bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-020: IP3 3-kinase B suppresses B-cell lymphoma by antagonizing PI3K/mTOR in B cells
Authors: Sauer Karsten , Conche Claire , Jin Hyun-Yong , Bethel Kelly , Rigaud Stephanie , Westernberg Luise , Siegemund Sabine , Xiao Changchun 
Published: July 2016

Abstract
Accounting for ∼4% of all cancers in the US, Non-Hodgkin Lymphoma (NHL) is the most prevalent blood cancer. Diffuse large B-cell Lymphoma (DLBCL) is the most common and aggressive type of NHL. Here, we identify inositol-trisphosphate (IP3) 3-kinase B (Itpkb) as a novel tumor suppressor whose deficiency triggers DLBCL in mice. We found that aging Itpkb-/- mice die prematurely with anemia and splenomegaly. 15% of these mice showed multiorgan-infiltration with neoplastic germinal-center phenotype B cells reminiscent of DLBCL. Itpkb-/- B cell lymphomas are mono-or oligoclonal, transplantable, and constitutively hyperactivate the oncogenic phosphoinositide 3-kinase (PI3K) signaling pathway. Growth of Itpkb-/- B cell lymphoma xenografts in immunodeficient mice is sensitive to treatment with PI3K or mTOR inhibitors. In humans, subsets of DLBCL patients carry Itpkb missense mutations, deletions or copy number reductions. Additionally, Itpkb expression is altered in several other hematopoietic and non-hematopoietic human cancers. We propose that Itpkb suppresses tumors by producing inositol-tetrakisphosphate (IP4), a soluble analog of the PI3K product phosphatidylinositol-trisphosphate (PIP3). We and others have previously shown that IP4 antagonism with PIP3 for Akt effector kinase binding prevents excessive Akt/mTORC1 signaling in hematopoietic cells. Our new results suggest that this mechanism prevents oncogenic PI3K signaling in the B cell lineage and possibly in other cell types. Thus, Itpkb might be a novel biomarker for tumor aggressiveness or prognosis, and Itpkb activating drugs or IP4 might have therapeutic potential.
This work was supported by NIH grants AI070845 and GM100785 to KS, The Leukemia & Lymphoma Society Scholar Award 1440-11 to KS, the AAI Careers in Immunology Fellowship Program to SR, DFG Fellowship SI 1547/1-1 to SS, and an ARC fellowship to CC.
Citation Format: Karsten Sauer, Claire Conche, Hyun-Yong Jin, Kelly Bethel, Stephanie Rigaud, Luise Westernberg, Sabine Siegemund, Changchun Xiao. IP3 3-kinase B suppresses B-cell lymphoma by antagonizing PI3K/mTOR in B 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 LB-020.
Abstract LB-021: LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of triple-negative/basal-B breast cancer cells
Authors: Yokdang Nucharee , Hatakeyama Jason , Wald Jessica , Simion Catalina , Tellez Joseph , Chang Dennis , Swamynathan Manojit , Chen Mingyi , Murphy William , Carraway Kermit , Sweeney Colleen 
Published: July 2016

