bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-206: Inhibition of MYC by the SMARCB1 tumor suppressor
Authors: Weissmiller April M. , Wang Jing , Lorey Shelly L. , Howard Gregory C. , Martinez Ernest , Liu Qi , Tansey William P. 
Published: August 2018

Abstract
The SMARCB1 tumor suppressor (SNF5) is a known interaction partner of the oncoprotein c-MYC (MYC), and thought to serve as a co-activator of its transcriptional properties. This role of SNF5, however, is at odds with the tumor suppressor function of SNF5, and with findings that loss of SNF5 is associated with activation of MYC target gene signatures. We have used biochemical, genetic, and genome-wide approaches to reexamine the relationship of SNF5 with MYC within the context of malignant rhabdoid tumor (MRT), an aggressive childhood cancer in which SNF5 is lost. We find that, consistent with activation of MYC target gene signatures in tumors that lack SNF5, MYC function is important for multiple aspects of MRT biology. Surprisingly, SNF5 is capable of inhibiting MYC binding to E boxes in vitro and globally within the context of chromatin. Using ATAC-seq, RNA-seq, and PRO-Seq, we demonstrate that regulation of MYC binding by SNF5 is independent of the role of SNF5 in chromatin remodeling, but instead is responsible for controlling RNA polymerase pause release at MYC-regulated genes. These findings inform a novel model of MRT tumorigenesis in which loss of SNF5 derepresses MYC function, raising the possibility that MYC contributes to disease progression in this malignancy.
Citation Format: April M. Weissmiller, Jing Wang, Shelly L. Lorey, Gregory C. Howard, Ernest Martinez, Qi Liu, William P. Tansey. Inhibition of MYC by the SMARCB1 tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-206.
Abstract LB-222: Culturing cancer cells from liquid biopsies for precision cancer therapy
Authors: Liu Xuefeng 
Published: August 2018

Abstract
Liquid biopsies include circulation tumor cells (CTC), ctDNA/RNA, exosomes from blood or tumor relevant information from other liquid samples (urine, pleural effusion, ascites, saliva, etc.). Culturing cancer cells from liquid biopsies is a simple, non-invasive technique that has the potential to advance the diagnosis, treatment and monitoring of cancer patients. In this study, we described several approaches that allow to enrich cancer cells from urine (for bladder cancer), blood (for prostate cancer), and pleural effusion (for non-small cell lung carcinoma). These cancer cells from liquid biopsies were cultured and further propagated in suspension and/or adherent cultures using a specialized cell culture medium. We also confirmed genetic alterations in both original tumors and cancer cells from liquid biopsies, for example, mutant EGFR for lung cancer, mutations of hTERT promoter for bladder cancer. We also reported that these cancer cells from liquid biopsies were used for identify therapies for the patients. For example, a woman patient with metastatic NSCLC harboring mutant EGFR was primarily resistant to TKI treatment, we were able to identify a combination of chemotherapy for the patient. Cancer cells from urine samples were used for predicting recurrence of the bladder cancer or monitoring treatment. We also used these cultured cancer from original tumors and liquid biopsies for study of tumor heterogeneity.
Citation Format: Xuefeng Liu. Culturing cancer cells from liquid biopsies for precision cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-222.
Abstract LB-246: TIGAR amplification promotes glutamine addition in the progression of esophageal squamous cell carcinoma
Authors: Chu Jiahui , Shao Mingming , Chang Jiang , Cui Qionghua , Peng Linna , Luo Yingying , Tan Wen , Wu Chen , Lin Dongxin 
Published: August 2018

