bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4245: A comparative analysis of PI3K inhibitors in human tumor primary culture microspheroids
Authors: Nagourney Robert Alan , Bernard Paula J. , Francisco Federico , Evans Steven S. 
Published: May 2015

Abstract
Altered phosphoinosotide metabolism is a hallmark of many human malignances. The phosphoinsotide kinases (PI3K) of which there are several sub-classes, have been explored as targets for cancer therapy. Beyond the first generation pan-PI3K inhibitors Wortmannin & LY294002, new, clinically active agents with subclass specificity and/or dual inhibitory functions (PI3K & mTOR) have been developed, including BEZ235 (PI3K/mTOR), GDC0941(αβδ), BYL719(α) & Idelalisib (δ). To examine the activity of these agents we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, R et al Anticancer Res., 2012)to human tumor microspheroids, isolated directly from surgical specimens. Lethal concentrations (LC50's) interpolated from 5-point dose response curves were compared for activity and for correlation by Pearson Moment. Results: Micro-molar activity favored BEZ &gt; BYL &gt; LY. Correlation coefficients reveal BYL vs. BEZ (N=15, R =0.69, P&lt; 0.01); BYL vs. LY (N=7, R=0.74, P=0.1); BEZ vs. LY (N=61, R=0.52, P&lt;0.001). A comparison of activity for hematologic (Heme) vs. Solid tumors (solid) for LY: Heme &gt; Solid; BEZ: Solid &gt; Heme; BYL: Heme &gt; Solid with preliminary evidence for Idelalisib showing Heme &gt; Solid.
Conclusions: The PI3K inhibitors are active in both Heme and Solid tumors, with relative concordance between agents, but some evidence of disease specificity. Additional comparisons with GDC 0941 and drug combination studies are being conducted to further characterize the clinical activity and combinatorial potential of this class of agents. EVA/PCD analyses, conducted in human tumor primary cultures, have the capacity to evaluate drug activity, synergy and sequence dependence offering clinically relevant insights into novel drug applications.
Citation Format: Robert Alan Nagourney, Paula J. Bernard, Federico Francisco, Steven S. Evans. A comparative analysis of PI3K inhibitors in human tumor primary culture microspheroids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4245. doi:10.1158/1538-7445.AM2014-4245
Abstract 4246: Probing the inhibitor selectivity site of class II PI3KC2β
Authors: Sundaram Krithika , Jennings Ian , Arcaro Alexandre , Thompson Philip 
Published: May 2015

Abstract
Ever since their discovery in 1980's, phosphoinositide 3-kinases (PI3Ks) have played a vital role in many intracellular signaling pathways and PI3K inhibitors are prominent targets in drug discovery, especially in cancer. PI3Ks catalyse the phosphorylation of phosphatidylinositol at the 3′-position of the inositol ring and the resulting secondary by-products are implicated in various cellular activities such as cell survival, growth and proliferation. Although class I PI3K has been studied extensively, not much is known about members of class II PI3K. The class II PI3K has gained attention recently as they are believed to be up-regulated in certain types of cancers. The class II PI3Ks consists of three mammalian isoforms: PI3KC2α, PI3KC2β and PI3KC2γ however, as of yet there are no potent, selective inhibitors of class II PI3Ks.
We have generated a homology model of PI3KC2β and carried out molecular docking studies of known class I PI3K inhibitors that also show activity against PI3KC2β. Our docking results have revealed that while the overall binding poses are common for the two classes, there are non-conserved residues involved in interactions with these compounds that could be targeted for selectivity. To pursue a screening program based on these concepts, we have expressed and purified active PI3KC2β. Compounds from within our 400 compound PI3K inhibitor library are being screened as our first step to develop novel PI3KC2β-selective inhibitors. In conclusion, identified differences in the catalytic pocket of PI3KC2β, compared to other PI3Ks which may aid discovery of the first novel potent inhibitors of a class II PI3K.
Citation Format: Krithika Sundaram, Ian Jennings, Alexandre Arcaro, Philip Thompson. Probing the inhibitor selectivity site of class II PI3KC2β. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4246. doi:10.1158/1538-7445.AM2014-4246
Abstract 4247: Characterization of the selective pan-RAF inhibitor TAK-632 with antitumor activity in BRAF inhibitor-resistant melanoma
Authors: Nakamura Akito , Arita Takeo , Tsuchiya Shuntarou , Donelan Jill , Chouitar Jouhara , Carideo Elizabeth , Galvin Katherine , Okaniwa Masanori , Ishikawa Tomoyasu , Yoshida Sei 
Published: May 2015