Abstract
LRIG1, a member of the LRIG family of transmembrane leucine rich repeat-containing proteins, is a negative regulator of receptor tyrosine kinase signaling and a tumor suppressor. LRIG1 expression is broadly decreased in human cancer and in breast cancer, low expression of LRIG1 has been linked to decreased relapse-free survival. Recently, low expression of LRIG1 was revealed to be an independent risk factor for breast cancer metastasis and death. These findings suggest that LRIG1 may oppose breast cancer cell motility and invasion, cellular processes which are fundamental to metastasis. However, very little is known of LRIG1 function in this regard. In this study, we demonstrate that LRIG1is down-regulated during epithelial to mesenchymal transition (EMT) of human mammary epithelial cells, suggesting that LRIG1 expression may represent a barrier to EMT. Indeed, depletion of endogenous LRIG1 in human mammary epithelial cells expands the stem cell population, augments mammosphere formation and accelerates EMT. Conversely, expression of LRIG1 in highly invasive triple-negative/Basal B breast cancer cells provokes a mesenchymal to epithelial transition accompanied by a dramatic suppression of tumorsphere formation and a striking loss of invasive growth in three-dimensional culture. LRIG1 expression perturbs multiple signaling pathways and represses markers and effectors of the mesenchymal state. Furthermore, LRIG1 expression in MDA-MB-231 breast cancer cells significantly slows their growth as tumors, providing the first in vivo evidence that LRIG1 functions as a growth suppressor in breast cancer.
Citation Format: Nucharee Yokdang, Jason Hatakeyama, Jessica Wald, Catalina Simion, Joseph Tellez, Dennis Chang, Manojit Swamynathan, Mingyi Chen, William Murphy, Kermit Carraway, Colleen Sweeney. LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of triple-negative/basal-B 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 LB-021.
Abstract LB-022: The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation
Authors: Armstrong Stephen R. , Wang Benfan , Abuetabh Yasser , Leng Roger 
Published: July 2016

Abstract
The p53 tumor suppressor family is comprised of three members: p53, p63, and p73. These transcription factors can negatively regulate cell proliferation by inducing the expression of proteins related to apoptosis (ex. bax) and cell cycle arrest (ex. p21). Isoforms of the p63 protein can be divided into two major groups, the transcriptionally active TAp63 variants, and the dominant-negative ΔNp63 variants. The TAp63 variants are considered to be tumor suppressor proteins that can cooperate with p53 and p73 to prevent cancer development. Unlike p53, which is frequently mutated in cancer, TAp63 is rarely mutated, and its transcription function is primarily regulated at the protein level. One such method of regulation at this level is proteasome-mediated degradation, initiated by tagging the substrate protein with a poly-ubiquitin chain recognized by the proteasome. This ubiquitination is mediated by E-3 ligases such as Mdm2 and AIP4, two previously characterized regulators of the p53 family. In this study, we report that CHIP, an E-3 ligase involved in protein chaperoning during the heat shock response is a negative regulator of TAp63. The purpose of this study was to characterize CHIP as a TAp63-interacting protein that negatively regulates TAp63 expression and function. Using transient transfection assays, we found that CHIP can bind to, ubiquitinate, and reduce the expression of TAp63 in H1299 lung carcinoma cells. Stably knocking down CHIP expression in these cells using anti-CHIP shRNA restores endogenous p63 expression. This negative regulation of TAp63 by CHIP is associated with a decrease in p21 promoter transcription (measured by a luciferase reporter assay), cell cycle arrest and cellular apoptosis (measured by flow cytometry), and accompanied by an increase in cell survival (measured by colony forming assay) and invasive capacity (measured by a cell scattering assay). An immunoblot analysis of carcinoma cell lines and invasive prostate cancer tissue samples also demonstrates a negative correlation between CHIP and TAp63 expression levels. We conclude that CHIP is a negative regulator of TAp63 expression and function, and, therefore, has an oncogenic role in context with TAp63.
Citation Format: Stephen R. Armstrong, Benfan Wang, Yasser Abuetabh, Roger Leng. The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation. [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-022.
Abstract LB-024: PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species
Authors: Sainz Alva G. , Song Jin H. , Kraft Andrew S. , Warfel Noel A. 
Published: July 2016

