bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2560: Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells
Authors: Lieb Simone , Blaha-Ostermann Silvia , Kamper Elisabeth , Ehrenhöfer-Wölfer Katharina , Schlattl Andreas , Wernitznig Andreas , Lipp Jesse , Nagasaka Kota , Bader Gerd , Neumueller Ralph , Kraut Norbert , Pearson Mark , Woehrle Simon , Petronczki Mark 
Published: August 2019

Abstract
Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent large-scale genomic profiling and functional screening of cancer cell lines we identified Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair is frequently detected in human malignancies, in particular in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in the emergence of chromosome breaks, chromatin bridges and micronuclei highlighting defective genome integrity. WRN variants harboring mutations abrogating the ATPase function of WRN helicase fail to rescue the viability phenotype of WRN-depleted MSI-H colorectal cells. Our study suggests that pharmacological inhibition of WRN helicase function might represent a novel opportunity to develop a targeted therapy for MSI-H cancers.
Citation Format: Simone Lieb, Silvia Blaha-Ostermann, Elisabeth Kamper, Katharina Ehrenhöfer-Wölfer, Andreas Schlattl, Andreas Wernitznig, Jesse Lipp, Kota Nagasaka, Gerd Bader, Ralph Neumueller, Norbert Kraut, Mark Pearson, Simon Woehrle, Mark Petronczki. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2560.
Abstract 2565: Type I interferons enhance chemosensitivity of breast cancer by inhibiting DNA repair
Authors: Ka Na-Lee , Lim Ga Young , Lee Mi-Ock 
Published: August 2019

Abstract
Type I interferons (IFNs) are known to have antineoplastic effects against several tumors by stimulating anticancer immune response. In this study, we identified a novel function of type I IFNs in DNA repair, which enhanced chemosensitivity in breast cancer cells. We investigated that IFNα and IFNβ inhibited both non-homologous recombination and homologous recombination double strand breaks repair. Moreover, IFNs accelerated the release of DNA into the cytoplasm in response to DNA damaging agent, doxorubicin. In agreement, IFNs synergistically activated DNA damage-induced STING pathway and increased the production of chemokines, CCL5 and CXCL11. In agreement, IFNβ greatly increased the sensitivity of cells to doxorubicin-induced suppression of cell survival. This sensitizing effect of IFNβ was also supported by in vivo xenograft experiments. Thus, combination therapy with chemotherapeutic agents and IFNs may be effective against breast cancer, particularly in patients with defective in DNA damage response pathways. The downstream effectors that modulate the effect of IFNs should be investigated as predictive biomarker in the treatment of breast cancer.
Citation Format: Na-Lee Ka, Ga Young Lim, Mi-Ock Lee. Type I interferons enhance chemosensitivity of breast cancer by inhibiting DNA repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2565.
Abstract 2566: CYT01B suppresses RAD51 focus formation and induces replication catastrophe following AID induced DNA damage
Authors: Day Melinda , Cyr Amber , Maclay Tyler , Mills Kevin 
Published: August 2019

Abstract
Activation Induced Cytidine Deaminase (AID) is a DNA-directed cytidine deaminase that plays a critical role in somatic hypermutation and immunoglobulin class switching in activated B- lymphocytes. AID is often ectopically expressed and promotes genomic hypermutation in a range of lymphoid malignancies. Deamination of genomic cytidines results in point mutations, single strand DNA breaks (SSB), and double strand DNA breaks (DSB). The resulting DNA damage stress leads to an obligate dependency on homologous recombination for cellular survival. RAD51 is a critical component of the homologous recombination pathway, forming nucleoprotein filaments at sites of DNA damage or replication fork stalls. RAD51 mediates homologous DNA strand exchange to promote recombinational repair of breaks and damaged replication forks. We have previously shown that RAD51 depletion leads to accumulation of DNA breaks, and ultimately cell death, in AID expressing cells. We now describe the mechanism of action for a novel small molecule, CYT01B, that targets RAD51 mediated recombination. Treatment of AID-expressing cells with CYT01B, attenuates RAD51 focus formation, reduces the nuclear concentration of RAD51, and promotes RAD51 protein degradation. CYT01B reduces homologous recombination activity in cells, culminating in cytologically visible chromosome fragmentation following DNA damage. Finally, CYT01B treated cells undergo replication catastrophe associated with caspase 3/7 activation and persistent PCNA nuclear signal. We conclude that CYT01B is a novel homologous recombination inhibitor, and propose a new synthetic lethality mechanism, induced by CYT01B, mediated by DNA replication stress and replication catastrophe.
Citation Format: Melinda Day, Amber Cyr, Tyler Maclay, Kevin Mills. CYT01B suppresses RAD51 focus formation and induces replication catastrophe following AID induced DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2566.
Abstract 2574: Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability
Authors: Kategaya Lorn , Perumal Senthil K. , Hager Jeffrey H. , Belmont Lisa D. 
Published: August 2019

