bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2670: Non-metabolic function of asparagine in regulating global protein translation
Authors: Zhang Ji , Pavlova Natalya , White Richard , Thompson Craig 
Published: July 2016

Abstract
Cancer cells rely on extracellular glutamine for growth and survival. Previously, we showed that asparagine, a nonessential amino acid that can be synthesized de novo from glutamine, is both necessary and sufficient for glutamine-dependent cell survival. In addition, asparagine synthetase (ASNS) expression positively correlates with the progression of the disease in human glioma patients, suggesting a critical role of asparagine during tumor progression. Interestingly, mammalian cells cannot catabolize asparagine for use as either a nitrogen source or a bioenergetic substrate, potentially due to the loss of asparaginase activity during evolution. Ectopic expression of yeast or zebrafish asparaginase restores the capacity of mammalian cells to utilize asparagine as both bioenergetic and biosynthetic substrates to support cell growth. Furthermore, asparagine restores translation of fast-turn-over proteins under glutamine starvation. Together, the data suggests that asparagine has been evolved to be a metabolic reserve to regulate cellular adaptation to nonessential amino acid limitation in mammalian cells and is therefore a potential target for cancer therapy.
Citation Format: Ji Zhang, Natalya Pavlova, Richard White, Craig Thompson. Non-metabolic function of asparagine in regulating global protein translation. [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 2670.
Abstract 2673: Inhibition of fatty-acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer
Authors: Camarda Roman , Zhou Alicia Y. , Kohnz Rebecca A. , Balakrishnan Sanjeev , Mahieu Celine , Anderton Brittany , Eyob Henok , Kajimura Shingo , Tward Aaron , Krings Gregor , Nomura Daniel K. , Goga Andrei 
Published: July 2016

Abstract
Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC) compared to estrogen, progesterone and/or human epidermal growth factor 2 receptor-positive (RP) breast tumors. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains largely unexplored. We hypothesized that pharmacologic inhibition of MYC-driven metabolic pathways may serve as a therapeutic strategy for this clinically challenging subtype of breast cancer. Using a targeted metabolomics approach, we identified fatty-acid oxidation (FAO) intermediates as dramatically upregulated in a MYC-driven model of TNBC. A lipid metabolism gene signature was identified in patients with TNBC in the TCGA and multiple other clinical datasets, implicating FAO as a dysregulated pathway critical for TNBC metabolism. We find that MYC-overexpressing TNBC, including a transgenic model and patient-derived xenograft (PDX), display increased bioenergetic reliance upon FAO. Pharmacologic inhibition of FAO catastrophically decreases energy metabolism of MYC-overexpressing breast cancer, blocks growth of a MYC-driven transgenic TNBC model and MYC-overexpressing PDX. Our results demonstrate that inhibition of FAO is a novel therapeutic strategy against TNBCs that overexpress MYC.
Citation Format: Roman Camarda, Alicia Y. Zhou, Rebecca A. Kohnz, Sanjeev Balakrishnan, Celine Mahieu, Brittany Anderton, Henok Eyob, Shingo Kajimura, Aaron Tward, Gregor Krings, Daniel K. Nomura, Andrei Goga. Inhibition of fatty-acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. [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 2673.
Abstract 2683: The landscape of chromosomal aberrations in mouse models of breast cancer reveals driver-specific routes to tumor development
Authors: Ben-David Uri , Ha Gavin , Khadka Prasidda , Jin Xin , Franke Lude , Golub Todd R. 
Published: July 2016

