bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 154: Inhibition of WEE1 expression reduces lipid metabolism and stemness in hepatocellular carcinoma
Authors: Park Keon Uk , Ko Min Ji , Hwang Ilseon , Ryoo Hun-Mo , Lee Yun-Han 
Published: August 2018

Abstract
Background: Classical therapeutic regimens predominantly target proliferating cells, which are unlikely to be cancer stem cells (CSCs). Similarly, new generation therapies, e.g. sorafenib for hepatocellular carcinoma (HCC), do not seem to target CSCs as evidenced by frequent tumor relapse and resistance after therapy. Thus, identification and characterization of signaling pathways and biomarkers associated with CSC biology are therefore priorities for developing new paradigms of molecular cancer therapeutics. Increase of WEE1 kinase activity through an epigenetic regulation plays an important role in the development of HCC. However, the functional role of WEE1 in HCC progression remains to be clarified.
Methods: Human HCC cell lines were transfected with WEE1 siRNA and tested for growth inhibition, apoptotic induction, molecular changes in both RNA and protein levels, and changes in CSC phenotype using various methods such as MTS, FACS, microscopic analysis, Real-time PCR, Western blotting, sphere forming assay. To obtain insights into the molecular changes in response to WEE1 knockdown, global changes in gene expression were examined using RNA sequencing.
Results: Here we demonstrated that WEE1 siRNA silencing caused inhibition of HCC cell growth through blockade of cell cycle progression and induction of apoptosis. The anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of cdk inhibitor p21 and the downregulation of AKT1, CDK2, cyclin B1 (CCNB1), PARP1 and GPAM which are functionally involved in control of cell cycle, apoptosis and lipid metabolism. Wee1 silencing in tumor cells also resulted in a strong inhibition of lipogenesis (SREBP1C, FAS) and caused a marked decrease in fat accumulation. Of importance, knockdown of WEE1 dramatically reduced the portion of liver CSC population through co-downregulation of cancer stemness genes and weakened the capacity of sphere formation and the ability of cancer cell migration. Systemic delivery of a modified WEE1 siRNA encapsulated in lipid nanoparticles significantly inhibited human HCC growth in murine xenograft models, and increased mice survival. Our findings suggest that the epigenetic modifier WEE1 functionally involve to HCC lipid metabolism and CSC-like phenotype maintenance and that molecular targeting of WEE1 may be an effective systemic therapy for prevention of tumor recurrence via elimination of CSCs in liver tumor microenvironment.
Citation Format: Keon Uk Park, Min Ji Ko, Ilseon Hwang, Hun-Mo Ryoo, Yun-Han Lee. Inhibition of WEE1 expression reduces lipid metabolism and stemness in hepatocellular 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 154.
Abstract 1543: Upregulation of mannose 6-phosphate receptor (MPR) has a potential to increase the efficacy of combined therapy for melanoma patients
Authors: Atay Cigdem , Lavilla-Alonso Sergio , Gabrilovich Dmitry 
Published: August 2018