Abstract
Prostate cancer (PCa) is the leading cause of cancer death in men worldwide. Patients diagnosed with metastatic prostate cancer initially respond to androgen deprivation therapy, but this response is not durable, and all patients develop hormone-refractory disease that ultimately leads to death. Current treatment options for metastatic PCa patients are limited (e.g., cytotoxic chemotherapy or radiation), and the response to these agents is invariably temporary and does not improve survival. A significant obstacle to the successful treatment of advanced PCa is tumor hypoxia. While hypoxia is toxic to normal cells, cancer cells take particular advantage of their ability to adapt to these harsh conditions by increasing the expression of proteins that promote angiogenesis and survival. Therefore, elucidating the molecular mechanisms controlling survival in hypoxia is important for the development of effective therapeutic strategies to selectively kill hypoxic tumor cells.
The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent a pro-survival pathawy that is upregulated in response to hypoxia in a HIF-1 independent manner. We demonstrate that pharmacological or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia versus normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo. Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors reduce the ability of Nrf2 to enter the nucleus and block the transcrption of cytoprotective genes, leading to the accumulation of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be succesfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediate therapeutic resistance and induce cell death in the hypoxic tumor microenvironment.
Citation Format: Alva G. Sainz, Jin H. Song, Andrew S. Kraft, Noel A. Warfel. PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species. [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-024.
Abstract LB-034: Tcf7: an essential mediator in Notch-induced T-ALL
Authors: Koch Ute , Sugrue Tara , Dubey Christelle , Radtke Freddy 
Published: July 2016

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer caused by the malignant transformation of immature thymocytes. Notch1 gain-of-function mutations are present in &gt;50% of T-ALL cases and result in the constitutive activation of Notch1 intracellular domain (N1ICD) in mutated cells. The mechanisms by which deregulated Notch1 signalling leads to T-ALL development are currently unresolved and stringently investigated. T cell factor-1 (TCF-1) is a transcription factor encoded by Tcf7. Not only playing crucial roles in Wnt signalling, Tcf7 is (i) a direct Notch1 target gene and (ii) required for driving early T lineage commitment of hematopoietic progenitors. Together, these findings suggest that Tcf7 may play a role in Notch1-driven T-ALL. Herein, we show that the conditional loss of Tcf7 in hematopoietic progenitors prevents T-ALL development in both genetic- and retroviral-based mouse models of N1ICD over-expression. However, T-ALL development was unaffected by conditional loss of the Wnt signalling mediator, β-catenin. Interestingly, conditional Tcf7 deficiency partially restored the B lineage potential of N1ICD over-expressing bone marrow progenitors. Similar to Tcf7-/- mice, conditional Tcf7 deficiency in bone marrow progenitors abrogated T cell development in adult thymi. However, unexpectedly, Tcf7-deficient hematopoietic progenitors adopted a B cell fate in these thymi, a phenotype that was found to be comparable to conditional loss of Notch1. Overall, our results indicate that Tcf7 is an important mediator of Notch1-driven T-ALL. Furthermore, our data suggests that, in addition to promoting T lineage commitment, Tcf7 may also function as a Notch1-dependent transcriptional repressor of B lineage commitment in adult hematopoiesis. We performed RNAseq to identify the molecular players involved in Tcf7-mediated lineage repression and complement this approach with CHIP_Seq.
Citation Format: Ute Koch, Tara Sugrue, Christelle Dubey, Freddy Radtke. Tcf7: an essential mediator in Notch-induced T-ALL. [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-034.
Abstract LB-042: Xenopatients help in redefining medical therapeutic algorithms in high risk ovarian cancer
Authors: Erriquez Jessica , Olivero Martina , Mittica Gloria , Scalzo Maria Stella , Vaira Marco , De Simone Michele , Ponzone Riccardo , Katsaros Dionyssios , Aglietta Massimo , Calogero Raffaele , Di Renzo Maria Flavia , Valabrega Giorgio 
Published: July 2016

