bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-314: Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation
Authors: Lu Jianrong 
Published: July 2016

Abstract
The Warburg effect, which reflects cancer cells’ preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. Cancer cells restrain pyruvate flux into mitochondrial oxidative metabolism in large part by inhibiting the pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential implication of Src in tumor metabolism remained largely unclear. Here we report that active Src enzyme directly tyrosine-phosphorylates the PDH E1α subunit (PDHA1). Conversely, pharmacological Src inhibitors or depletion of Src by shRNA abolish PDHA1 tyrosine phosphorylation in cancer cells, suggesting that Src is the main kinase responsible for PDHA1 tyrosine phosphorylation. This Src-mediated modification inactivates PDH. Consistently, activation of Src attenuates PDH activity and generation of reactive oxygen species (ROS), which are byproducts of mitochondrial respiration. Src inhibitors activate PDH and increase cellular ROS levels. Importantly, expression of a tyrosine non-phosphorable PDHA1 mutant in Src-activated cancer cells restores PDH activity, increases mitochondrial respiration and oxidative stress, decreases experimental metastasis, and sensitizes cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg metabolic phenotype by inactivating PDH through tyrosine phosphorylation, and this metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. As inhibition of Src sensitizes cancer cells to pro-oxidants, combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.
Citation Format: Jianrong Lu. Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-314.
Abstract LB-328: Subtypes of urothelial carcinoma of the urinary bladder defined by genomic alteration combinations predict clinical characteristics
Authors: Khan Alyna , Fichtenholtz Alex , Ross Jeffrey , Frampton Garrett , Neumann Eric , Ali Siraj M. , Stephens Phil J. 
Published: July 2016

Abstract
Introduction: At least 70,000 patients will be diagnosed with bladder urothelial carcinoma (UC) in the United States this year. Current pathologic staging divides UC into muscle invasive (MIBC) and non-muscle invasive bladder cancer (NMIBC). Existing molecular classifications reveal a heterogeneous mutational landscape especially in the MIBC group, with studies finding that UC breaks down to anywhere from two to six classes defined by molecular features. These studies have utilized either select somatic alterations or high-dimensional mRNA expression data. Classifications of UC based on comprehensive genomic profiling (CGP) and subsequently detected somatic tumor alterations are conspicuously absent.
Methods: To create this CGP-based classification, 638 cases of mostly refractory or metastatic UC patients were assayed with CGP in the course of clinical care sequencing the coding exons of 287 cancer-related and 47 introns of 19 genes frequently rearranged in cancer and analyzing base-pair substitutions, indels, copy number alterations, and select gene fusions. Hierarchical latent class analysis (HLCA) a mixed-model classification method that finds highly statistically significant combinations of gene alterations, was applied to the resultant alteration profiles.
Results: HLCA detected the structure of somatic alteration combinations in UC, finding two main super classes driven by either CDKN2A/B co-deletion or TP53 and RB1 mutations, and subclasses further defined by altered genes in signal transduction (FGFR3, ERBB2, PIK3CA) and chromatin modifying (KDM6A, MLL2, ARID1A) pathways. These classes are predictive of clinical characteristics and tumor progression, and outperform existing molecular-based UC classifiers.
Conclusions: Identifying robust molecular subtypes of UC allows for appropriate assignment of patients to relevant clinical trials and can aid in electing suitable therapeutic strategies. Investigating the clinical context and targeted and immunotherapy implications of these subclasses will be essential for diagnostic, prognostic and therapeutic purposes.
Citation Format: Alyna Khan, Alex Fichtenholtz, Jeffrey Ross, Garrett Frampton, Eric Neumann, Siraj M. Ali, Phil J. Stephens. Subtypes of urothelial carcinoma of the urinary bladder defined by genomic alteration combinations predict clinical characteristics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-328.
Abstract LB-330: Somatic copy number alterations at oncogenic loci show diverse correlations with gene expression
Authors: Roszik Jason , Wu Ching Jiun , Siroy Alan E. , Lazar Alexander J. , Davies Michael A. , Woodman Scott , Kwong Lawrence N. 
Published: July 2016

