bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1873: Preclinical activity of tipifarnib in cutaneous T-cell lymphoma
Authors: Kohnken Rebecca , McNeil Betina , Wen Jing , McConnell Kathleen , Burrows Francis , Porcu Pierluigi , Mishra Anjali 
Published: August 2018

Abstract
Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma characterized by malignant infiltration of skin-homing CD4+ T-cells, manifesting clinically as patches and plaques on the skin (Wong HK, et al. Br J Haematol 2011). The disease will often progress from an indolent skin-limited form, Mycosis Fungoides (MF), to an aggressive leukemic variant, Sezary Syndrome (SS) (Kohnken R, et al. Curr Hematol Malig Rep 2016). As there are few effective therapies available for advanced-stage CTCL, we sought to explore potential novel therapeutic modalities. Farnesyl transferase inhibitors (FTIs) are a relatively new class of anticancer drugs, the exact mechanism of which is unknown. Tipifarnib is one such FTI, which has demonstrated clinical activity as a single agent in patients with relapsed and refractory lymphomas (Witzig, TE, et al. Blood 2011). We utilized CTCL patient-derived cell lines to evaluate the potential efficacy of tipifarnib in vitro. EC50 doses ranged from 7.5nM for HuT78 to 50nM for SeAx. Importantly, there was no cytotoxic effect on normal donor CD4+ T-cells in vitro. Based on these promising findings, we evaluated tipifarnib in vivo using a recently described interleukin-15 (IL-15) transgenic mouse model of CTCL (Mishra A, et al. Can Discov 2016). Following two weeks of dosing in 5-week old mice, we found a significant decrease in gross lesion severity in tipifarnib-treated mice (0.5±1.22 out of a possible score of 5) compared to vehicle-treated mice (3.33±0.57, p=0.0076). Histologically, IL-15 transgenic mice develop characteristic malignant CD4+ T-cell infiltrates in the dermis and epidermis. Tipifarnib-treated mice, however, have minimal lesions in the skin. These dramatic changes are reflected in a significantly decreased histologic severity score in tipifarnib-treated mice (3.8±0.75 out of a possible score of 7 compared to vehicle-treated mice (7±0, p=0.0002). These findings demonstrate that tipifarnib is active in patient-derived cell lines and the mouse model of cutaneous T-cell lymphoma. Further studies to elucidate the mechanism of antitumor activity of farnesyl transferase inhibition in this cell type are in progress.
Citation Format: Rebecca Kohnken, Betina McNeil, Jing Wen, Kathleen McConnell, Francis Burrows, Pierluigi Porcu, Anjali Mishra. Preclinical activity of tipifarnib in cutaneous T-cell lymphoma [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 1873.
Abstract 1895: Landmark development of PI3K delta specific inhibitors for hematologic cancer therapeutics by data-driven drug design
Authors: Hong Suji , Kim Jong Woo , Lee Chi Woo 
Published: August 2018

Abstract
PI3K δ is hyper activated primarily in B cell malignancy and plays a central role in the malignant cell retention in proliferation, survival and homing at the lymphoid tissue and bone marrow in a variety of signaling pathways. Our BW compounds(BW-101, BW-108) are highly potent and selective PI3K δ inhibitors with marked selectivity over the other PI3K isoforms(α, β, γ). BW compounds are designed for the purpose of advancing the PI3K δ inhibition activity and overcoming the toxicities in which are hepatotoxicity and immunotoxicity due to small ratio of PI3K γ/PI3K δ. BW compounds are proven to be best-in-class in PI3K δ inhibition activity and to possess a bigger ratio of PI3K γ/PI3K δ related to the immunotoxicity than that of Idelalisib As small molecules, they inhibit PI3Kδ in the way of competing with ATP strongly at PI3Kδ binding site that issues in apoptosis of malignant B and T cell through blocking AKT down pathway. BW compounds have shown the good PK profiles in rat so that their in vivo efficacies were superior to those of Idelalisib in xenograft studies. Such a result demonstrated the therapeutic potential of these compounds in acute leukemia mediated via the PI3Kδpathway. In the side of toxicity, BW compounds also are showing desirable properties.
Citation Format: Suji Hong, Jong Woo Kim, Chi Woo Lee. Landmark development of PI3K delta specific inhibitors for hematologic cancer therapeutics by data-driven drug design [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 1895.
Abstract 1897: Determining the role of PRCP/PREP in triple negative breast cancer
Authors: Perez Ricardo E. , Duan Lei , Maki Carl G. 
Published: August 2018