Abstract
Melanoma is one of the deadliest and most aggressive forms of skin cancer, arising from the malignant transformation of pigment-producing cells, melanocytes. The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of melanoma cells and somatic mutations in BRAF and NRAS are frequently observed in melanoma. Recently, it has been reported that the BRAF inhibitors vemurafenib and dabrafenib showed high response rates and improved overall survival in melanomas with BRAF-activating mutations. However, as BRAF inhibitors induce RAF paradoxical activation via RAF dimerization in BRAF wild-type cells, rapid emergence of acquired resistance and secondary skin tumors as well as presence of few effective treatment options for melanoma bearing wild-type BRAF (including NRAS mutant melanoma) are clinical concerns. In this preclinical study, we describe the biological characterization of TAK-632 as a potent and selective pan-RAF inhibitor that suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation. We used both genetic and chemical approaches to investigate the dependence of NRAS-mutated melanoma and BRAF inhibitor-resistant BRAF mutant melanoma cells on RAF. Our analysis reveals that the MAPK pathway and proliferation of these cells is highly dependent on RAF. Such dependence was not observed in several RAS/RAF-wild type and KRAS-mutated cells. We also show that TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer, probably because of its slow dissociation from RAF. Furthermore, we demonstrate that the combination of TAK-632 and various MAPK kinase (MEK) inhibitors exhibits synergistic anti-proliferative effects on these cells. Our findings indicate that TAK-632 has favorable characteristics in terms of suppressing the proliferation of NRAS mutant melanoma and BRAF inhibitor-resistant BRAF mutant melanoma cells.
Citation Format: Akito Nakamura, Takeo Arita, Shuntarou Tsuchiya, Jill Donelan, Jouhara Chouitar, Elizabeth Carideo, Katherine Galvin, Masanori Okaniwa, Tomoyasu Ishikawa, Sei Yoshida. Characterization of the selective pan-RAF inhibitor TAK-632 with antitumor activity in BRAF inhibitor-resistant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4247. doi:10.1158/1538-7445.AM2014-4247
Abstract 4250: Nitric oxide synthase activity and its modulation in the treatment of colorectal cancer
Authors: Alam Asim , Rabender Chris , Wang Li , Gobalakrishnan Sundaresan , Zweit Jamal 
Published: May 2015

Abstract
The American Cancer Society estimates more than 141,000 new cases of and about 50,000 deaths from colorectal cancer every year. Treatment options include surgery, radiation therapy and targeted therapies such as anti-angiogenics. However, no therapies address the key driving factor of colorectal cancer: inflammation. It is well known that chronic inflammatory conditions such as Crohn's Disease, ulcerative colitis, diabetes, obesity and cigarette smoking all elevate the risk of developing colorectal cancer. One of the hallmarks of chronic inflammation is the elevated levels of reactive oxygen/nitrogen species (ROS/RNS). A primary source of these ROS/RNS is uncoupled Nitric Oxide Synthase. Under non-inflammatory conditions NOS generates Nitric Oxide. However, in an inflammatory environment, such as the oxidative tumor microenvironment, NOS's cofactor tetrahydrobiopterin (BH4) is oxidized to dihydrobiopterin (BH2). NOS bound to BH2 is said to be uncoupled and produces superoxide O2- and peroxyinitrite (ONOO-). Previous work in our and other's labs have shown that increased production of ROS/RNS leads to the activation of pro-inflammatory/proliferative molecules such as NFκB, Stat3, β-Catenin and Akt. NOS can be re-coupled by supplementing cells and animals with BH4 or its precursor Sepiapterin (SP). Herein Wwe have shownshow that by recoupling NOS with SP in HCT116, Caco-2 and HT29 cells, decreased tumor cell proliferation, increased β-Catenin degradation and decreased Akt activity. We have also seen increased tumor cell death measured via by in vitro clonogenic assays, as well decreased metabolic uptake in AOM/DSS induced colorectal cancer in vivo measured via by F18Deoxy-Glucose PET imaging. We believe by recoupling NOS both in vivo and in vitro we are modulatingion Wnt signaling via Akt and GSK-3β. Further studies are needed to elucidate the mechanism of decreased Akt activity and the downstream effectors of Wnt signaling which are affected by NOS recoupling. Lastly, we wish to combine radiation therapy with Sepiapterin SP to determine if the combination of these therapies can increase tumor cell deathincrease tumor control.
Citation Format: Asim Alam, Chris Rabender, Li Wang, Sundaresan Gobalakrishnan, Jamal Zweit. Nitric oxide synthase activity and its modulation in the treatment of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4250. doi:10.1158/1538-7445.AM2014-4250
Abstract 4259: The radiogenomic landscape of cancer
Authors: Abazeed Mohamed , Adams Drew , Tamayo Pablo , Meyerson Matthew , Hammerman Peter , Schreiber Stuart 
Published: May 2015