Abstract
Somatic copy number alterations (SCNAs) affecting oncogenic drivers have a firmly established role in promoting cancer. However, no agreed-upon standard exists for calling locus-specific amplifications and deletions in each patient sample. Here, we report the correlative analysis of copy number amplitude and length with gene expression across 6,109 samples from The Cancer Genome Atlas (TCGA) dataset across 16 cancer types. Using specificity, sensitivity, and precision-based scores, we analyzed over 30 recurrently focally altered loci that had sufficient pan-cancer penetrance for robust statistical assessment. We were able to assign optimized amplitude and length cutoffs for nine recurrent SCNAs affecting known oncogenic drivers, using mRNA expression as a functional readout. These cutoffs captured the majority of SCNA-driven, highly-expression-altered samples. The majority of oncogenes required only amplitude cutoffs, as high amplitude samples were almost invariably focal; however, CDKN2A and PTEN uniquely required both amplitude and length cutoffs as primary predictors. For PTEN, these extended to downstream AKT activation. In contrast, the remaining 20+ assessed SCNA genes, particularly ones located peri-telomerically or in fragile sites, showed poor expression-copy number correlations. Finally, we describe several novel associations between copy number and gene expression that have implications for how SCNAs are assessed as harboring candidate cancer driver genes. Overall, our analyses identify optimized amplitude and length cutoffs as efficient predictors of gene expression changes for specific oncogenic SCNAs, yet warn against one-size-fits-all interpretations across all loci. Our results have implications for cancer data analyses and the clinic, where copy number and mutation data are increasingly used to personalize cancer therapy.
Citation Format: Jason Roszik, Ching Jiun Wu, Alan E. Siroy, Alexander J. Lazar, Michael A. Davies, Scott Woodman, Lawrence N. Kwong. Somatic copy number alterations at oncogenic loci show diverse correlations with gene expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-330.
Abstract LB-338: Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing
Authors: Fox Edward J.P. , Schmitt Michael W. , Reid-Bayliss Kate S. , Beckman Robert A. , Loeb Lawrence A. 
Published: July 2016

Abstract
The accumulation of somatic mutations is a defining hallmark of cancer. The genomes of solid tumors contain thousands of mutations that are present in most or all of the malignant cells in that tumor. In addition to these clonal mutations, subclonal mutations - those occurring only in a fraction of malignant cells - likely contribute to the phenotypic and morphologic heterogeneity of cancer cells within a tumor. These sub-populations may be the source for the rapid emergence of therapeutic resistance. The extent of subclonal mutations in cancer, however, has been difficult to quantify, as the high error rate of next-generation sequencing precludes reliable detection of mutations present in fewer than 5% of cells. Here, we apply the highly accurate Duplex Sequencing methodology to quantify the extent of subclonal mutations in 15 colorectal cancers (CRC) and paired normal mucosa. We also quantify the clonal somatic mutation load by exome sequencing. By sequencing known CRC driver and non-driver genes (depth &gt;5,000X and accuracy &gt;10-7), we find that colorectal cancers without known DNA repair deficits harbor an extensive complement of subclonal mutations, suggesting that mutational diversity of CRCs has been greatly underestimated. We show that normal colonic mucosa also accumulates substantial numbers of subclonal mutations, predominantly CG&gt;TA transitions at CpG dinucleotides, in an age-dependent manner. However, the burden of tumor-associated subclonal mutations does not correlate with age and has a distinct spectrum (relative increase in TA&gt;CG transitions) indicating different mechanisms of mutation accumulation are operative in normal and tumor tissue. The frequency of tumor cells harboring unique subclonal mutations is so high that it is likely that every possible neutral somatic point mutation is present by the time a tumor is clinically detectable This could account for the high frequency by which tumors become resistant to chemotherapeutic agents.
Citation Format: Edward J.P. Fox, Michael W. Schmitt, Kate S. Reid-Bayliss, Robert A. Beckman, Lawrence A. Loeb. Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-338.
Abstract LB-342: HDAC inhibition promotes tubulin-independent cancer cell migration
Authors: Hessler Lindsay K. , Boggs Amanda E. , Whipple Rebecca A. , Vitolo Michele I. , Chakrabarti Kristi R. , Bhandary Lekhana , Thompson Keyata N. , Martin Stuart S. 
Published: July 2016

