp2 (Ptpn11) and this may contribute to the suppression of these negative feedback mechanisms to promote Bcr-Abl-activated SFK signaling. Csk and a kinase-deficient Csk mutant both produced similar globally repressive signaling consequences, suggesting a critical role for the adaptor protein function of Csk in its inhibition of Bcr-Abl and SFK signaling. The identified Bcr-Abl-activated SFK regulatory mechanisms are candidates for dysregulation during leukemia progression and acquisition of SFK-mediated drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-25. doi:10.1158/1538-7445.AM2011-LB-25
Abstract LB-251: The checkpoint molecules LAG-3 and PD-1 synergize to maintain tolerance to tumors
Authors: Goldberg Monica V. , Woo Seng-Ryong , Bankoti Jaishree , Selby Mark , Nirschl Christopher J. , Bettini Matthew L. , Vogel Peter , Grosso Joseph F. , Netto George , Chaux Alcides , Smeltzer Matthew , Workman Creg J. , Pardoll Drew M. , Korman Alan J. , Vignali Dario AA , Drake Charles G. 
Published: June 2012

Abstract
Checkpoint molecules like CTLA-4 are important regulators of tumor-specific tolerance, and monoclonal antibodies that block this class of molecules have emerged as important therapeutic modalities in multiple cancer types. Recent data suggest that tumor infiltrating, non-functional ("exhausted") CD8 cells may express more than one checkpoint molecule, implying a more subtle control system for modulating CD8 T cell function in vivo. Based on their frequent co-expression on tumor-infiltrating lymphocytes, we investigated the relative roles of PD-1 (programmed death - 1) and LAG-3 (lymphocyte activation gene -3) in tumor tolerance. Single knockout (KO) mice lacking either of these genes were relatively unaffected, with PD-1 KO mice developing a late-onset strain-specific myocarditis. However, double knockout mice (DKO) lacking both PD-1 and LAG-3 developed early autoimmune pathology, with infiltrating lymphocytes present in multiple organs, and eventual lethality. More significantly, DKO mice spontaneously rejected the poorly immunogenic B16 melanoma, while rejection was not observed when either PD-1 or LAG-3 was knocked out individually. Moreover, established tumors in wild-type mice could be cured by combined treatment anti-PD-1 and anti-LAG-3 antibodies, while single antibody treatment was sufficient only to delay tumor outgrowth. Taken together, these data demonstrate a previously unappreciated synergy between these two checkpoint molecules in tumor-specific tolerance, and suggest a novel combinatorial strategy for cancer immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-251. doi:10.1158/1538-7445.AM2011-LB-251
Abstract LB-257: Profiling the effects of IDH1 and IDH2 mutants on the glioma cell metabolome
Authors: Yan Hai , Reitman Zachary J. , Jin Genglin , Spasojevic Ivan , He Yiping , Bigner Darell D. , Karoly Edward D. , Yang Jian , Kinzler Kenneth W. , Vogelstein Bert 
Published: June 2012