Abstract
Aneuploidy and large copy number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscape remains largely unexplored because large-scale CNA data have not been generated. Here we used gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalog of chromosomal aberrations in cancer GEMMs. Mining this expansive resource, we found that most chromosomal aberrations accumulated late during breast tumorigenesis, and we observed marked differences in CNA prevalence between mouse mammary tumors initiated with distinct drivers. Some of these aberrations were recurrent and unique to specific GEMMs, suggesting distinct driver-dependent routes to tumor development. Synteny-based comparison of mouse and human tumors narrowed critical regions in CNAs, thereby identifying candidate driver genes that were not obvious from the analysis of either dataset alone. Specifically, we experimentally validated that loss of Stratifin (SFN) promotes HER2-induced tumorigenesis in human cells. These results demonstrate the power of GEMM CNA analysis in the understanding of human cancer pathogenesis.
Citation Format: Uri Ben-David, Gavin Ha, Prasidda Khadka, Xin Jin, Lude Franke, Todd R. Golub. The landscape of chromosomal aberrations in mouse models of breast cancer reveals driver-specific routes to tumor development. [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 2683.
Abstract 2704: Radiotherapy and immunotherapy in cancer: A mathematical model
Authors: Serre Raphael , Muracciole Xavier , Ciccolini Joseph , Benzekry Sebastien , Barbolosi Dominique 
Published: July 2016

Abstract
The rise of immunotherapy is a major breakthrough in oncology. Recently, the combination of radiotherapy with the blockade of immune checkpoint inhibitors such as the PD1-PDL1 axis or the CTLA4 pathway has shown a synergistic potential: in addition to the direct cell kill induced by irradiation, radiotherapy unleashes neoantigens that can further induce an anti-tumoral immune response. However, this immune response can be inhibited by the immunosuppressive nature of the tumor micro-environment (TME). Hence, radiotherapy combined with immune check-point inhibitors is a promising solution and is the subject of preclinical and clinical research. However, defining the most efficient scheduling between radiotherapy and immunotherapy is a crucial issue that cannot be properly addressed solely by empirical trial-and-error practices. Consequently, developing mathematical models that can describe the synergy between immune checkpoint inhibitors and radiotherapy is critical. Hence, we have built a pharmocodynamic model of the combination of radiotherapy with inhibitors of the PD1-PDL1 axis and/or the CTLA4 pathway. We describe a mathematical representation of how a growing tumor first elicits and then inhibits an anti-tumoral immune response. This anti-tumoral immune response is described by a primary and a secondary response. The primary immune response appears first and is down-regulated by the PD1-PDL1 axis, while the secondary immune response happens next and is down-regulated by the CTLA4 pathway. We describe the effects of irradiation by a slightly modified version of the Linear-Quadratic model. In particular, we explain the biphasic relationship between the size of a tumor and its immunogenicity, as measured by the abscopal immune response. The ability of the model to forecast pharmacodynamic endpoints was retrospectively validated by reproducing results from experimental studies investigating radiotherapy and immune checkpoint inhibitors. This model clarifies the issue of synchronisation of immunotherapy with radiotherapy and it also explains why the CTLA4 blockade often occurs with a delay. The model also explains why a sustained response to immunotherapy may or may not happen after treatment discontinuation. We believe that this mathematical model could be further used as a simulation tool to help decision-makers determine the optimal scheduling between radiotherapy and immunotherapy and could be a building block for the in-silico design of optimized multimodal strategies.
Citation Format: Raphael Serre, Xavier Muracciole, Joseph Ciccolini, Sebastien Benzekry, Dominique Barbolosi. Radiotherapy and immunotherapy in cancer: A mathematical model. [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 2704.
Abstract 2714: Inhibition of human telomerase by new purine analogs
Authors: Hernandez-Sanchez Wilnelly M. , Baus Diane , Berdis Anthony J. , Taylor Derek J. 
Published: July 2016