Abstract
BRAF -targeting therapy demonstrates impressive clinical response in patients with metastatic melanoma. However, patients quickly develop resistance associated with rapid tumor progression. Therefore, additional therapeutic approaches are necessary. Our group has previously shown that transient induction of cation-independent mannose 6-phosphate receptor (MPR) is important for the antitumor effect of chemo-immunotherapy. In this study, we aimed to decipher the role of MPR during possible combination therapy of BRAF inhibitor with adoptive T-cell therapy of BRAF inhibitor-resistant melanoma. For this aim, we have used PLX4720 as a BRAFV600E inhibitor and observed that in vitro PLX4720 treatment of human V600E-positive melanoma cells, including WM-35, SK-Mel-624 and WM983B, resulted in a dose-dependent upregulation of MPR on the cell surface. Importantly, increased levels of MPR on the cell surface induced the uptake of recombinant Granzyme B, which is a major mechanism of cell killing by cytotoxic T cells (CTL). We found that PLX4720 treatment rendered WM35 cells more prone to lysis by HLA-matching tumor-infiltrating lymphocytes (TILs) and increased cell killing is not due to PLX4720 treatment itself but increased levels of MPR on the cell surface. In order to prove this, we generated MPR-overexpressing WM35 cell line and showed that upregulation of MPR, independently of PLX4720 treatment, sensitizes melanoma cells for T cell killing in vitro. We further showed that PLX4720 treatment leads to upregulation of MPR in vivo by a mouse model bearing xenograft WM35-derived subcutaneous tumors as well. According to our data, 3 days of PLX4720 treatment is enough to induce MPR in tumors and this effect continues up to 6 days after 5 days treatment ends. Unexpectedly, we found that PLX4720 caused upregulation of MPR in resistant cell lines and that those cell lines became more sensitive to cytotoxic effect of TILs. Thus, our data suggest that adoptive T-cell therapy can be potentially effective in melanoma resistant to BRAF inhibitor. (This study is supported by NIH grant P50 CA168536.)
Citation Format: Cigdem Atay, Sergio Lavilla-Alonso, Dmitry Gabrilovich. Upregulation of mannose 6-phosphate receptor (MPR) has a potential to increase the efficacy of combined therapy for melanoma patients [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 1543.
Abstract 1580: Separation of circulating biomarkers by nanoDLD lab-on-a-chip technology
Authors: Gifford Stacey M. , Wunsch Benjamin H. , Smith Joshua T. , Dogra Navneet , Kim Sungcheol , Stolovitzky Gustavo 
Published: August 2018

Abstract
Efficient isolation of circulating biomarkers is key for enabling liquid biopsies for cancer diagnosis and prognosis. Circulating biomarkers such as exosomes and cell-free DNA hold promise for non-invasive early cancer diagnosis, determining cancer stage and prognosis, as well as monitoring treatment progression and the development of drug resistance. However, isolation of these biomarkers has proven challenging in the clinic. Exosomes range in size from approximately 30 to 150 nm and the current gold standard isolation method includes large-scale ultracentrifugation, which is time-consuming and lacks reproducibility. Circulating cell-free DNA is found in a variety of sizes and states and while clinical applications for prenatal testing have emerged, applications in oncology remain elusive in part due to high background and challenges in isolating relevant molecules. We have developed a lab-on-a-chip technology based on deterministic lateral displacement at the nanoscale (nanoDLD) which separates and concentrates particles as small as 20 nm from smaller particles in continuous flow. Analysis of nanoDLD isolation of exosomes and DNA show improved resolution, recovery, and concentration compared to standard techniques. Current efforts to scale nanoDLD technology to clinically relevant volumes will provide a reproducible and automated tool for isolation, study, and clinical use of these important non-invasive biomarkers.
Citation Format: Stacey M. Gifford, Benjamin H. Wunsch, Joshua T. Smith, Navneet Dogra, Sungcheol Kim, Gustavo Stolovitzky. Separation of circulating biomarkers by nanoDLD lab-on-a-chip technology [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 1580.
Abstract 1581: Circulating cell-free DNA for metastatic cervical cancer detection, genotyping and monitoring
Authors: Kang Zhigang , Stevanović Sanja , Hinrichs Christian , Cao Laing 
Published: August 2018

Abstract
Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA is a unique tumor marker for metastatic cervical cancers. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for disease monitoring and treatment-related decision making.
Patients and Methods: In this retrospective study, HPV ccfDNA was measured in serum samples from metastatic cervical cancer patients by duplex digital droplet (dd) PCR. Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV data, drug treatment, and clinical outcome.
Results: In blinded tests, HPV ccfDNA was detected in 19/19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87/87 (100%) sequential patient serum samples. In three patients who experienced objective responses after TIL immunotherapy, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, a persistent clearance of HPV ccfDNA was observed in only two patients with a complete response (CR) after TIL immunotherapy.
Conclusions: HPV ccfDNA represents a promising tumor marker for non-invasive HPV genotyping and may be used in selecting patients for HPV type-specific T-cell-based immunotherapies. It may also have value in detecting the anti-tumor activities of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission.
Citation Format: Zhigang Kang, Sanja Stevanović, Christian Hinrichs, Laing Cao. Circulating cell-free DNA for metastatic cervical cancer detection, genotyping and monitoring [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 1581.
Abstract 1584: Comparison of circulating tumor cell (CTC) capture/identification methods and NanoString evaluation of gene expression in CTCs and cell-free circulating tumor mRNA (cctmRNA) in patients with metastatic lung cancer
Authors: Boumber Yanis , Aggarwal Charu , Thrash-Bingham Catherine , Fittipaldi Patricia , Guseva Polina , Vlasenkova Ramillya , Rao Chandra , Pei Jianming , Egleston Brian L. , Borghaei Hossein , Cristofanilli Massimo , Mehra Ranee , Serebriiskii Ilya , Alpaugh R. Katherine 
Published: August 2018