Abstract
Somatic hotspot mutations in the NADP+-dependent isocitrate dehydrogenases, IDH1 and IDH2, arise frequently in gliomas. These gliomas include WHO grades II and III oligodendrogliomas and astrocytomas, as well as WHO grade IV secondary glioblastomas. When mutated, IDH1 and IDH2 gain the ability to produce (R)-2-hydroxyglutarate (2HG) and may dominant-negatively inhibit IDH1-WT. Aside from these specific functions, the downstream effect of these metabolic enzyme mutations on cellular metabolism is unknown. To identify metabolic alterations caused by IDH1 and IDH2 mutants, we used three mass spectrometry methods (GC-MS/MS, LC-MS/MS +ESI, and LC-MS/MS -ESI) to profile &gt;200 biochemicals in lysates of human oligodendroglial cell line (HOG) cells that homologously express IDH1-R132H or IDH2-R172K, which are the most frequent IDH1 and IDH2 mutants in glioma, respectively. To determine whether 2HG production or inhibition of IDH1-WT could mediate similar effects on cellular metabolism as IDH mutant expression, we also analyzed cells treated cells with either 7.5mM or 30mM 2HG as well as cells with stable shRNA knockdown of endogenous IDH1-WT. Unsupervised hierarchical clustering, univariate threshold tests, correlation analysis, and principal component analysis revealed that cells expressing IDH1-R132H and IDH2-R172K have similar metabolite profiles, and that 2HG treatment also results in a similar profile. However, cell with shRNA IDH1 knockdown shared few metabolic features with cells expressing IDH mutants. Metabolite set enrichment analyses revealed that numerous amino acids, N-acetylated amino acids, TCA cycle metabolites, glutathione metabolites, and choline derivatives were markedly altered in IDH-mutant expressing cells. Strikingly, we found that N-acetyl-aspartyl-glutamate (NAAG), a common brain metabolite, is 50-fold reduced in cells expressing IDH1-R132H and &gt;2-fold reduced in human glioma tissues with IDH1-R132H compared to glioma tissues without IDH mutations. This work shows that IDH mutants can induce widespread cellular metabolic changes. Additionally, the metabolites that were found to be altered in this study may play a role in glioma pathogenesis and may be useful for diagnosis or treatment for gliomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-257. doi:10.1158/1538-7445.AM2011-LB-257
Abstract LB-258: Small-molecule inhibitors of de-ubiquitinating enzymes for cervical cancer treatment
Authors: Anchori Ravi , Sueblinvong Thanasak , Roden Richard , Bazzaro Martina 
Published: June 2012

Abstract
Title. Small-Molecule Inhibitors of de-Ubiquitinating Enzymes for Cervical Cancer Treatment Abstract: Human Papillomavirus (HPV) is the primary cause of cervical cancer and responsible for 5% of all cancers worldwide. While HPV vaccines can be an effective preventive measure against cervical cancer, there are currently no virus-specific therapies for it, and the efficacy of standard surgical and chemo/radiotherapies is limited for advanced disease. The E6 oncoprotein of HPV exerts its oncogenic activity by binding to the E3 ubiquitin ligase E6-AP and redirects its activity towards p53 and other tumor suppressor proteins for rapid ubiquitin-mediated proteasomal degradation. Therefore, stabilization of p53 via preventing its ubiquitin-mediated degradation represents a valid therapeutic approach for cervical cancer treatment. De-ubiquitinating enzymes are an attractive novel “druggable” target for cervical cancer as they are responsible for controlling the steady state levels of proteins (i.e. p53 and E6-AP) crucial for maintaining the transformed status of cervical cancer cells, upstream proteasome. Thus, their inhibition is potentially associated with less toxic effects as compared to inhibition of proteasomes.
During a structure-based screening of chalcone-based small-molecule inhibitors of ubiquitin-mediated protein degradation we have recently identified a novel class of molecules capable of inhibiting the ubiquitin-mediated protein degradation upstream proteasomes. The lead compound of the series, contains the α-β unsaturated carbonyl system, as the molecular determinant for inhibiting de-ubiquitinating enzyme activities and: i) is capable of inducing acute perturbation of the ubiquitin-mediated protein degradation pathways accompanied by accumulation of poly-ubiquitinated species and reduction of mono-, di-, and tri-ubiquitin species, ii) has no effect on the catalytic activities of purified proteasomes or proteasome in living cells, iii) is capable of induce aggresome formation, iv) is capable of rescuing p53 levels/functions in cervical cancer cells which are accompanied by decrease in the levels of Cyclin D1 and failure for the cells to enter the S-phase of the cell cycle, v) is capable of preventing tumor-colony formation and induces onset of apoptosis via caspase-3 activation in cervical cancer cells without affecting the viability of normal cells. Therefore, we believe in the feasibility of using our lead compound in preclinical model of cervical cancer to test its efficacy as antineoplastic agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-258. doi:10.1158/1538-7445.AM2011-LB-258
Abstract LB-259: The gluconeogenic pathway is operative in lung cancer cells
Authors: Fan Teresa WM , Lorkiewicz Pawel , Higashi Richard M. , Lane Andrew N. 
Published: June 2012