Abstract
Telomeres are the end caps of linear chromosomes that help to ensure genomic stability. Because of the inability of DNA polymerases to synthesize the extreme ends of the lagging strand, telomeres get slightly shorter each time a cell divides. When telomeres get extremely short, a state of senescence is triggered which halts cell division. Some cells that require an extended lifespan (e.g. embryonic cells, germ lines and stem cells) use an enzyme called telomerase to maintain telomeres at a length that is sufficient to escape senescence. Whereas telomerase is undetectable, in adult somatic tissue, it is upregulated in 85-90% of all metastatic tumors; enabling cancer cells to divide indefinitely. Due to this unique property of cancer cells, targeting telomerase is a viable chemotherapeutic approach. Nucleotide analogs have been shown to inhibit telomerase activity (e.g. azidothymidine or AZT), albeit modestly, to promote telomere shortening in cancer cell lines. Also, most of these nucleotide analogs are limited by requirement of high dosage (e.g. The IC50 of AZT varies from 0.25 to 1.35 mM). Therefore, while promising, there is a need to develop other nucleotide analogs that are more potent in inhibiting telomerase activity. We have screened a series of new purines analogs using a direct in vitro telomerase assay. These nucleotide analogs were developed to have different chemical modifications around the indole group of the nucleobase. We have identified two purine analogs (5-MeCITP and 6-NITP) that inhibit telomerase activity in vitro. 5-MeCITP was measured to have an inhibition constant (ki) of ∼45μM, which is significantly efficient. Future efforts will include evaluation of the lead nucleoside analogs in telomerase positive cancer cell lines to determine their effect on telomere length and cell survival.
Citation Format: Wilnelly M. Hernandez-Sanchez, Diane Baus, Anthony J. Berdis, Derek J. Taylor. Inhibition of human telomerase by new purine analogs. [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 2714.
Abstract 2715: Cell cycle regulated mitophagy: a key step at the G1/S metabolic checkpoint
Authors: Annibali Daniela 
Published: July 2016

Abstract
How tumor cells coordinate their high demand for biosynthetic processes with nutrient availability, proliferation rate and oxidative stress tolerance is still not completely understood. We recently showed that highly proliferating cells, whether normal or tumorigenic, display different metabolic requirements throughout the cell cycle, in term of glucose and glutamine utilization. The role of autophagy in cancer cells is still debated, but recent evidence pointed to its involvement in the regulation of cellular bioenergetics and nutrients utilization. To investigate autophagy regulation during cancer cells proliferation and to characterize in detail the metabolic behaviour associated with tumor cell proliferation in the different phases of the cell cycle, we used synchronized HeLaS3, a human epithelial carcinoma cell line. Treatment of the cells with a double thymidine block (DTB) results in an arrest at the G1/S boundary and the possibility to study their progression through a complete division cycle. Here we show that in the highly proliferating HeLaS3 cancer cells basal autophagy is a cell cycle regulated phenomenon, responsible for mitochondria quality control and that it plays an essential role at the G1/S checkpoint. Both general autophagy genetic inhibition and mitophagy pharmacological inhibition with Mdivi-1 during cell cycle progression lead the cells to enter faster in S phase. However, probably due to the high levels of oxidative stress dictated by their proliferation rate, autophagy-incompetent cells start to accumulate insulted and less functional mitochondria. Autophagy is likely to be involved in the induction of resistance mechanisms to treatments in different types cancers. Because of this, there is an increased interest in the possibility to use inhibitors of the autophagic pathways as adjuvants for current anti-tumor therapies. Further investigations of the mechanisms here described will be of importance to elucidate whether drugs which inhibit autophagy may be a viable and effective approach in combination with chemotherapy for the treatment of highly proliferating cancers.
Citation Format: Daniela Annibali. Cell cycle regulated mitophagy: a key step at the G1/S metabolic checkpoint. [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 2715.
Abstract 2719: ADA3, a cell cycle regulator, regulates chromosome segregation
Authors: Srivastava Shashank , Mohibi Shakur , Wang-France June , Mirza Sameer , Zhao Xiangshan , Band Hamid , Bnad Vimla 
Published: July 2016

