bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B040: MERTK activates Akt by antagonizing SAV1 binding
Authors: Liu Pengda , Jiang Yao 
Published: August 2018

Abstract
Hyperactivation of the PI3K-Akt pathway is observed in virtually all solid tumors. Multiple genetic events such as PTEN loss and PIK3CA amplification partially account for the increase in the pathway activation. In addition to genetic changes, dysregulation of post-translational modifications of Akt, including phosphorylation, acetylation, hydroxylation, methylation, and others that are necessary for Akt activation is also frequently observed in various types of cancers. However, whether and how Akt is regulated by its binding partners is minimally understood. To this end, through a proteomic approach, we have identified the tumor suppressor SAV1 as a novel Akt-interacting partner to suppress Akt activation. Furthermore, we identified MERTK as a major upstream kinase phosphorylating Akt1-Y26 to disrupt SAV1 binding and subsequently activate Akt. Mechanistically, MERTK-mediated Akt1-Y26 phosphorylation facilitates Akt plasma membrane recruitment by PI(3,4,5)P3 and promotes PDK1 binding to promote Akt activation. Importantly, cancer patient-derived SAV1 mutants and Akt1 mutants were identified to exert elevated oncogenicity by bypassing SAV1 binding and suppression, further supporting a pathophysiologic role of the identified MERTK/Akt/SAV1 signaling in tumorigenesis.
Citation Format: Pengda Liu, Yao Jiang. MERTK activates Akt by antagonizing SAV1 binding [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B040.
Abstract B042: Anticancer effects of processed garlic constituent diallyl trisulfide on head and neck squamous cell carcinoma
Authors: Mathan Sivapar , Singh Shivendra , Singh Rana P. 
Published: August 2018

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite significant advances in therapeutic approaches, survival rate is less than 50%. Early detection and treatment will help in prevention of spreading of invasive cancer and thereby improve the survival rates. Studies showed that dietary intake of Allium vegetables lowered the risk of various cancers. Studies reported DATS as a promising chemopreventive constituent of processed garlic that induced cell cycle arrest and apoptosis in prostate and breast cancer. However, it has not been investigated for its efficacy and molecular mechanisms of chemopreventive effects of DATS against HNSCC. Herein, we investigated the effect of DATS on HNSCC FaDu, D562, UMSCC-22A, UMSCC-22B, and Cal33 cells in culture. DATS (10-100 µM) treatment significantly reduced the growth, proliferation, and survival of HNSCC cells. We observed that DATS treatments significantly induced G2/M cell cycle arrest. DATS treatment resulted in the accumulation of cyclin B1 and induced the levels of cip1/p21. DATS-induced mitotic arrest was attenuated by NAC pretreatment, which suggested that DATS mediates growth-suppressive effects by induction of ROS. DATS induced cell death through apoptosis, which was associated with ROS production. Further, DATS increased the ratio of Bax/Bcl2 and cleavage of caspase-3 and PARP and decreased the levels of XIAP. Exposure of HNSCC cells to pharmacologic concentrations of DATS (1-10 μM) resulted in inhibition of cancer stem cells (CSC) fraction as evidenced by CD133high/CD44high fraction of cells, aldehyde dehydrogenase 1 (ALDH1) activity, and spheroid formation. DATS-treated tumor xenograft also revealed its in vivo inhibitory effect on CSCs. We observed for the first time that DATS treatment decreased tumor incidence and inhibited tumor promotion and progression in 4-Nitroquinoline 1-oxide (4-NQO)-induced mouse oral carcinogenesis model. Taken together, DATS strongly inhibited cell proliferation, induced cell cycle arrest, cell death via apoptosis, mitochondrial dysfunction and ROS generation and reduced CSC fraction, and decreased tumor incidence, promotion, and progression in 4-NQO model.
Citation Format: Sivapar Mathan, Shivendra Singh, Rana P. Singh. Anticancer effects of processed garlic constituent diallyl trisulfide on head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B042.
Abstract B044: Novel compounds suppressing p53-dependent growth of tumor cells
Authors: Tatsuda Daisuke , Momose Isao , Watanabe Takumi , Kunisada Takao , Kawada Manabu , Shibasaki Masakatsu 
Published: August 2018