Abstract
Accelerated aerobic glycolysis has been a hallmark of cancer metabolism since Otto Warburg's seminal discovery [1]. Glucose oxidation via glycolysis and the pentose phosphate pathway (PPP) not only produces energy and reducing equivalents but also anabolic precursors to meet the demands of proliferation and many essential functions of cancer cells. Although many of the anabolic precursors can be obtained from alternative fuel substrates, the de novo synthesis of ribose and therefore nucleotides normally requires glucose metabolism. Thus, under glucose deficiency, cancer cells will cease proliferation due to a lack of new synthesis of nucleic acids. This can occur in poorly vascularized areas of a tumor. We now have direct evidence that lung cancer cells can circumvent this problem by making ribose from Gln using part of the gluconeogenic pathway. By using U-13C5,15N2-Gln as tracer, we tracked the fate of the 13C and 15N atoms simultaneously into various metabolites of A549 and H1299 cells using FT-ICR-MS and NMR. We found that both labels were incorporated into ATP and other nucleotides. Although the expected 15N labeling patterns were found based on the purine biosynthetic pathway, the 13C labeling patterns show that the adenine ring and/or ribosyl unit of ATP were also labeled. This can only occur through the metabolic sequence of glutaminolysis, Krebs cycle, pyruvate carboxylation, PEP carboxykinase (PEPCK) reaction, gluconeogenesis, and PPP. We believe this is the first time that gluconeogenesis is demonstrated for cancer cell lines not known to be gluconeogenic, which could have important implications for how cancer cells adapt to a glucose-limited microenvironment and the role of Gln in such adaptations.
1. Warburg, O., On the origin of cancer cells. Science, 1956. 123: p. 309–314.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-259. doi:10.1158/1538-7445.AM2011-LB-259
Abstract LB-269: Genome-wide expression profiling of highly degraded formalin-fixed paraffin-embedded tissue from non-small cell lung carcinoma
Authors: Su Li , Wu I-Chen , Wu Ming-Tsang , Chirieac Lucian R. , Wang Zhaoxi , Christiani David C. 
Published: June 2012

Abstract
Microarray-based genome-wide gene expression analysis on fresh frozen tissue is widely used in cancer studies. Compared to fresh frozen tissues, formalin-fixed paraffin-embedded (FFPE) tissues are more accessible in the clinical setting for genomic analysis, but its use has been hampered by technical difficulty. In this study, we investigated the potential use of the Whole-Genome DASL HT Assay (Illumina, San Diego, CA) for global expression profiling (covering &gt;47,000 annotated transcripts) in 24 tumor/non-affected FFPE tissues obtained by biopsy from patients with non-small cell lung cancer (NSCLC). We obtained high-quality microarray data on 11 FFPE samples (46%). The FFPE samples had a relatively lower median call rate of 12.2% (range: 10–14.5%), as compared with those from fresh samples; ranging from 10% to 25%. Among genes differentially expressed between squamous carcinomas and adjacent non-affected lung tissue, we found that the RECK gene, encoding a tumor suppressor of reversion-inducing cysteine-rich protein with Kazal motifs, was decreased strongly in tumors (fold change: -2.7; p=0.018). This finding was consistent with previous reports that there was a significantly lower expression of RECK mRNA in NSCLC tissue in samples with promoter hypermethylation. During pathway-based analysis using GeneGo database, we found that differentially expressed genes were significantly enriched in several pathways, such as the RAS regulation pathways, epithelial-to-mesenchymal transition pathway, WNT signaling pathway, and signal transduction pathway of lung neoplasms. When comparing expression between adenocarcinoma and squamous NSCLC, the differentially expressed genes were clustered in keratin filaments pathway for cytoskeleton remodeling, WNT signaling pathway, and disease pathways related to bronchial neoplasms and NSCLC. The WNT/PCP signaling pathway has been implicated in human carcinogenesis. MAP3K7 is one of the key signaling molecules of non-canonical WNT pathway, which demonstrated high level expression in lung carcinoma but was not expressed in non-affected pulmonary tissues. Our study demonstrated that DASL expression profiling technology, genome-wide expression profiles can be successfully generated from FFPE lung tissues.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-269. doi:10.1158/1538-7445.AM2011-LB-269