Abstract
Circulating tumor cells (CTC) and cell free circulating tumor mRNA (cctmRNA) can serve as biomarkers for prognosis and treatment response in lung and other cancers. A barrier to CTC use in some cancers is the low numbers of CTC captured, and the low percent of patients with detectable CTCs. Past comparisons of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients have shown larger cohorts of patients with detectable CTCs, and higher CTC numbers, for SCLCs. We compared methods for CTC capture/identification, and profiled mRNA from both the CTCs and cell free plasma RNA (cctmRNA) for to identify tumor-associated biomarkers. Peripheral blood was collected from 10 SCLC and 10 NSCLC patients prior to therapy, and from 4 normal controls. Capture using the standard EpCAM CellSearch reagent (unicapture) was run in parallel with EpCAM plus Her2, EGFR and MUC-1 combined ferrofluid (quadcapture) plus the use of anti-cytokeratin 7 (CK7) to assist in CTC identification. Unicapture detected CTCs in 40% of NSCLC and 60% of SCLC; whereas, quadcapture/CK7 identified 20% CTCs in NSCLC and 80% in SCLC. Overall, the quadcapture did not improve CTC capture efficiency. Exploratory NanoString analysis was performed on cell-free plasma from these patients and the ferrofluid isolated CTCs. Cancer-specific biomarkers were detected in mRNA from plasma and CTCs by NanoString included CCL5, CLU and SRGN. In summary, quadcapture ferrofluid reagent did not improve the capture efficiency, although the addition of CK7 may have the potential to identify additional CTCs. Nanostring analysis of cctmRNA and CTCs mRNA suggested potential new lung cancer biomarkers that require validation in larger studies.
Citation Format: Yanis Boumber, Charu Aggarwal, Catherine Thrash-Bingham, Patricia Fittipaldi, Polina Guseva, Ramillya Vlasenkova, Chandra Rao, Jianming Pei, Brian L. Egleston, Hossein Borghaei, Massimo Cristofanilli, Ranee Mehra, Ilya Serebriiskii, R. Katherine Alpaugh. Comparison of circulating tumor cell (CTC) capture/identification methods and NanoString evaluation of gene expression in CTCs and cell-free circulating tumor mRNA (cctmRNA) in patients with metastatic lung cancer [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 1584.
Abstract 1646: Discovery and characterization of BAY-6035, a novel benzodiazepine-based SMYD3 inhibitor
Authors: Gradl Stefan , Steuber Holger , Weiske Jörg , Schmees Norbert , Siegel Stephan , Stoeckigt Detlef , Christ Clara D. , Li Fengling , Organ Shawna , Barsyte-Lovejoy Dalia , Szewczyk Magdalena M. , Kennedy Steven , Trush Viacheslav , Vedadi Masoud , Arrowsmith Cheryl H. , Brown Peter J. , Husemann Manfred , Fernandez-Montalvan Amaury E. , Badock Volker , Bauser Marcus , Haegebarth Andrea , Hartung Ingo V. , Stresemann Carlo 
Published: August 2018