Abstract
Background: p53, a tumor suppressor gene, is required for cell cycle checkpoint signaling pathways and induction of apoptosis. In cell growth conditions, Mdm2, a ubiquitin E3 ligase, binds and ubiquitinates p53 and induces p53 degradation by 26S proteasomes. Suppression of p53 degradation, however, can activate p53 and induce cell cycle arrest and apoptosis. Because p53 regulates tumor cell survival, activation of p53 is an attractive target for antitumor drugs. We established a cell-based assay to screen natural products and searched for a new p53 activator. As a result of screening, we identified quinofuracins A-E. Materials and Methods: To search for a new activator of the p53-dependent signaling pathway, we screened microbial metabolites using human glioblastoma LNZTA3 cells in which p53 expression can be regulated by tetracycline. Human glioblastoma LNZTA3 cells (tetracycline regulated p53 expression) and human gastric cancer MKN45 cells (p53 wild-type) and MKN7 cells (p53 mutant-type) were incubated with the compounds for 3 days, and cell viability was measured by MTT assay. Results: As a result of screening, we identified quinofuracins A-E, novel anthraquinone derivatives containing ß-D-galactofuranose, from Staphylotrichumboninense PF1444. Quinofuracins induced p53-dependent cell death; upregulated the expression of p53, p21, and PUMA; and stimulated PARP degradation in p53-expressing LNZTA3 cells. Quinofuracins also induced p53-dependent cell death in colon and stomach cancer cells. Conclusions: These findings suggest that quinofuracins induce the apoptotic pathway in vitro by activating p53, and thus may suppress tumor growth in vivo.
Citation Format: Daisuke Tatsuda, Isao Momose, Takumi Watanabe, Takao Kunisada, Manabu Kawada, Masakatsu Shibasaki. Novel compounds suppressing p53-dependent growth of tumor cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B044.
Abstract B054: Impairing the reseeding of circulating tumor cells decelerates metastatic progression
Authors: Qian Chen , Worrede-Mahdi Asurayya , Shen Fei , Salvino Joseph , Meucci Olimpia , Fatatis Alessandro 
Published: August 2018

Abstract
This study aims to understand the mechanisms and dynamics by which cancer cells, departing from existing metastases as circulating cancer cells (CTCs), further seed and colonize skeleton and soft tissues, expanding metastatic spreading and precipitating the clinical progression to terminal disease. We have previously shown that the chemokine receptor CX3CR1 is implicated in the metastatic seeding of breast cancer cells and that FX-68, a novel small-molecule antagonist for this receptor, effectively contains both number of lesions and total tumor burden in animal models of metastatic disease. Here we established that FX-68 impairs the reseeding of skeleton and soft-tissue and that the CTCs unable to reseed and forced to remain in the blood eventually succumb to apoptotic death. The metastatic potential of CTCs was confirmed by reinoculation experiments as well as by forcefully mobilizing cancer cells from metastases back in the blood and assessing the number of additional lesions generated, in the presence and absence of FX-68. Finally, we hypothesized that prolonging the permanence of CTCs in the blood could improve their exposure to chemotherapy drugs. This paradigm was tested by combining FX-68 with doxorubicin or docetaxel and assessing drug bioavailability and antimetastatic effects. In summary, our results strongly support developing CX3CR1 antagonists and promoting their clinical use, as this approach will provide novel and effective tools to contain the progression of metastatic disease in patients.
Citation Format: Chen Qian, Asurayya Worrede-Mahdi, Fei Shen, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis. Impairing the reseeding of circulating tumor cells decelerates metastatic progression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B054.
Abstract B070: Deciphering the ubiquitin code with polyubiquitin chain selective affinity matrices
Authors: Singh Rajesh , Than Don Bosco , Julius Sarah , Lu Xiaolong , Foote Peter , Song Chengcheng 
Published: August 2018