Abstract
Platinum-based chemotherapy is the recommended first-line treatment for high-grade serous (HGS) epithelial ovarian cancer (EOC). However, most patients relapse because of platinum refractory/resistant disease. We aimed at assessing whether other drugs, commonly used to treat relapsed HGS-EOC and poorly active in this clinical setting, might be more effective against chemotherapy-naïve cancers. We collected samples of advanced HGS-EOC from the same patients before and after neo-adjuvant platinum-based chemotherapy. Samples were propagated as Patient Derived Xenografts (PDXs) in immunocompromised mice (“xenopatients”). Xenopatients were treated with carboplatin, gemcitabine, pegylated liposomal doxorubicin (PLD) and trabectedin. One patient was studied who experienced clinically platinum-sensitivity first and then discordant responses of different tumor sites to platinum re-challenge. PDXs derived from this patient before chemotherapy showed responsiveness to carboplatin, trabectedin and gemcitabine. The PDXs from the same patient after chemotherapy did no longer respond to trabectedin and gemcitabine and showed a heterogeneous response to carboplatin. Expression profiling showed that loss of responsiveness to drugs of the post-chemotherapy PDXs was associated with the up-regulation of NR2F2 gene expression. A second patient with platinum refractory HGS-EOC responded poorly to PLD as second-line treatment. PDXs obtained from this patient's tumor before chemotherapy showed a complete response to PLD, which was lost in the post-chemotherapy PDXs. Response to PLD was associated with the over-expression of the TOP2A protein, which was lost in the post-chemotherapy PDXs. Thus, PDXs demonstrated that chemotherapy-naïve HGS-EOC might display susceptibility to agents not used commonly as first line treatment. These data suggest the importance of tailoring chemotherapy.
Citation Format: Jessica Erriquez, Martina Olivero, Gloria Mittica, Maria Stella Scalzo, Marco Vaira, Michele De Simone, Riccardo Ponzone, Dionyssios Katsaros, Massimo Aglietta, Raffaele Calogero, Maria Flavia Di Renzo, Giorgio Valabrega. Xenopatients help in redefining medical therapeutic algorithms in high risk ovarian 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 LB-042.
Abstract LB-058: Linker variation and structure-activity relationship analyses of salicylic, benzoic and hydroxamic acid-based small molecule Stat3 inhibitors
Authors: Yue Peibin , Lopez-Tapia Francisco , Brotherton-Pleiss Christine , Tius Marcus , Turkson James 
Published: July 2016

Abstract
Benzoic acid, salicylic acid and hydroxamic acid-based small molecules have been reported that inhibit Stat3 activation. However, the structural basis for their Stat3-inhibitory activities are not clearly defined. To investigate the molecular determinants for activity and to derive structurally optimized analogs of improved pharmacokinetic parameters and potency, we conducted a computer-aided molecule optimization program and synthesized new analogs of the previously reported lead Stat3 inhibitors, BP-1-102 (IC50, 6.8 ± 2.5), SH4-54 (IC50 4.4 ± 0.3), and SH5-07 (IC50 3.9 ± 0.6). All three leads are based on N-methylglycinamide scaffold with its two amine moieties condensed with three different functionalities. The three functionalities or the CH2 group of the glycolamide scaffold were separately modified to generate a series of compounds, some of which show improved potency compared to the corresponding parental compounds. Specifically, H012, H070 and H072 had improved inhibitory activity against Stat3 DNA-binding activity in vitro, with IC50 of 3.0 ± 0.9, 2.4 ± 0.4, and 2.2 ± 0.9 μM, respectively. The replacement of the pentafluorobenzene or the cyclohexylbenzene with other components was detrimental to activity and led to decreased potency of the new analogues, as did the substitution of the benzene of the pTyr-mimetic moiety with heterocyclic components containing nitrogen and oxygen elements. Pharmacokinetic study showed that analog H058 has improved permeability in Caco-2 bidirectional permeability studies, compared to the lower relative permeability of the lead agents. Ala-based analogs, such as H048 and H058, were low in microsomal stability, presumably due to the labile methyl groups of the Ala. Select active analogs inhibited constitutive Stat3 activation and the DNA-binding activity of Stat3 in cancer cells, and they further decreased the growth, colony formation, and migration of human cancer cells harboring persistently active Stat3. Studies together demonstrate a significant progress towards developing a more suitable Stat3 inhibitor with drug-like features. Additional efforts are focused on refining the physicochemical properties to further improve the activity and efficacy and ultimately furnish suitable Stat3-inhibiting candidates for clinical application.
Citation Format: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Marcus Tius, James Turkson. Linker variation and structure-activity relationship analyses of salicylic, benzoic and hydroxamic acid-based small molecule Stat3 inhibitors. [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-058.
Abstract LB-062: Evaluation of drug conjugation sites in an anti-EGFR Centyrin
Authors: Cardoso Rosa , Goldberg Shalom , Lin Tricia , Spinka-Doms Tracy , Klein Donna , Jacobs Steven , Gilliland Gary , O’Neil Karyn 
Published: July 2016