Abstract
Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancer cases. Currently, the only effective treatment for TNBC is chemotherapy agents. A well-established characteristic of TNBC is the ability of these cells to become metastatic following chemotherapy treatment resulting in increased mortality. New forms of treatment which target TNBC are urgently needed. Insulin receptor substrate 1 (IRS1) has been extensively studied in the regulation of the insulin and insulin-like growth factor receptor signaling cascades, specifically in the induction of the intracellular PI3K/AKT/mTORC1 and MAP kinase pathways. The roles of such pathways in cancer are currently being studied and considered for therapeutic targeting. We previously showed that the stability and levels of IRS1 are maintained by prolylcarboxypeptidase proteins PRCP/PREP in pancreatic cancer cells. Our hypothesis is that PRCP/PREP are potential therapeutic targets in TNBC. Specifically, we hypothesize that blocking the expression or reducing the activity of PRCP/PREP will inhibit the PI3K/AKT/mTORC1 pathway in TNBC cells and, in turn, reduce growth and survival in these cells. To test this, we will be treating a number of TNBC cell lines with a PRCP/PREP inhibitor and determining IRS1/2 protein levels, AKT/mTORC1 signaling, and growth and survival. TNBC cells were screened for sensitivity against the PRCP/PREP inhibitor, Y-ox. Sensitive cells treated with Y-ox showed earlier reduction in the IRS1/AKT/mTORC1 signaling, as well as earlier loss of cell viability compared to those cells with relative resistance to Y-ox. Similarly, cells treated with the IRS1/2 inhibitor NT-157 and the AKT inhibitor, MK-2206 showed loss of cell viability similarly seen with the PRCP/PREP inhibitor, Y-ox. In conclusion, the results shown in this study show a possible new therapeutic target against triple negative breast cancer in the inhibition of PRCP/PREP leading to loss of cell proliferation and viability.
Citation Format: Ricardo E. Perez, Lei Duan, Carl G. Maki. Determining the role of PRCP/PREP in triple negative breast 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 1897.
Abstract 1904: Polyprenoic acid, the first-discovered hepatocyte nuclear factor 4 alpha agonist, inhibits multistep liver carcinogenesis
Authors: Yamashita Taro , Okada Hikari , Honda Masao , Kaneko Shuichi 
Published: August 2018