Abstract
Radiotherapy is the mainstay of treatment for many solid malignancies. Despite this, there have not been extensive systematic analyses of the correlation between therapeutic sensitivity and genomic parameters. To accelerate discovery of patient-matched radiotherapy, or precision radiotherapeutics, systematic approaches are needed to identify specific genetic features that confer radiotherapeutic resistance and target these features with small-molecule drugs. We have quantitatively measured the sensitivity of 533 genomically characterized cancer cell lines to radiation, uncovering novel and established genetic, lineage, chromosomal copy number, and gene-expression-based dependencies. We show that small molecules that target genetic alterations driving therapeutic resistance effect genotype selective radiosensitization, establishing a preclinical basis for personalized therapeutic regimens. This dataset is an important resource that can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs given concurrently with radiation matched to patients by their cancer genotype, thereby enhancing efficacy and limiting toxicity in the context of a new approach of precision radiotherapy.
Citation Format: Mohamed Abazeed, Drew Adams, Pablo Tamayo, Matthew Meyerson, Peter Hammerman, Stuart Schreiber. The radiogenomic landscape of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4259. doi:10.1158/1538-7445.AM2014-4259
Abstract 4263: Identifying somatic mutation hotspots across protein family alignments
Authors: Imielinski Marcin , Du Charles , Meyerson Matthew 
Published: May 2015

Abstract
In cancer, somatic driver mutations often target “hotspots” of paralogous residues across evolutionarily related members of a single protein family. These hotspots usually confer a dominant oncogenic function, such as constitutive catalytic activity or binding. These hotspots generally represent the most “druggable” genetic alterations. Examples of protein families targeted in such a manner include the Ras and receptor Tyrosine Kinase family. Protein family hotspots are not directly assessed by standard computational approaches for statistically nominating genes under positive somatic selection, such as MutSig, InVex, or MuSic. These methods only assess single genes for statistical enrichment of total mutation burden or the presence of mutation hotspots. As a result, such approaches are only powered to detect protein family hotspots in cases where each (or at least one) protein family member is very frequently mutated (e.g. KRAS, NRAS, HRAS). They are not powered to detect hotspots in highly functionally redundant families, of which each member may be only mutated in &lt;&lt;1% of a tumor type. To directly identify such protein-family hotspots, we have developed a computational framework, MutPfam. This framework superimposes mutation data onto Pfam (http://pfam.sanger.ac.uk/) (protein family and subfamily multiple sequence alignments and identifies statistically significant hotspots. We demonstate our method on protein families involved in the catalysis of small-molecular catabolism using the TCGA Pan-Cancer dataset (https://tcga-data.nci.nih.gov/) comprising somatic mutation calls for 4608 whole-exome sequenced patients and 21 tumor types. As we demonstrate, our framework enables the de novo discovery of mutation hotspots across protein families. Though developed for somatic mutation analysis, this framework could also be applied to the analysis of inherited mutations. Computational issues meriting future investigation include (1) alternate definitions of protein alignments and sub-families (e.g. involving three dimensional structure, biophysical constraints) (2) improved statistical modeling of the local background mutation rate (incorporating local genomic covariates that mediate heterogeneity) (3) incorporation of variant functional impact scores for missense variants.
Citation Format: Marcin Imielinski, Charles Du, Matthew Meyerson. Identifying somatic mutation hotspots across protein family alignments. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4263. doi:10.1158/1538-7445.AM2014-4263
Abstract 4266: Moving beyond in vitro models and addressing the challenges of pooled RNAi screens in mouse xenografts
Authors: Tedesco Donato , Bonneau Kyle , Makhanov Mikhail , Deng Debbie , Diehl Paul , Sun Peiqing , Chenchik Alex 
Published: May 2015

Abstract
RNAi loss-of-function screening with pooled shRNA expression libraries has proven to be a useful tool to identify essential cancer genes and drug resistance mechanisms in numerous cell lines in vitro. The effects of knocking down large numbers of genes on cancer cell growth and viability can be measured simultaneously using this approach. Now there is considerable interest to adapt RNAi viability screens to ex vivo xenograft mouse models. However, small take rates, growth rate variance of cells, and differing cell microenvironments in these more complex tumor models impose significant challenges to this sort of assay. We have developed a novel approach based on the use of pooled shRNA libraries with clonal barcodes that enables proliferation measurements of clonal populations produced by the individual shRNA-expressing founder cells that produce the tumor. This RNAi clonal analysis provides a basis to separate, across large cell populations, the external parameters that strongly influence cell growth rates from shRNA-induced growth inhibition in these systems. We will present in vivo RNAi screening validation data for several cancer models.
Citation Format: Donato Tedesco, Kyle Bonneau, Mikhail Makhanov, Debbie Deng, Paul Diehl, Peiqing Sun, Alex Chenchik. Moving beyond in vitro models and addressing the challenges of pooled RNAi screens in mouse xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4266. doi:10.1158/1538-7445.AM2014-4266
Abstract 427: Upregulation of KLF4 and inhibition of HDAC activity by methylseleninic acid in human esophageal squamous cells
Authors: Hu Chenfei , Zhang Wei , Xu Qing , Chen Lechuang , Ma Kai , Liu Mei , Zhu Hongxia , Xu Ningzhi 
Published: May 2015