Abstract
BACKGROUND: Our previous whole-genome sequencing in esophageal squamous-cell carcinoma (ESCC) has identified 23 focal regions with recurrent gain of copy number that contain 1591 genes. Further integrative analysis of copy number alterations with mRNA expression levels showed 141 copy-number amplified genes that had higher mRNA levels, suggesting an important role of these genes in ESCC. This study was to investigate the functional roles of these genes and their potential as biomarkers and therapeutic targets for ESCC.
METHODS: An siRNA library was used to knock down all these 141 genes in ESCC cells and change of the malignant phenotype of these cancer cells was examined by using a high-throughput imaging method and in vitro proliferation and colony formation assays. The acting mechanism of the interest genes on malignant phenotypes of cells was explored using biochemical and molecular biological assays. We also examined the effect of the amplified genes on sensitivity of cancer cells to anticancer agents in vitro and in vivo in mice.
RESULTS: We found that, among the 141 examined genes, TIGAR was the top one influencing ESCC cell proliferation in vitro and in vivo in xenografts. We confirmed that TIGAR can inhibit glycolysis and divert the carbon flux into the PPP to produce ribose-5-phosphate (R5P) for nuclear synthesis in cells. Overexpression of TIGAR may activate AMPKα that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain energy balance in cells with a reduced glycolysis ability, which was responsible for energy production under normal conditions. We found that ESCC cells overexpressing TIGAR had an addiction to glutamine metabolism and were sensitive to glutaminase inhibitors. Glutamine restriction or glutaminase inhibitors had a synergistic effect with chemotherapy drugs, such as DDP and 5-Fu, on killing of ESCC cells, suggesting that glutaminase inhibitors may be used as adjuvant agents for treatment of ESCC with TIGAR amplification.
CONCLUSION: These results suggest that amplification or overexpression of TIGAR may prevent ESCC cells from killing by anticancer drugs and thus may represent a therapeutic target for ESCC.
Citation Format: Jiahui Chu, Mingming Shao, Jiang Chang, Qionghua Cui, Linna Peng, Yingying Luo, Wen Tan, Chen Wu, Dongxin Lin. TIGAR amplification promotes glutamine addition in the progression of esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-246.
Abstract LB-250: Oncogenic activation of mitochondrial phosphocreatine energy shuttle creates a druggable metabolic liability in cancer cells
Authors: Hitosugi Taro , Kurmi Kiran 
Published: August 2018

Abstract
Many important metabolic processes such as energy homeostasis, regulation of reactive oxygen species (ROS) levels, production of signaling metabolites, and synthesis of precursors for macromolecules occur in mitochondria of cancer cells. However, targeting mitochondrial metabolism in cancer has been challenging due to toxicity in normal cells, which also depend on mitochondrial metabolism. Therefore, identification of tumor specific mitochondrial metabolic alterations would be crucial to develop drugs that can selectively target cancer cells while sparing normal tissue.
Here, by using targeted metabolite profiling and mitochondria-specific phospho-proteomics approach, we identified Mitochondrial Creatine Kinase (MtCK) 1 as a metabolic target in HER2+ breast cancer cells. We show that the oncogenic HER2-ABL axis stabilizes MtCK1 through tyrosine 153 (Y153) phosphorylation to activate the PCr energy shuttle pathway that transfers ATP from mitochondria to cytosol. Inhibition of the PCr energy shuttle pathway either by genetically depleting MtCK1 or by pharmacologically with a creatine analogue cyclocreatine, decreases proliferation of trastuzumab-sensitive and -resistant HER2+ cancer cells and reduces tumor growth in vivo without obvious toxicity. These findings suggest that, once ATP is produced in the mitochondria, it is equally important for breast cancer cells to transfer this energy from mitochondria to the cytosol for maintenance of various biochemical processes and tumor growth. In summary, our study reveals MtCK1 stabilization by Y153 phosphorylation as a key molecular mechanism underlying the intersection between oncogenic HER2 signaling and mitochondrial energy metabolism, which creates a druggable metabolic vulnerability in cancer. Since cyclocreatine has been used as a dietary sport supplement, cyclocreatine might be able to inhibit trastuzumab-resistant tumors with much less toxicity in patients as compared to conventional anticancer drugs.
Citation Format: Taro Hitosugi, Kiran Kurmi. Oncogenic activation of mitochondrial phosphocreatine energy shuttle creates a druggable metabolic liability in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-250.
Abstract LB-299: Cynomolgus monkey plasma cell gene signature to quantify the in vivo activity of a half-life extended anti-BCMA BiTE® for the treatment of multiple myeloma
Authors: Goyos Ana , Li Chi-Ming , Deegen Petra , Bogner Pamela , Thomas Oliver , Wahl Joachim , Goldstein Rebecca , Friedrich Maththias , Coxon Angela , Balazs Mercedesz , Arvedson Tara 
Published: August 2018