Abstract
The RNA polymerase II mediated transcription requires the higher degree structure of chromatin to be relieved so that general transcription machinery can access the DNA. The acetylation of DNA bound histones at specific loci is the major epigenetic modification by which opening of chromatin is achieved. HATs (Histone Acetyl Transferase) are the enzymes that catalyze the acetylation of histones and require association with mediator proteins for their function. One such mediator protein is ADA3 (Alteration/Deficiency in Activation 3), which was initially discovered as a component of multi-protein complex that contains either GCN5 (General Control Non-repressed 5) or PCAF (p300/CBP Associated Factor) as HAT and subsequent studies showed that ADA3 associates with another HAT, p300. As a HAT interacting protein, ADA3 enhances the acetylation of histones as well as non-histone proteins, such as p53.
We have recently shown that ADA3 is a cell cycle regulatory protein and is important for both G1 to S phase transition as well as mitosis. Conditional deletion of Ada3 from Ada3FL/FL MEFs (Mouse Embryonic Fibroblasts) causes cell cycle arrest and severe mitotic defects. To further explore the mechanism of ADA3 mediated mitosis, we performed ChIP-seq analyses and found that ADA3 bound to higher order repeat region of the centromere across most of the chromosomes. Further studies showed ADA3 interaction with centromere was mediated by a centromeric protein CENP-B. More importantly, siRNA mediated knockdown of ADA3 decreases the occupancy of CENP-B at centromere and causes chromosomal segregation defects during mitosis. These studies demonstrate a novel function of ADA3 in cell cycle regulation. Our current studies are focused on defining the exact mechanism of recruitment of ADA3 complex to CENP-B to regulate mitosis and its effect on genomic stability.
Citation Format: Shashank Srivastava, Shakur Mohibi, June Wang-France, Sameer Mirza, Xiangshan Zhao, Hamid Band, Vimla Bnad. ADA3, a cell cycle regulator, regulates chromosome segregation. [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 2719.
Abstract 273: Inhibition of EGFR/STAT3/CEBPD axis reverses cisplatin cross-resistance with paclitaxel in urothelial carcinoma of urinary bladder
Authors: Wang. Ju-Ming 
Published: July 2016

Abstract
Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel (PTX) in the treatment of urothelial carcinomas of the urinary bladder (UCUB). The development of CDDP cross-resistance with PTX has been suggested and remains a challenge that hinders successful UCUB treatment. Consequently, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative, and this knowledge will aid in the development of novel strategies. CEBPD expression was maintained in post-operative chemotherapy patients, and this expression was responsive to CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. The EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Treatment with gefitinib and S3I-201 significantly decreased CEBPD expression and enhanced sensitivity of CDDP-resistant NTUB1/P cells to CDDP and PTX. Our results demonstrate the risk of CEBPD activation in CDDP-resistant UCUB cells and suggest a potential therapeutic strategy for treating patients with UCUB and UCUB with CDDP-induced PTX resistance using CDDP in combination with either gefitinib or S3I-201.
Citation Format: Ju-Ming Wang. Inhibition of EGFR/STAT3/CEBPD axis reverses cisplatin cross-resistance with paclitaxel in urothelial carcinoma of urinary bladder. [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 273.
Abstract 2733: Novel function of the RAI2 protein in genomic integrity of breast cancer cells
Authors: Werner Stefan , Borgmann Kerstin , Pantel Klaus , Wikman Harriet 
Published: July 2016