Abstract
SMYD3 (SET and MYND domain-containing protein 3) is a protein lysine methyltransferase (PKMT) which was initially described as H3K4 methyltransferase involved in transcriptional regulation. SMYD3 has recently been reported to methylate and regulate several non-histone cancer relevant proteins such as mitogen-activated protein kinase kinase kinase 2 (MAP3K2), vascular endothelial growth factor receptor 1 (VEGFR1), and the human epidermal growth factor receptor 2 (HER2). In addition overexpression of SMYD3 has been linked to poor prognosis in certain cancers, thus supporting a possible oncogenic role for SMYD3 and making it an attractive target for anticancer drug development. Here we report the discovery of a novel potent and selective SMYD3 inhibitor series. We performed a thermal shift assay based (TSA) high throughput screening followed by extensive biophysical validation resulting in identification of a benzodiazepine-based SMYD3 inhibitor series. The co-crystallization structures revealed that this series binds to the substrate binding site and occupies the hydrophobic pocket for lysine binding using an unprecedented hydrogen bond pattern. The competitive behavior of the inhibitor in biochemical assays was consistent with the binding mode observed in the crystal structure. Further optimization generated BAY-6035, which showed improved nanomolar potency and was selective against kinases and other PKMTs. Furthermore, BAY-6035 specifically inhibited methylation of MAP3K2 by SMYD3 in a cellular assay with similar potency. In summary, BAY-6035 is a novel selective and potent SMYD3 inhibitor probe and will foster the exploration of the biologic role of SMYD3 in diseased and non-diseased tissues.
Citation Format: Stefan Gradl, Holger Steuber, Jörg Weiske, Norbert Schmees, Stephan Siegel, Detlef Stoeckigt, Clara D. Christ, Fengling Li, Shawna Organ, Dalia Barsyte-Lovejoy, Magdalena M. Szewczyk, Steven Kennedy, Viacheslav Trush, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Manfred Husemann, Amaury E. Fernandez-Montalvan, Volker Badock, Marcus Bauser, Andrea Haegebarth, Ingo V. Hartung, Carlo Stresemann. Discovery and characterization of BAY-6035, a novel benzodiazepine-based SMYD3 inhibitor [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 1646.
Abstract 1660: Unraveling isoform selectivities of a broad class of HDAC inhibitors with QM/MM molecular dynamics simulations
Authors: Lin Jung-Hsin 
Published: August 2018

Abstract
Therapeutics that have been used by large populations and showed limited or little adverse effects can be good candidates for cancer chemo-prevention. As an example of such therapeutics, statins, i.e., HMG-CA reductase inhibitors, have been widely prescribed for lowering the blood cholesterol level and for treating cardiovascular diseases. In 2008, we discovered that statins are moderate inhibitors of histone deacetylases (HDACs), which provides an epigenetic mechanism for their efficacy in cancer prevention. HDACs have been long recognized for as an important class of therapeutic targets, and these enzymes utilize a Zn2+ ion at its active site for catalysis. Subsequently, in our 2013 J. Med. Chem. article, we showed that we are able to strengthen this epigenetic mechanism and designed more potent and effective therapeutic agents for cancer prevention and treatment, including cancer metastasis, and published in Clin. Cancer Res. in 2016. To investigate the structure-activity relationships of a broad class of HDAC inhibitors with distinct chemical moieties, we have conducted QM/MM molecular dynamics simulations of several systems of HDAC isoforms bound with various ligands. In contrast to molecular dynamics simulations with classical force fields, which always rendered over-coordinated configurations of the Zn2+ at the active site, with the coordination numbers (CN) to be either 6 or 7, in our QM/MM molecular dynamics simulations, the CNs of Zn2+ remain 4 or 5. With the structural and energetics analysis from these QM/MM molecular dynamics simulations, we are able to delineate the origins of isoform-selectivity of different HDAC inhibitors, including the aforementioned HMGR-HDAC dual-action inhibitors that we recently developed.
Citation Format: Jung-Hsin Lin. Unraveling isoform selectivities of a broad class of HDAC inhibitors with QM/MM molecular dynamics simulations [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 1660.
Abstract 1663: Identification and characterization of a small-molecule inhibitor of the human uracil-DNA glycosylase for use in combination with DNA damage-based anticancer therapies
Authors: Nguyen Mya T. , Yan Yan , Fedorvo Yuriy , Pink John , Adams Drew , Gerson Stanton 
Published: August 2018