Abstract
Post-translational modification of proteins by ubiquitin (Ub) is a versatile process, highly dynamic, and involved in nearly all aspects of biologic functions in eukaryotes. Dysregulation of ubiquitylation has been implicated in a plethora of pathologic conditions ranging from developmental abnormalities and autoimmune to neurodegenerative diseases and a variety of cancers. Ub is attached, via isopeptide bonds, to lysine residues in the target protein through a cascade of enzymatic reactions. These Ub-moieties can then serve as substrates for the conjugation of additional Ubs, forming poly-ubiquitin chains, again through the formation of isopeptide bonds between the C-terminus of one Ub and any of seven lysine, or N-terminal methionine in the target Ub. The reversibility, heterogeneity, and diversity of these modifications combined with the lack of suitable tools have made it difficult to properly isolate and characterize poly-ubiquitylated cellular proteins. This chain complexity known as the “Ub code” requires diverse technical approaches to unravel its complexity. Recent publications have demonstrated that antibodies against Ub display linkage bias or are of poor quality for experiments requiring precise measurements. However, in 2009 a novel technology called TUBEs (Tandem-repeated Ub-Binding Entities) was developed. TUBEs have revolutionized the Ub field by allowing poly-ubiquitylated proteins to be purified from cellular extracts. Development of TUBEs that selectively bind K48, K63 poly-ubiquitylated proteins has helped understand the role of modified proteins in cell physiology. In addition, derivatives of chain selective TUBEs have been used to develop novel assays for DUBs and ubiquitin ligases. This presentation will describe variants of TUBEs and their applications, as well as the new iterations of TUBEs aimed at identifying Ub-linkage specific functions and their biologic relevance.
Citation Format: Rajesh Singh, Don Bosco Than, Sarah Julius, Xiaolong Lu, Peter Foote, Chengcheng Song. Deciphering the ubiquitin code with polyubiquitin chain selective affinity matrices [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B070.
Abstract B073: PD-L1 expression in urothelial cancer: first results from RUSSCO-RSP assay comparision study
Authors: Zavalishina Larisa , Povilaitite Patritsiya , Andreeva Yulia , Petrov A. , Pugach Inna , Kharitonova Ekaterina , Rumyantsev Alexey , Raskin Grigory , Frank Georgy , Tjulandin Sergei , Tsimafeyeu Ilya 
Published: August 2018

Abstract
Background: To compare similarities and differences between PD-L1 IHC assays in patients with urothelial cancer (UC), collaborative Russian Society of Clinical Oncology (RUSSCO) and Russian Society of Pathology (RSP) study was conducted. The first results, presented here, describe a rate of PD-L1 IHC expression assessed by each test and evaluate concordance between 3 assays. Methods: 100 UC tumors were stained with PD-L1 IHC assays (clones SP142, 22C3 and SP263) as used in the clinical trials of second-line therapy of atezolizumab (Ventana SP142), pembrolizumab (Dako 22C3), and durvalumab (Ventana SP263). Four trained pathologists certified by Ventana/Roche and Dako/Agilent in interpreting respective assays independently evaluated the percentages of tumor (TC) and tumor-infiltrating immune cells (IC) staining positive at any intensity. Single clinical cut-off for inclusion in this comparative analysis was used: IC ≥5% for SP142, TC+IC/TC ≥10% for 22C3, and TC or IC ≥25% for SP263. Results: Patients were predominantly male (89%), 47/100 (47%) had grade 3 tumors, 45/100 (45%) and 45/100 (45%) had T1 and T2 stages, respectively. 300 IHC slides were scored. The percent of immune cell staining across 3 assays appears to be higher than for tumor cell staining (45% vs. 8% for SP142; 55% vs. 24% for 22C3; 72% vs. 27% for SP263). There were variabilities in immune cell staining for all assays and in tumor cell staining across SP142 and other assays. The percentage of PD-L1-positive patients was comparable with SP142 (9%), 22C3 (11%) and SP263 (7%). Table indicates the number of cases that were concordant with the index assay scoring algorithm, when an alternative cut-off was used to determine the allocation of cases to clinical groups above and below the cut point.
Table Assay clone used for slide stainingScoring AlgorithmSP142IC ≥5%22C3TC+IC / TC ≥10%SP263TC or IC ≥25%SP142100/100 (100%)92/100 (92%)95/100 (95%)22C395/100 (95%)100/100 (100%)95/100 (95%)SP26396/100 (96%)95/100 (95%)100/100 (100%)
Conclusions: First comparison showed that concordance was more than 90% between SP142, 22C3, and SP263 assays used for evaluation of PD-L1 expression in patients with urothelial carcinoma. Further analysis is required to draw a final conclusion.
Citation Format: Larisa Zavalishina, Patritsiya Povilaitite, Yulia Andreeva, A. Petrov, Inna Pugach, Ekaterina Kharitonova, Alexey Rumyantsev, Grigory Raskin, Georgy Frank, Sergei Tjulandin, Ilya Tsimafeyeu. PD-L1 expression in urothelial cancer: first results from RUSSCO-RSP assay comparision study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B073.
Abstract B074: Ubiquitin proteomics: profiling the landscape of ubiquitin modification by ubisite-omics
Authors: Song Chengcheng , Akimov Vyacheslav , Foote Peter , Lu Xiaolong , Blagoev Blagoy , Singh Rajesh 
Published: August 2018