Abstract
Background: Multiple myeloma (MM) is a hematologic malignancy where abnormal plasma cells (PC) accumulate in the bone marrow (BM). Patients often develop relapsed/refractory disease leading to significant morbidity and mortality. Elimination of residual disease is required for curative treatments. Patient outcome can be improved by using T-cell engaging agents, such as bispecific T-cell engager (BiTE®) antibody constructs, to redirect T cells to tumor cells. B-cell maturation antigen (BCMA), a TNF receptor superfamily member, supports PC survival and is widely expressed on MM and normal PC.
Methods: A half-life extended (HLE) anti-BCMA BiTE® (BCMA HLE-BiTE®) antibody construct was generated and characterized in vitro, and in vivo in a mouse xenograft model and in non-human primates (NHP). To quantify on-target activity of the BCMA HLE-BiTE® in NHP it was necessary to follow changes in PC numbers. Because PC are rare (0.1 - 3%) in the BM and blood, detection using traditional assays is not possible. To address this limitation, a PC gene signature was defined and used to develop a quantitative ddPCR assay (sensitivity = 0.01%) to assess the effect of the BCMA HLE-BiTE® in a 12-day repeat-dose NHP study.
Results: A BCMA HLE-BiTE® was selected that demonstrated cytotoxic activity using human effector cells (EC50: 0.13 ± 0.07 pM in MM.1R cells) and comparable activity using NHP effector cells. In a sub-cutaneous mouse xenograft model in which BCMA-positive NCI-H929 cells and human PBMC were co-administered, the BCMA HLE-BiTE® completely inhibited tumor formation, in contrast to vehicle controls with/without PBMC. The serum half-life of the BCMA HLE-BiTE® in NHP was 112 hours following a single 15 µg/kg IV dose. The PK/PD relationship in NHP was next evaluated in a 12-day repeat-dose study. A dose-dependent PK behavior as well as depletion of PC in blood and BM was observed, reaching 93% depletion in the blood and 85% in the BM in the high-dose group on day 12.
Conclusions: These results demonstrate that the BCMA HLE-BiTE® is potent and effective at inducing cytotoxicity of target cells in vitro and in vivo, and may be suitable for once-weekly dosing in MM patients. This molecule is being evaluated in humans: trial NCT03287908.
Citation Format: Ana Goyos, Chi-Ming Li, Petra Deegen, Pamela Bogner, Oliver Thomas, Joachim Wahl, Rebecca Goldstein, Maththias Friedrich, Angela Coxon, Mercedesz Balazs, Tara Arvedson. Cynomolgus monkey plasma cell gene signature to quantify the in vivo activity of a half-life extended anti-BCMA BiTE® for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-299.
Abstract LB-312: GRK5 activity mediates in vivo and in vitro prostate cancer progression and chemoresistance
Authors: Black Joseph B. , Purayil Hamsa Thayele , Mahmud Iqbal , Liao Daiqing , Daaka Yehia 
Published: August 2018