Abstract
Breast cancer remains the most common cancer and second-leading cause of cancer-related death in women, with metastatic disease carrying a particularly poor prognosis. Despite advances with chemotherapeutic drugs aimed at tumor growth, we do not fully understand the effects of these drugs on the metastatic process. Histone deacetylase inhibitors (HDACi) are novel epigenetic therapies that induce cancer cell death through various mechanisms, including apoptosis, cell-cycle arrest and antiangiogenesis. Clinical trials investigating HDACi use in solid tumors are ongoing but have yielded mixed results. To date, very few studies have examined how HDACi influence the metastatic potential of breast tumor cells.
Since HDAC enzymes act on both histone and non-histone targets, HDACi drugs cause dramatic increases in non-histone protein acetylation, including acetylation of alpha-tubulin. A well-known marker of stable microtubules, tubulin acetylation increases in metastatic breast tumors and predicts poor patient survival. However, the effects of HDACi on tubulin-related cytoskeletal dynamics of tumor cells have not been previously examined. The current study investigates whether the use of HDACi in breast cancer cells could promote metastatic phenotypes.
Clinically-relevant HDAC pan-inhibitors that target multiple Class I HDAC enzymes (Entinostat) or both Class I and Class II (FDA-approved Vorinostat) yielded strong and rapid increases in the migration of both MCF-7 and Bt-549 breast cancer cells. In addition, Vorinostat and Entinostat were each able to strongly induce histone acetylation, while only Vorinostat induced tubulin acetylation. To determine if the increased tubulin acetylation induced by HDACi drugs was sufficient to induce tumor cell migration, we used an isotype-specific HDACi (Tubastatin) that selectively targets the Class II HDAC6 and therefore can increase tubulin acetylation. At doses which strongly induce tubulin acetylation, Tubastatin did not increase tumor cell migration or other tubulin-dependent cancer cell processes, including reattachment and microtentacle formation. Vorinostat and Entinostat therefore induce tumor cell migration through a tubulin-independent mechanism, indicating that more precise targeting of HDAC enzymes could help avoid therapeutic approaches that induce metastatic phenotypes.
Citation Format: Lindsay K. Hessler, Amanda E. Boggs, Rebecca A. Whipple, Michele I. Vitolo, Kristi R. Chakrabarti, Lekhana Bhandary, Keyata N. Thompson, Stuart S. Martin. HDAC inhibition promotes tubulin-independent cancer cell migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-342.
Abstract LB-345: Acetylenic tricyclic bis-(cyano enone) interacts with cysteine residues of actin and inhibits non-small cell lung cancer cell migration
Authors: Chan Eddie , Saito Akira , Honda Tadashi , Di Guglielmo John 
Published: July 2016

Abstract
During epithelial-to-mesenchymal transition (EMT), epithelial cells lose their cell-cell junctions, apical-basal polarity, and reorganize their actin cytoskeleton. These changes, among others, increase the motility of individual cells and promote a highly invasive phenotype. The actin cytoskeleton is also key in cell migration and invasion, as the polymerization of actin at the leading edge provides the necessary driving force for translocation and protrusions. Therefore, the actin cytoskeleton is a potential target for inhibiting tumour progression. In this study we characterized a novel tri-cyclic synthetic triterpenoid derivative, TBE-31, in its ability to associate with actin and inhibit cell migration. Using a pull-down approach, we demonstrate that TBE-31 binds directly to actin. Furthermore, TBE-31 inhibited branched and linear actin polymerization in vitro, and stress fibre formation in cultured cells. Actin cytoskeleton reorganization and stress fiber formation was also inhibited in TGFβ-dependent EMT of non-small cell lung cancer cells. We next used SwissDock software to investigate the potential molecular interaction between TBE-31 and actin. Swissdock predicted that TBE-31 would have a high affinity for binding to the same cleft as Cytochalasin D, a bona-fide actin polymerization inhibitor. As triterpenoids associate with cysteine residues in target proteins, we generated cysteine to alanine mutants of actin and verified TBE-31 binding using pull-down assays. We identified that cysteine 374 is important for TBE-31 interaction with actin. Finally, we observed that TBE-31 inhibited fibroblast and non-small cell lung tumour cell migration with an IC50 of 1.0 and 2.5 μM, respectively. Taken together, our results suggest that TBE-31 targets actin polymerization to alter cell morphology and inhibit cell migration.
Citation Format: Eddie Chan, Akira Saito, Tadashi Honda, John Di Guglielmo. Acetylenic tricyclic bis-(cyano enone) interacts with cysteine residues of actin and inhibits non-small cell lung cancer cell migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-345.
Abstract LB-362: A six-gene classifier stratifies low-grade glioma patients with wild-type IDH
Authors: Huebner Alexander , Oehlke Oliver , Juratli Tareq A. , Meng Wei , Ibrahim Ahmed , Li Bin , Erny Daniel , Robe Pierre , Krex Dietmar , Schackert Gabriele , Prinz Marco , Grosu Anca , Chakravarti Arnab 
Published: July 2016