Abstract
We have recently identified the RAI2 protein as putative metastasis-suppressor related to dedifferentiation, early occurring bone metastasis formation, and survival of hormone dependent breast carcinomas. Nevertheless, low RAI2 expression is also predictive for poor patient outcome in hormone independent tumors and is furthermore associated with mutation of p53 in primary breast tumors. Thus, besides sustaining luminal differentiation, RAI2 might possess a general function as tumor suppressor that is, as indicated by association with p53 status, possibly related to maintenance of genomic stability.
In order to characterize its potential role in genomic integrity, we screened lysates from RAI2 depleted MCF-7 and KPL-1 breast cancer cell lines with phosphorylation-specific antibody arrays. Additionally, we analyzed changes in expression of cell cycle related genes and proteins by qPCR and Western Blot analysis. We also conducted cytogenetic assays to investigate whether RAI2 depletion affects chromosomal stability and mitotic progression. Finally, we evaluated a possible association of RAI2 expression with aneuploidy in published expression data sets from breast cancer patients.
As revealed by antibody array analysis, RAI2 depletion causes activation of p53 protein in MCF-7 and KPL-1 breast cancer cells, which was accompanied by a significant increase of senescent cells in the corresponding cell populations. Furthermore RAI2 depletion causes downregulation of several key factors of G2/M transition, like Aurora kinases A and B as well as Cyclins A2, B1 and B2. Concomitantly, we found in RAI2-depleted cell cultures reduction of mitotic index, increase of unattached chromosomes in metaphase and lagging chromosomes and during anaphase. This finding was further approved by an increase of numerical aberrations in RAI2 knockdown cells. Finally, we could show an association between low RAI2 expression and higher level of chromosomal instability in primary tumors from breast cancer patients.
In conclusion, we found that loss of RAI2 function is associated with decreased mitotic fidelity. Thus, besides sustaining differentiation in hormone dependent breast tumor, RAI2 also acts as general tumor suppressor that maintains genomic integrity.
Reference: Werner S et al., Cancer Discovery. 2015 May;5(5):506-19
Citation Format: Stefan Werner, Kerstin Borgmann, Klaus Pantel, Harriet Wikman. Novel function of the RAI2 protein in genomic integrity of breast cancer cells. [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 2733.
Abstract 2737: Quantitative assessment of chromosome instability induced through chemical disruption of mitotic progression
Authors: Markossian Sarine , Arnaoutov Alexei , Saba Nakhle S. , Larionov Vladimir , Dasso Mary 
Published: July 2016

Abstract
Most solid tumors are aneuploid, carrying an abnormal number of chromosomes, and they missegregate whole chromosomes in a phenomenon termed chromosome instability (CIN). CIN is associated with poor prognosis in many cancer types, and targeting of CIN is an attractive strategy for anti-cancer therapeutics. The mechanisms causing CIN and its contributions to tumor initiation and growth are not well defined, partly because there is no straightforward, quantitative assays for CIN in human cells. To address this problem, we have developed the first Human Artificial Chromosome (HAC)-based quantitative live-cell assay for mitotic chromosome segregation in mammalian cells, with which we can easily score the rates of CIN within one cell division under different experimental conditions.
We have constructed a HAC encoding copies of enhanced green fluorescent protein (eGFP) fused to the destruction box (DB) of hSecurin, a substrate of the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase, which becomes active during anaphase to catalyze the proteolysis of critical mitotic target proteins. This HAC also contains tet operator (tetO) arrays and sequences encoding the tetracycline repressor fused to monomeric cherry fluorescent protein (tetR-mCherry). We have produced human U2OS cells (U2OS-Phoenix) carrying this HAC, in which we monitor HAC segregation in two ways: First, APC/C degrades the DB-eGFP fusion expressed from the HAC at anaphase onset, and DB-eGFP re-accumulates in the daughter cells after G1 phase, when APC/C becomes inactive. Daughter cells that do not obtain a copy of the HAC will thus be GFP negative in the subsequent interphase. Second, because tetR-mCherry binds to the tetO arrays, the HAC itself could be followed by live imaging. Following the HAC by live cell imaging experiments, we show that U2OS-Phoenix cells have low inherent levels of CIN, but HAC missegregation is markedly increased by treatment with Reversine, an inhibitor of Mps1, and microtubule agents Nocodazole and Paclitaxel.
In summary, we have developed new assays to score CIN levels in human cells and have shown that CIN levels increase upon chemical disruption of mitotic progression, which makes our assays ideal for chemical screens.
Citation Format: Sarine Markossian, Alexei Arnaoutov, Nakhle S. Saba, Vladimir Larionov, Mary Dasso. Quantitative assessment of chromosome instability induced through chemical disruption of mitotic progression. [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 2737.