Abstract
Despite decades of research targeting the activity of the androgen receptor (AR), patients diagnosed with locally advanced and metastatic prostate cancer face an incurable disease. The Daaka lab investigates constituents of G-protein-coupled receptor signaling cascades for their ability to provide mitogenic signaling, which promotes PCa progression. We previously identified G protein-coupled receptor 5 (GRK5) for its ability to regulate PCa progression, independent of AR activity. GRK5 partially partitions to the nucleus, wherein it has been shown to regulate the transcriptome in non-PCa models. To globally elucidate the mechanistic impact of GRK5 on PCa progression, we are investigating the impact of GRK5 on the PCa transcriptome. We hypothesize that GRK5's regulation of the PCa transcriptome promotes tumor progression. To assay the effect of GRK5 on the PCa transcriptome, RNA sequencing was performed in two cell lines: PC3 Control (PC3 shGFP) and PC3 GRK5 Knockdown (PC3 shGRK5). Ontologic analysis identified the epithelial–mesenchymal transition (EMT) as being affected when GRK5 is depleted. The epithelial–mesenchymal transition (EMT) is highly associated with promoting PCa progression and chemoresistance, thus we selected this pathway for further investigation. Confirmatory western blot analysis and quantitative PCR (qPCR) validated that depleting GRK5 suppresses the expression of the mesenchymal markers Vimentin and N-Cadherin. Similarly, overexpression of GRK5 increases the expression of these mesenchymal markers. Stable overexpression of GRK5 promotes cells to develop a spindle-like morphology, indicative of a mesenchymal state. GRK5 mediates this mesenchymal transition through increasing the expression of the EMT transcription factor, Twist1. Further analysis identifies that GRK5 activity promotes in vitro invasion. Cell lines overexpressing GRK5 demonstrate an increase in resistance to docetaxel, the mainstay chemotherapy for advanced PCa. Overexpression of GRK5 promotes lymphatic intravasation. Overexpression of mutated forms of GRK5 that are relegated to the nucleus are able recapitulated all aforesaid changes, arguing that the nuclear activity of GRK5 mediates this effect. Collectively, this data presents a novel mechanism promoting PCa progression, independent of AR activity.
Citation Format: Joseph B. Black, Hamsa Thayele Purayil, Iqbal Mahmud, Daiqing Liao, Yehia Daaka. GRK5 activity mediates in vivo and in vitro prostate cancer progression and chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-312.
Abstract LB-327: Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake
Authors: Fletcher Alice , Thompson Rebecca , Read Martin , Turnell Andrew , Smith Vicki , McCabe Chris J. 
Published: August 2018

Abstract
Ablative radioiodide therapy is an effective treatment for thyroid cancer, but around a quarter of patients do not accumulate therapeutically-sufficient doses of radioiodide due to decreased expression and/or plasma membrane (PM) localization of the sodium iodide symporter (NIS). Putative use of radioiodide therapy in breast cancer is hampered by low levels of NIS membrane localisation. Currently, the regulation of NIS trafficking is ill-defined. Mass spectrometry was performed on proteins co-immunoprecipitating with lentivirally expressed NIS in whole cell and plasma membrane extracts. NIS activity was significantly altered by ADP-ribosylation factor 4 (ARF4) and valosin containing protein (VCP) in TPC1 thyroid and MDA-MB-231 breast cancer cells lentivirally-expressing NIS. ARF4 downregulation markedly decreased radioiodide uptake, and VCP downregulation increased radioiodide uptake in thyroid and breast cells. Transient overexpression of these genes significantly reversed siRNA effects on NIS function. Co-immunoprecipitation assays confirmed NIS interacts with ARF4 and VCP in vitro, and proximity ligation assays revealed the subcellular sites of interaction. Critically, human primary thyroid culture experiments confirmed that ARF4 and VCP regulate endogenous NIS function in vivo. In addressing the mechanisms of NIS trafficking we identified a C-terminal VXPX motif of NIS which is required for Arf4 regulation, whilst TIRF microscopy revealed coincident Arf4 and NIS localization to shared PM vesicles. Pharmacological inhibitor studies identified that the VCP inhibitors Eeyarastatin-1 and NMS-873 overcome VCP inhibition of NIS function. VCP, which is central to ER-associated Degradation (ERAD), selectively targeted a dimeric form of NIS, which we now identify through co-immunoprecipitation, 3D modelling and Förster resonance energy transfer (FRET) assays. TCGA data analysis of 58 matched papillary thyroid cancers revealed that Arf4 was significantly repressed and VCP highly upregulated in thyroid cancer, providing a putative explanation for repressed NIS function. Our data suggest a possible model for NIS trafficking: NIS dimerises in the ER, a process monitored by VCP and the ERAD pathway, with correctly processed and folded NIS being trafficked to the PM via C-terminal interaction with Arf4. We thus now identify two new potential therapeutic targets for enhancing radioiodide uptake in patients with radioiodide-refractory thyroid cancer.
Citation Format: Alice Fletcher, Rebecca Thompson, Martin Read, Andrew Turnell, Vicki Smith, Chris J. McCabe. Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-327.
Abstract LB-360: JNKs-mediated phosphorylation of human stromal xbp1s regulates multiple myeloma growth & osteolysis
Authors: Chen Risheng , Xu Guoshuang , Beaino Wissam , Lui Kai , Zeng Xuemei , Yates Nathan , Chong Rong , Verdelis Konstas , Roodman G. David , Toscani Denise , Giuliani Nicola , Lin Yan , Anderson Carolyn J. , Ouyang Hongjiao 
Published: August 2018