Abstract
Hepatocyte nuclear factor 4 alpha (HNF4α) is one of the most ancient nuclear receptors known as a master regulator of hepatocytes in lipids, carbohydrates, and drug metabolism. It also works as a tumor suppressor to regulate cell cycle in hepatocellular carcinoma (HCC), but the ligand activating HNF4α has not yet been discovered thus far. Here we evaluated the effect of polyprenoic acid (PA), formerly known as an acyclic retinoid, on HNF4α activation in dysplastic nodule and HCC in vitro and in vivo. PDGF-C transgenic (Tg) mice was evaluated by Gd-EOB-DTPA-enhanced MRI to examine the effect of PA on HCC development in vivo. Whole exome sequence analysis was performed using Illumina Hiseq 2000 system. Contrast enhanced CT scan data of patients enrolled in previous phase II/III randomized placebo-controlled study were collected and analyzed (n = 124 for PA and 127 for placebo). PA treatment regressed the liver dysplastic nodule and a subset of HCCs in PDGF-C Tg mice evaluated by MRI. This tumor regression was accompanied with the reduction of accumulated gene mutations, inactivation of cell cycle, and transcriptional activation of HNF4α-target genes. The binding of PA on ligand binding domain of HNF4α was shown by docking simulation in silico and immunoprecipitation-mass spectrometry analysis in vitro. Transcriptional activation of HNF4α by PA was also verified using a luciferase reporter assay and binding of HNF4α on DNA binding elements. PA treatment in HCC cells immediately resulted in the degradation of HNF4α by ubiquitin-proteasome system with activation of DNA damage responses when cultured in lipid depleted medium. In vivo knockdown of HNF4A cancelled the effect of PA on regression of liver tumor growth in PDGF-C Tg mice. PA treatment (600 mg/day) suppressed the HCC development from dysplastic nodule compared with placebo in human with statistical significance (HR 0.41; 95% CI, 0.17~0.98, P = 0.046). Taken together, our data indicated that PA is the first-discovered HNF4α ligand to activate its function. PA activates the DNA damage responses and suppresses the accumulation of gene mutations especially in dysplastic nodule, warranting the future prospective study to evaluate the effect of PA on suppression of HCC development from dysplastic nodules in human.
Citation Format: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko. Polyprenoic acid, the first-discovered hepatocyte nuclear factor 4 alpha agonist, inhibits multistep liver carcinogenesis [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 1904.
Abstract 1915: Validation of ero1l as a therapeutic target for the treatment of multiple myeloma
Authors: Chen Weichih , Geldenhuys Werner , Hazlehurst Lori 
Published: August 2018

Abstract
Validation of ERO1L as a therapeutic target for the treatment of multiple myeloma
Wei-Chih Chen1, Werner Geldenhuys1 and Lori Hazlehurst1,2,3
1. Department of Pharmaceutical Sciences, School of Pharmacy.
2. Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University.
3. West Virginia University Cancer Institute, Morgantown, WV, USA.
Multiple myeloma (MM) is a hematologic malignancy of plasma cells and remains an incurable disease. MM is exquisitely sensitive to agents which induce ER stress including inhibitors that target the proteasome such as Bortezomib. However, MM patients eventually relapse with drug resistant disease, indicating that additional therapies are required to improve patient outcomes. Endoplasmic reticulum oxidase 1-alpha (ERO1L) is an endoplasmic reticulum (ER) resident protein that plays a critical role in disulfide bonds formation and contributes to proper folding of secretory proteins. High expression of ERO1L has been reported to be associated with poor prognosis in several cancer indications. However, the role of ERO1L in MM remains unclear. Our data indicate the ERO1L expression is increased in MM cells compared to normal controls. Because MM cells are known to secrete high levels of paraprotein resulting in basal ER stress, we investigated the role of ERO1L in tumor growth. Our data indicate that overexpression of ERO1L in U266 MM cells enhanced cell growth using both in vitro and in vivo models. Moreover, inducible reduction of ERO1L using shRNA strategies inhibited colony formation in U266 cells. Using a pharmacological inhibitor of, ERO1L referred to as EN460, we show that inhibition of ERO1L induced markers of ER stress and triggered apoptosis. Together our findings indicate that ERO1L maybe a tractable strategy for the treatment of MM.
Keywords: multiple myeloma (MM), endoplasmic reticulum oxidase 1 alpha (ERO1L)
Citation Format: Weichih Chen, Werner Geldenhuys, Lori Hazlehurst. Validation of ero1l as a therapeutic target 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 1915.
Abstract 1922: Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma
Authors: Yokota Etsuko , Yamatsuji Tomoki , Takaoka Munenori , Haisa Minoru , Takigawa Nagio , Miyake Noriko , Ikeda Tomoko , Mori Tomoaki , Serika Ohno , Sera Takashi , Fukazawa Takuya , Naomoto Yoshio 
Published: August 2018