Abstract
Gliomas are the most common primary brain tumors presenting a heterogeneous group of malignancies. Particularly, there is a significant heterogeneity in outcomes of patients with grade II and grade III gliomas. There has been recent progress in reclassifying glomas by integrating molecular signatures such as IDH mutation status, 1p/19q co-deletion and alternative telomer maintenance to the established histopathological classification scheme. Patients with IDH wild-type (WT) gliomas are found to have the worst prognosis. Currently there is no prognostic or predictive biomarker within this group of patients.
To this end, the goal of the current study was to develop a gene classifier for identifying a prognostic/predictive biomarker model for grade II and grade III gliomas with IDH WT, which would have the potential of identifying patient groups with distinct degrees of risk for disease progression, treatment options, and survival outcome. Our approach was to identify a robust list of candidate genes using multiple datasets and create a single score classifier based on the expression of identified genes. We analyzed multiple datasets comprising a total of 756 glioma patients using a meta-analysis approach which identified six prognostic genes. A linear model consisting of these six genes was trained in an institutional cohort by employing RNAseq and qRT-PCR techniques to measure the gene expression and validated in an independent grade II/III glioma set (TCGA LGG).
The classifier performed significantly in both the institutional cohort of 85 grade II/III glioma patients (HR, 29.94; 95% CI, 3.96-226.36; p = 0.001) and in the TCGA LGG dataset consisting of 416 glioma patients (HR, 4.03; 95% CI, 1.82-8.92; p = 0.001, for low versus high risk group). Multivariate Cox regression analysis validated the risk classifier independent of other clinical factors. After analyzing patient populations separately, based on IDH mutation status, we discovered that the classifier performed with high significance in the patients with IDH WT both in the institutional cohort and the TCGA LGG dataset (HR, 1.93; 95% CI, 1.24-3.02; p = 0.004 and HR, 1.99; 95% CI, 1.38-2.87; p &lt; 0.001 respectively) reliably predicting the clinical outcomes.
Citation Format: Alexander Huebner, Oliver Oehlke, Tareq A. Juratli, Wei Meng, Ahmed Ibrahim, Bin Li, Daniel Erny, Pierre Robe, Dietmar Krex, Gabriele Schackert, Marco Prinz, Anca Grosu, Arnab Chakravarti. A six-gene classifier stratifies low-grade glioma patients with wild-type IDH. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-362.
Abstract PL02-01: Isogenic tumors can utilize heterogeneous mechanisms of nutrient uptake
Authors: Thompson Craig B. , Palm Wilhelm , Ye Jiangbin , Pavlova Natalya N. , King Bryan 
Published: July 2016

Abstract
An emerging feature of cancer cell metabolism is the ability to acquire the anabolic precursors necessary to support cell viability and growth from a nutrient-poor environment. Cell proliferation studies undertaken under nutrient-limiting conditions have led us to define two distinct pathways by which tumor cells gain a competitive advantage over their nontransformed counterparts. One pathway is defined by enhanced capture of existing glucose and amino acids through nutrient-selective transporters. The key mediators of this pathway are AKT and its downstream effector, mTORC1. The other pathway depends on the uptake and degradation of extracellular proteins and lipids. Oncogenic forms of RAS are potent activators of this pathway. Many tumors appear capable of using both nutrient uptake pathways and can switch between them depending on extracellular nutrient conditions. Implications of these findings for tumor heterogeneity and therapeutic responsiveness will be discussed.
Citation Format: Craig B. Thompson, Wilhelm Palm, Jiangbin Ye, Natalya N. Pavlova, Bryan King. Isogenic tumors can utilize heterogeneous mechanisms of nutrient uptake. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL02-01.
Abstract PL04-03: Heterogeneity, drug resistance, and clonal evolution in colorectal cancers
Authors: Bardelli Alberto 
Published: July 2016

Abstract
When metastatic cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? To address this question a deeper understanding of the evolutive nature of cancer cells is necessary. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor's evolution the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. Another approach is to unleash the ability of the immune system to recognize drug resistant cells. We tested this possibility in syngeneic mouse models of CRC sensitive to targeted therapies. Our findings indicate that manipulation of the mutational loads can trigger prolonged therapeutic responses that are not observed when cancer cells are challenged with targeted drugs alone. We postulate that rationally combined targeted and immuno-therapies can restrain tumor evolution, and can limit the emergence of drug resistance thus leading to long-term responses.
Citation Format: Alberto Bardelli. Heterogeneity, drug resistance, and clonal evolution in colorectal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL04-03.