Abstract
Spliced X-box binding protein-1 (XBP1s) is a major effector of the unfolded protein response (UPR) signaling. We previously reported that human XBP1s in bone marrow stromal cells plays an essential role in regulating stromal support of multiple myeloma bone disease (MMBD). Here we report that human XBP1s (hXBP1s) is a physiological & direct phosphorylation substrate of JNKs. This phosphorylation greatly increases hXBP1s protein degradation by the E3 ubiquitin ligase β-TrCP. Mutation of the phosphorylation site of JNKs to alanine largely prevents JNK phosphorylation of XBP1s & JNK-induced protein degradation of hXBP1s. Further, we found that bone marrow stromal cells (BMSCs) harboring this XBP1s mutant are resistant to JNK phosphorylation and provided significantly greater support of MM growth and MM-induced bone destruction both in vitro & in vivo, compared with counterparts expressing WT hXBP1s. Finally, we observed that JNK-mediated phosphorylation of hXBP1s is associated with favorable therapeutic responses of MM patients to combination therapy of bortezomib, &/or dexamethasone &/or thalidomide, MM drugs known to stimulate JNK. These results suggest p-hXBP1sJNK is a potential predictive biomarker for MM patients' response to the drug treatment. Taken together, our study provides the first evidence that hXBP1s is a novel physiological & direct target of JNK phosphorylation and demonstrates the pathophysiological significance of this event in the hXBP1s-mediated bone microenvironment support of MM growth and MM-induced bone destruction.
Citation Format: Risheng Chen, Guoshuang Xu, Wissam Beaino, Kai Lui, Xuemei Zeng, Nathan Yates, Rong Chong, Konstas Verdelis, G. David Roodman, Denise Toscani, Nicola Giuliani, Yan Lin, Carolyn J. Anderson, Hongjiao Ouyang. JNKs-mediated phosphorylation of human stromal xbp1s regulates multiple myeloma growth & osteolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-360.
Abstract LB-361: Tumor-derived microvesicles promote tumor immune escape through PD-1/PD-L1 interaction
Authors: Kim Dong Ha , Choi Yun Jung , Kim Seon Ye , Lee Jung-Eun , Sung Ki Jung , Lee Jae Cheol , Rho Jin Kyung 
Published: August 2018

Abstract
PD-1/PD-L1 pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 therapy has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that microvesicles (MVs) derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T cell activity and promoting tumor growth. The abundance of PD-L1 on MVs represented the quantity of PD-L1 expression on cell surfaces. MVs containing PD-L1 inhibited IFN-γ secretion by Jurkat T cells. The IFN-γ secretion was restored by PD-L1 knockout or masking on the MVs. Both the forced expression of PD-L1 on cells without PD-L1 and treatment with MVs containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on MVs isolated from the plasma of patients with non-small cell lung cancer, and its abundance in the MVs was correlated with the PD-L1 positivity on tumor tissues. MVs could impair immune functions by reducing cytokine production and inducing apoptosis in CD8+ T cells. Our findings indicate that tumor-derived MVs expressing PD-L1 may be an important mediator of tumor immune escape.
Citation Format: Dong Ha Kim, Yun Jung Choi, Seon Ye Kim, Jung-Eun Lee, Ki Jung Sung, Jae Cheol Lee, Jin Kyung Rho. Tumor-derived microvesicles promote tumor immune escape through PD-1/PD-L1 interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-361.