Abstract
In the present study, we investigated the potential mechanisms of the inhibition of cell growths induced by methylseleninic acid, MSA. Our result showed that MSA could induce cell growth inhibition and apoptosis in esophageal squamous cell carcinoma (ESCC) cells and inhibit tumor growth measured by xenograft volume in nude mice. Upon treated with MSA, HDACs activity was decreased and GCN5, one of histone acetyltransferases, upregulated as well in human esophageal squamous cell lines. Meanwhile a significant increase of H3K9 acetylation (H3K9ac) was detected. Notably,upregulation of KLF4, which has been wildly reported usually downregulated expression in cell lines and tumor tissues of ESCC, was also observed after MSA treatment. Additionally the acetylated histone H3 could locate more at KLF4 promoter region than non-acetylated one did, showed by chromatin immunoprecipitation assay. Moreover knockdown of GCN5 reduced the protein levels of both H3K9ac and KLF4, along with less cell growth inhibition. Taken all, our result indicates that MSA can exert its anti-tumor effects, at least in part, by up-regulation KLF4, probably via inhibiting the HDAC activity and up-regulation GCN5. By our best of knowledge, this is the first report of selenium-induced selective, post-translational acetylation of histone H3 at Lys9, which may depend on the activities of and the balance between HDACs and HATs.
Note: This abstract was not presented at the meeting.
Citation Format: Chenfei Hu, Wei Zhang, Qing Xu, Lechuang Chen, Kai Ma, Mei Liu, Hongxia Zhu, Ningzhi Xu. Upregulation of KLF4 and inhibition of HDAC activity by methylseleninic acid in human esophageal squamous cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 427. doi:10.1158/1538-7445.AM2014-427
Abstract 4273: An enhanced microRNA backbone for potent single-copy RNAi
Authors: Fellmann Christof , Hoffmann Thomas , Sridhar Vaishali , Hopfgartner Barbara , Lai Dan Y. , Zuber Johannes 
Published: May 2015

Abstract
Short-hairpin RNA (shRNA) technology enables stable and regulated gene repression through RNA interference (RNAi). Synthetic shRNAs can be embedded into the context of an endogenous microRNA (miRNA) to create natural substrates of RNAi pathways and minimize cellular toxicities. While such “shRNAmir” reagents provide an experimentally versatile RNAi system, their design remains challenging due to our limited understanding of miRNA processing factors. Consequently, shRNAmir reagents often fail to trigger potent target knockdown, especially when expressed from a single genomic integration (“single-copy”), a common scenario in pool-based screens and other key applications. To tackle this issue, we recently developed a high-throughput Sensor assay that enables functional identification of effective shRNAs and has been used to establish shRNA-specific prediction rules. Following these advances in design of the synthetic shRNA stem, here we take a systematic approach to improve the experimental miR-30 backbone. Among several sequence features enhancing knockdown efficiency, we identify a conserved element 3′ of the basal stem that is critically required for optimal shRNAmir processing. Implementation of this feature in an optimized backbone termed “miR-E” results in a 10-30 fold increase in mature shRNA levels, and generally boosts knockdown efficacy. Importantly, combination of the enhanced miR-E backbone with Sensor-based design rules establishes a validated and easily accessible platform for generating single-copy effective shRNAs for pool-based RNAi screening and transgenic animals, and will facilitate the functional annotation of the genome.
Citation Format: Christof Fellmann, Thomas Hoffmann, Vaishali Sridhar, Barbara Hopfgartner, Dan Yu Lai, Johannes Zuber. An enhanced microRNA backbone for potent single-copy RNAi. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2014-4273
Abstract 4277: Alternative splicing in cancer transcriptomes
Authors: Shen Shihao , Wu Ying Nian , Xing Yi 
Published: May 2015

Abstract
Alternative splicing of precursor mRNA is a key mechanism of eukaryotic gene regulation. Cancer-associated changes in alternative splicing can modulate gene function or activity, and consequently affect downstream molecular pathways critical for tumorigenesis or metastasis. RNA-Seq has become a powerful technology for genome-wide analysis of alternative splicing. We have developed sensitive and robust computational methods for quantitative analysis of alternative splicing using RNA-Seq data. Using these methods, we have analyzed the alternative splicing profiles of &gt;4000 cancer samples across multiple types of cancer. Our analysis has identified important alternative splicing events that may contribute to the development and progression of cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Shihao Shen, Ying Nian Wu, Yi Xing. Alternative splicing in cancer transcriptomes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4277. doi:10.1158/1538-7445.AM2014-4277