Abstract
The ubiquitin pathway has emerged as a promising druggable target for cancer. Ubiquitylation regulates various cellular functions including cell cycle, differentiation, apoptosis, and stress response. Ubiquitylation of proteins is encrypted bya variety of chain-selective K48, K63, K6, K11 poly-ubiquitins as well as mono-ubiquitin attached to target proteins. Proteomics provides an effective approach for decoding the complex ubiquitin signals. Ubiquitylation is a very dynamic process and ubiquitylated proteins are low in abundance and stoichiometry. Enrichment of ubiquitylated proteins by affinity metrics TUBE (Tandem Ubiquitin Binding Entities) is essential to improve quantitative, reproducible, and sensitive proteomics analysis. The most common approach is to use antibody that pulls down DiGlyGly-lysine (C-terminal di-Gly of ubiquitin attached to epsilon amino group of lysine), the so-called “ubiquitin remnant.” However, ubiquitylation from ubiquitin-like proteins (UBLs) such as SUMO, NEDD8, and ISG15 that are undistinguishable by DiGlyGly-lysine antibody makes it impossible to assign a role for ubiquitin or UBLs. Here we demonstrate a novel ubiquitylation-specific proteomics approach. This method utilizes UbiSite antibody that recognizes the ubiquitin C-terminus (13 a.a.), which creates the specificity for ubiquitin remnant. HepG2 and Jurkat cells were chosen as model systems. The alteration in cellular protein ubiquitylation were promoted by treatment with the inhibitor of a proteasome-associated DUB, USP14, a USP7 DUB inhibitor that is an immune oncology target or bortezomib, a 26S proteasome inhibitor. Cell lysates were digested with Lys C and immuneprecipitated with UbiSite antibody. Enriched ubiquitylated peptides were further digested with trypsin and analyzed by LC-MS/MS. The total proteome and ubiquitome were compared among treated and untreated samples. In addition, the ubiquitome of proteins, the site-specific ubiquitylation levels, were also compared with other published studies. We have identified a number of novel ubiquitylated proteins using the UbiSite proteomics approach. We believe this approach will facilitate discovery of pharmacologic markers for drugs, uncover new substrates for DUBs and ubiquitin ligases, and open doors for cell biologists to specifically identify genome-wide patterns of poly-ubiquitylated proteins.
Citation Format: Chengcheng Song, Vyacheslav Akimov, Peter Foote, Xiaolong Lu, Blagoy Blagoev, Rajesh Singh. Ubiquitin proteomics: profiling the landscape of ubiquitin modification by ubisite-omics [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B074.
Abstract B078: MiXenoTM: a fast and efficient humanized tumor model system for in vivo efficacy evaluation of novel immunotherapeutics
Authors: Zhang Lan , Zhang Juan , Qiao Meng , Yan Xuefei , Ding Jian , Chen Fei , An Xiaoyu , Tan Weibin , Fu Xiaoyan , Yang WenQing , Shi Qian 
Published: August 2018