Abstract
S0X2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad- ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC.
Citation Format: Etsuko Yokota, Tomoki Yamatsuji, Munenori Takaoka, Minoru Haisa, Nagio Takigawa, Noriko Miyake, Tomoko Ikeda, Tomoaki Mori, Ohno Serika, Takashi Sera, Takuya Fukazawa, Yoshio Naomoto. Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and 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 1922.
Abstract 1941: Constitutive IRAK4 activation contributes to NF-κB activity and chemoresistance in colorectal cancer
Authors: Li Qiong , Li Lin , Zhang Daoxiang , Jiang Hongmei , Wang-Gillam Andrea , Ruzinova Marianna B. , Lim Kian-Huat 
Published: August 2018

Abstract
Aberrant activation of the NF-κB transcription factors is a major molecular mechanism that contributes to the aggressive behavior and treatment resistance of colorectal cancer (CRC). Understanding how these factors are activated will provide novel therapeutic opportunities to improve treatment response and outcome of CRC patients. In the present study, we showed that the Interleukin-1 Receptor-Associated Kinases 1 and 4 (IRAK1 and IRAK4) are constitutively activated by phosphorylation in a majority of CRC cell lines and patients samples. Notably, we observe significant positive correlation between phospho-IRAK4 and phospho-NF-kb/p65 staining by immunohistochemistry in patient CRC samples. Moreover, we showed that pharmacologic IRAK4 inhibitors dose-dependently suppressed phosphorylated -IRAK1, -IRAK4 and -IKKa/b by western blots, as well as significantly reducing NF-κB-driven luciferase activity in CRC cells. Furthermore, IRAK4 inhibitor dose dependently inhibit colony formation and anchorage-independent (AI) growth of CRC cells in soft agar. In three CRC cell lines, we observed various degrees of synergism between IRAK4 inhibitors and each chemotherapeutic agents including 5-FU, oxaliplatin and irinotecan, mainly through induction of apoptosis. Lastly, we showed that IRAK4 inhibitor augments the therapeutic effect of 5-FU and oxaliplatin in nude mice bearing CRC xenografts. Together, our data established IRAK4 kinase inhibitors as a promising novel class of targeted agent in CRC.
Citation Format: Qiong Li, Lin Li, Daoxiang Zhang, Hongmei Jiang, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Constitutive IRAK4 activation contributes to NF-κB activity and chemoresistance in colorectal 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 1941.
Abstract 1954: Functional analyses of CLDN18-ARHGAP26 fusion gene in gastric cancers
Authors: Nakayama Izuma , Shinozaki Eiji , Mashima Tetsuo , Kawaguchi Tokuichi , Sakata Seiji , Yamamoto Noriko , Baba Satoko , Dobashi Akito , Togashi Yuki , Sugawara Minoru , Takahashi Shunji , Yamaguchi Kensei , Takeuchi Kengo , Noda Tetsuo 
Published: August 2018