Abstract
Our research aims to develop therapeutically active inhibitors of the human uracil-DNA glycosylase (UNG). UNG, a highly conserved enzyme, plays a pivotal role in preventing abnormal bases, uracil and 5-fluorouracil, from incorporation into DNA as a result of treatment with chemotherapeutic drugs, floxuridine (5-FdU) and pemetrexed (PEM). Our previous publication reports that the depletion of UNG by shRNA causes uracil and 5-FU incorporation into DNA following 5-FdU or PEM exposure, and highly sensitizes certain human cancer cells to these chemotherapeutic drugs. These data suggest that UNG specific inhibitors could improve the anticancer effect of 5-FdU or PEM. However, a few known inhibitors have not been shown to function at therapeutic concentrations in human cells. Therefore, in order to identify a novel, small-molecule compound targeting the human UNG enzymatic activity, we have previously optimized a biochemically high-throughput screening (HTS) assay that measures the removal of uracil from a DNA hairpin based on the un-quenching of fluorescence. This assay has been successfully employed in a pharmacologically active compound collection screen (&gt;3,000 small-molecules+ approved drugs). In 384-well plate runs using control wells in which enzyme is not added, the average assay provides signal to background ratios of 3.0 to 4.0. Typical Z factors range from 0.6-0.7, indicating a robust assay. We have identified five bioactive compounds with IC50 values &lt; 1uM and have selected a nanoMolar inhibitor of the human UNG enzyme termed, UNGi-A. By using an in vitro DNA glycosylase activity assay, this compound displays a significant inhibitory activity towards the purified human UNG enzyme over time, in a dose-dependent manner. Further characterization shows a significant effect of this inhibitor on UNG activity in cellular extract that expresses endogenous UNG from DLD1 human colon cancer cell line. The result suggests that UNGi-A compound diminishes UNG activity in cell extracts. In addition, thermal shift assay (TSA) data suggest that UNGi-A binds directly to the human UNG enzyme. Together, this compound shows potential activity that blocks the human UNG activity and we are currently evaluating the effect of UNGi-A in combination with 5-FdU on UNG activity in human cancer cells.
Citation Format: Mya T. Nguyen, Yan Yan, Yuriy Fedorvo, John Pink, Drew Adams, Stanton Gerson. Identification and characterization of a small-molecule inhibitor of the human uracil-DNA glycosylase for use in combination with DNA damage-based anticancer therapies [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 1663.
Abstract 1665: AZ304, a novel dual BRAF inhibitor, exerts antitumor activity in colorectal cancers independent of BRAF status
Authors: Ma Rui , Xu Ling , Che Xiaofang , Qu Xiujuan , Drew Lisa , Shen Minhui , Cheung Tony , Liu Yunpeng 
Published: August 2018

Abstract
Background: BRAF mutation is associated with poor clinical outcome of malignant tumors and mediates resistance to chemotherapy and targeted therapy. We aimed to determine whether wild type and V600E mutant BRAF colorectal cancers exhibit distinct sensitivities to dual BRAF inhibitor, AZ304.
Methods: We measured kinase activity by AlphaScreen assay. MTT assays, colony-formation assays, and Western blot were performed to evaluate the in vitro anti-tumor effects of AZ304. In vivo efficacy was investigated by xenograft study and Immunohistochemistry.
Results: AZ304 exhibited potent inhibitory activity against both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF with enzyme IC50values of 79nM and 38nM, respectively. By suppressing the ERK phosphorylation, AZ304 led to effective cell proliferation inhibition against a panel of human cancer cell lines with different BRAF and RAS generic status. In selected colorectal cancer cell lines, AZ304 significantly inhibited cell growth in vitro and in vivo, regardless of BRAF genetic status. Additionally, combination with the EGFR inhibitor Cetuximab enhanced the potency of AZ304 independent of BRAF mutational status.
Conclusions: The BRAF inhibitor, AZ304, had a broad spectrum of antitumor activities and the combination with Cetuximab significantly enhanced AZ304 potency against colorectal cancers in vitro and in vivo.
Citation Format: Rui Ma, Ling Xu, Xiaofang Che, Xiujuan Qu, Lisa Drew, Minhui Shen, Tony Cheung, Yunpeng Liu. AZ304, a novel dual BRAF inhibitor, exerts antitumor activity in colorectal cancers independent of BRAF status [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 1665.