Abstract
Recently approved cancer immunotherapy drugs have been shown to not only suppress tumor growth but also prolong survival of patients with various tumor types. More and more relevant and sophisticated preclinical tumor models are required by the I/O drug discovery industry. Different strategies of humanized mouse model systems have been published, including human hematopoietic stem cell (HSC) humanized and human PBMC reconstituted tumor models; each has advantages and disadvantages. Compared with HSC humanization, using human PBMC cells to reconstitute human immune system demonstrated fast engraftment and less variable results. CrownBio has successfully established a platform, known as MiXenoTM,that uses PBMC-humanized xenograft models to evaluate the in vivo antitumor activity of immunotherapeutics of human origin. The platform has proven to be a valuable tool and is being widely used by our collaborators. The current study is designed to address model optimization and application aspects of the MiXeno platform, including PBMC donor to donor variation, feasibility of in vitro PBMC donor screening, and selection of suitable models for different targets. More than a dozen MiXeno tumor models have been established and validated where human immune cells were reconstituted in the mouse system for evaluation of human-origin bispecific antibodies, immune checkpoint inhibitors, or immune modulators. These MiXeno models were characterized with regards to reconstitution of T cells, tumor response to anti-PD-1 and anti-CTLA4 antibodies, and onset of possible graft-versus-host disease (GVHD) or graft-versus-tumor response (GVT). Evaluation of expanded immune-oncology therapeutics is in progress, including NK and dendritic cells-targeted immune-modulating drugs.
Citation Format: Lan Zhang, Juan Zhang, Meng Qiao, Xuefei Yan, Jian Ding, Fei Chen, Xiaoyu An, Weibin Tan, Xiaoyan Fu, WenQing Yang, Qian Shi. MiXenoTM: a fast and efficient humanized tumor model system for in vivo efficacy evaluation of novel immunotherapeutics [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B078.
Abstract B087: A systematic approach to JAK/STAT pathway shut-down
Authors: Montazeri Aliabadi Hamidreza , Bousoik Emira , Mahdipoor Parvin 
Published: August 2018

Abstract
Janus Kinase Protein (JAK) plays a crucial role in a variety of intracellular mechanisms, and has been extensively studied for its role in proliferation and survival of cancer cells. One of the unique characteristics of this kinase is the variety of cell membrane receptors with which it is associated, and can trigger JAK activation process. Family of Signal Transducer and Activators of Transcription (STATs) are the direct downstream proteins that further transfer JAK signaling to the nucleus, which results in modification of expression level of a wide range of proteins. Triple-negative breast cancer (TNBC) represents one of the most aggressive and challenging subtypes of human breast cancer, due to lack of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors, which renders the cells nonresponsive to hormone therapy. Several studies have confirmed that IL-6/gp130/JAK2/STAT3 signaling pathway is one of the crucial pathways that is implicated in TNBC development. However, monotherapies targeting JAK2 or STAT3 with molecularly targeted drugs have faced several challenges, including inherent and acquired resistance. Therefore, we aimed to determine feasibility and efficacy of therapy of TNBC using combinatorial silencing of different components in gp130/JAK2/STAT3 pathway. The downregulatory effects of siRNA targeting gp130, JAK2, STAT3, Importin α-3 alone or in combination were evaluated in human TNBC cells MDA 231 and MDA 468, and their effect on downstream targets involved in cell apoptosis and cell cycle were determined by real-time PCR and Western blot. The effect of individual and combinatorial silencing of the pathway components on cell proliferation and cell migration were also examined using CCK assay and Scratch assay, respectively. The siRNA treatment effectively reduced gene expression of gp130/JAK2/STAT pathway components at the mRNA level. Simultaneous inhibition of selected components significantly decreased TNBC cell proliferation rate. Moreover, combinatorial siRNA silencing inhibited the migration of TNBC cells. In conclusion, simultaneous inhibition of well-selected components of JAK/STAT pathway could represent an effective therapy for human TNBC. This warrants further in vivo study in animal models.
Citation Format: Hamidreza Montazeri Aliabadi, Emira Bousoik, Parvin Mahdipoor. A systematic approach to JAK/STAT pathway shut-down [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B087.