Abstract
[Introduction]Comprehensive molecular analyses by TCGA have classified Gastric Cancers (GC) into 4 groups: EB virus -associated (EBV), Microsatellite instability (MSI), Genomically stable (GS) and Chromosomal instability (CIN). Among these 4 subtypes, patients with GS subtype have few actionable genetic alterations and thus a limited number of molecular-targeted treatments are available. A fusion gene between CLDN18 and ARHGAP26 was first reported by TCGA to be enriched in GS subtype (13.8%), but the prospective functions of this gene product remain unknown.
[Methods]We have previously established 124 GC-Patient derived xenografts (PDXs) from surgically resected specimens in our institute. There are various types of GCs in the PDX panel, including intestinal and diffuse type tumors or tumors of primary and metastatic site. In an attempt to assess roles of CLDN18-ARHGAP26 fusion gene in gastric cancers, we used the cultured cells obtained from GC-PDXs. We first prepared tissue micro-array of formalin-fixed and paraffin-embedded (FFPE) specimen of PDXs and screened for the patients harboring a CLDN18-ARHGAP26 fusion genes by FISH and RT-PCR. In addition, fusion positive cases were sequenced to determine the breakpoints by direct sequencing. Then, we conducted several functional analyses, including assays for cellular proliferation and mobility, by RNAi-knockdown experiments.
[Results]Among 124 GC-PDXs, we detected two CLDN18-ARHGAP26 fusion positive cases. Both of these 2 cases were derived from tumors with diffuse-type GC patient and had identical breakpoint between CLDN18 (exon 5) and ARHGAP26 (exon 10). We successfully established cell lines of these 2 cases. Furthermore, we would verify that PDX derived cells preserved the original patient properties, as transplantation of the PDX-derived cells histologically recapitulated the original tumors. To address its function, we introduced siRNA into cultured cells to reduce their protein levels. Our data so far indicate that the CLDN18-ARHGAP26 fusion might promote anchorage independent cell growth.
[Conclusion] The CLDN18-ARHGAP26 fusion gene potentially contributes to malignant phenotypes of GC. Further analyses in vivo are awaited.
Citation Format: Izuma Nakayama, Eiji Shinozaki, Tetsuo Mashima, Tokuichi Kawaguchi, Seiji Sakata, Noriko Yamamoto, Satoko Baba, Akito Dobashi, Yuki Togashi, Minoru Sugawara, Shunji Takahashi, Kensei Yamaguchi, Kengo Takeuchi, Tetsuo Noda. Functional analyses of CLDN18-ARHGAP26 fusion gene in gastric cancers [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 1954.
Abstract 1976: Identification of 4 novel markers in the chemotherapy resistance of esophageal adenocarcinoma
Authors: Fleegel Jonathan P. , Abdo Joeseph , Agrawal Devendra 
Published: August 2018

Abstract
Esophageal adenocarcinoma (EAC) has seen a steady and steep rise in prevalence since the 1970's. This increase in incidence is correlated with the increase in gastro-esophageal reflux disease and Barrett's esophagus (BE). Unfortunately, where many other cancers have seen progress with advancements in treatments, EAC has not. This cancer is very resistant to almost all first line chemotherapy treatments including the most common platinum based treatments. Although few targeted therapies have been developed, they only show a modest survival advantage for eligible individuals and are not commonly integrated into patient treatment regimens. In our study, we have identified several markers associated with resistance to platinum based chemotherapies that have not previously been documented in EAC. Our study utilized a large-scale discovery mass spectrometric experiment such that the proteome of the 3 different tissue samples could be analyzed, (EAC, BE, and Normal). Part of the novelty of our experiment was that all the tissues collected were from esophagetomies of patients before they had received any chemotherapy. From the data generated we have identified 4 novel markers that are overexpressed in the BE and EAC tissue compared to the normal tissue. In BE tissue DAD1 was over expressed in 9/10 samples, ISG15 (10/10), S100P (10/10) and UBE2N (10/10). In the EAC samples, DAD1 was significantly overexpressed in 20 /20 samples, ISG15 (20/20), S100P (20/20) and UBE2N (19/20). DAD1 inhibits apoptosis and is upregulated by cisplatin and then contributes to cisplatin resistance. S100P has been shown to increase drug resistance in gastric cancer and decrease chemosensitivity 5-FU in vitro in colorectal cancer cells while facilitating proliferation and inhibiting apoptosis. UBE2N plays a role in glycolytic control and in various cellular damage responses. And ISG15 is important in development and metastatic progression of adenocarcinomas through the enhancement of cancer stem cells. We are confident that expression of these four markers can provide clinical utility in assessment of at risk patients with Barrett's esophagus while simultaneously informing treatment regimens. Our goal is to investigate the specific mechanisms by which these markers contribute to cancerous development and chemotherapy resistance in order to elucidate targets for future treatment of EAC.
Citation Format: Jonathan P. Fleegel, Joeseph Abdo, Devendra Agrawal. Identification of 4 novel markers in the chemotherapy resistance of esophageal adenocarcinoma [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 1976.