Abstract
Centyrins are engineered alternative scaffold proteins that combine the affinity and specificity of antibodies with increased tissue penetration and simplified manufacturing. To identify optimal positions for chemical conjugation within the Centyrin scaffold, the crystal structure of an anti-EGFR Centyrin was solved and a library consisting of all possible single-cysteine variants was constructed and assessed for expression level in E. coli, efficiency of conjugation to maleimide derivatives, protein aggregation, thermostability, and EGFR binding. The best variants were conjugated to cytotoxic drugs and compared in a cell-killing assay. Three optimal positions were identified at which the Centyrin conjugated efficiently to maleimides; retained high expression, antigen binding, and biophysical properties; and showed increased cell-killing potency relative to the parent molecule.
Citation Format: Rosa Cardoso, Shalom Goldberg, Tricia Lin, Tracy Spinka-Doms, Donna Klein, Steven Jacobs, Gary Gilliland, Karyn O’Neil. Evaluation of drug conjugation sites in an anti-EGFR Centyrin. [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-062.
Abstract LB-065: Comparison of the serum proteome in individuals with cancers versus those without cancer, and its application to wellness
Authors: Zheng Haiyan , Zhao Caifeng , Roy Swapan , Soherwardy Amenah , Amin Ravish , Roy Devjit , Kuruc Matthew 
Published: July 2016

Abstract
For many diseases, pancreatic cancer for example, long term survival is critically dependent upon early detection. So various strategies for early detectable markers are being investigated. One such strategy is hypothesis driven, first by identifying a singular biomarker, usually derived from genomic analysis of the tumor type, and then determine its derivative protein concentration in blood. This has been challenging as many differentially regulated genes do not generate a differentially regulated protein, or one of sufficient concentration for current means of detection. An alternative biomarker strategy is purely data driven, as panels of proteins may be up and/or down regulated, or altered by post-translational modifications. These can be monitored and quantified to differences in diseased and normal/healthy individuals. In this study we adopt such a data driven strategy using a new product which combines Albumin depletion and on-bead digestion of the enriched serum proteome in a seamless process, called AlbuVoid™ LC-MS On-Bead. From these methods, we were able to compare labeled quantification of proteins from normal and disease state sera - for this case, breast, lung and pancreatic cancer at different clinically defined stages. The methods spectrally quantify over 250 total proteins, in a cost effective and reproducible manner. No offline peptide level fractionation prior to LC-MS was employed, lowering the LC-MS acquisition time 5-10x compared to common serum proteomic workflows. We describe these workflow advantages applied towards a “wellness” proteome algorithm combining knowledge and data surrounding individual normal and healthy proteomes, compared and contrasted to those with a clinically definable disease. From our initial tests, a candidate panel of 20 proteins are determined to be differentially expressed and such data suggests the feasibility for their use in the early detection of cancer. The critical parameters for success to our strategy are considered as well as some of the remaining challenges to clinical utility.
Citation Format: Haiyan Zheng, Caifeng Zhao, Swapan Roy, Amenah Soherwardy, Ravish Amin, Devjit Roy, Matthew Kuruc. Comparison of the serum proteome in individuals with cancers versus those without cancer, and its application to wellness. [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-065.