Abstract
Werner Syndrome protein (WRN) is a RecQ enzyme involved in the maintenance of genome integrity. Germline loss of function mutations in WRN lead to premature aging and pre-disposition to cancer. We evaluated synthetic lethality (SL) between not only of WRN, but also of another human RecQ helicase, BLM, with DNA damage response genes in cancer cell lines. We found that WRN exhibited SL with a DNA mismatch repair protein MutL homolog 1 (MLH1), loss of which is associated with high microsatellite instability (MSI-H). We then demonstrated that MSI-H cells exhibited increased double-stranded DNA breaks, altered cell cycles and decreased viability in response to WRN knockdown. Although WRN is the only human RecQ enzyme with a distinct exonuclease domain, only loss of helicase activity drives the MSI SL interaction. This SL interaction in MSI cancer cells positions WRN as a relevant therapeutic target in patients with MSI-H tumors.
Citation Format: Lorn Kategaya, Senthil K. Perumal, Jeffrey H. Hager, Lisa D. Belmont. Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2574.
Abstract 2585: The development of a novel microRNA replacement therapy for ovarian cancer - a potential of patient derived-exosomes as a carrier
Authors: Kobayashi Masaki , Sawada Kenjiro , Shimizu Aasa , Miyamoto Mayuko , Nakatsuka Erika , Kawano Mahiru , Matsumoto Yuri , Kodama Michiko , Hashimoto Kae , Mabuchi Seiji , Kimura Tadashi 
Published: August 2019

Abstract
Objective: microRNAs (miRNAs) affect key features of cancer cells and some are identified as tumor suppressor (TS) miRNAs. In spite of many preclinical studies with promising results, all translational clinical trials with TS miRNAs have failed due to the difficulties of miRNA systemic delivery. Therefore, the development of a novel carrier is urgently needed. Exosomes, non-sized vesicles secreted from cells, are stable in body fluid and therefore can serve as a promising candidate for miRNA carrier. In ovarian cancer treatment, omentum should be taken at surgery and normal fibroblasts can be collected from omentum. The aim of this study is to pursue the possibility of fibroblast derived-exosomes as a carrier for miRNA replacement therapy to treat ovarian cancer.
Methods: At surgery, omentum was collected and fibroblasts were primary cultured. Thereafter, exosomes were collected from culture media. miR-199a-3p was selected as a TS miRNA. Synthesized miR-199a-3p was corporated into exosomes by electroporation. miR-199a-3p-loaded exosomes (M199-exosomes) were treated with ovarian cancer cells and the expression levels of miR-199a-3p and target genes were assessed. The treatment effect of M199-exosomes was analyzed focusing on peritoneal dissemination.
Results: The treatment of M199-exosomes drastically increased miR-199a-3p expression in ovarian cancer cells (CaOV3; 8592-fold, SKOV3; 67188-fold, OVCAR3; 2280-fold). Treatment with M199-exosomes suppressed c-Met expression and significantly inhibited the proliferation and invasion of ovarian cancer cells in vitro (P&lt;0.01). In a xenograft study, M199-exosomes significantly inhibited peritoneal dissemination and extended the survival of mice.
Citation Format: Masaki Kobayashi, Kenjiro Sawada, Aasa Shimizu, Mayuko Miyamoto, Erika Nakatsuka, Mahiru Kawano, Yuri Matsumoto, Michiko Kodama, Kae Hashimoto, Seiji Mabuchi, Tadashi Kimura. The development of a novel microRNA replacement therapy for ovarian cancer - a potential of patient derived-exosomes as a carrier [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2585.
Abstract 2586: Therapeutic potential of the topical treatment of miR-634 ointment for cutaneous squamous cell carcinoma
Authors: Inoue Jun , Gokita Kentaro , Kishikawa Masahiro , Hamamoto Hidetoshi , Kobayashi Katsunori , Fujiwara Kyoko , Asakage Takahiro , Kojima Kazuyuki , Inazawa Johji 
Published: August 2019

Abstract
Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancers. Surgery represents the gold standard for CSCC treatment, however it is needed to develop the noninvasive and effective treatments as the nonsurgical options for CSCC patients whose conditions are not suitable for or who refuse operation. On the other hand, microRNAs (miRs) are endogenous small non-coding RNAs negatively regulate gene expression by interfering with the translation or stability of target transcripts. Some tumor-suppressive miRs can target multiple cancer-promoting genes concurrently and may be useful as a therapeutic agent for cancer therapy. We have previously found that overexpression of miR-634 activated the mitochondrial apoptotic pathway by directly targeting genes associated with cytoprotective processes, including mitochondrial homeostasis, anti-apoptosis, antioxidant ability, and autophagy, in various cancer cells. The development of drug delivery system (DDS) is critical for the implementation of miR-based therapeutics. While topical pharmacotherapy represents a nonsurgical option to consider in CSCC, we validated the therapeutic potential of topical treatment of miR-634 ointment in mice model of CSCC. In xenograft tumors of A431 cells, a human epidermoid carcinoma cell line, in mice the topical treatment of ointment incorporated double-strand miR-634 mimics significantly reduced tumor growth. Furthermore, the topical treatment of miR-634-ointment also inhibited tumor growth in carcinogen-induced mouse skin papilloma model. Taken together, these findings suggest that topical treatment of miR-634-ointment may be useful as a noninvasive and effective treatments for CSCC.
Citation Format: Jun Inoue, Kentaro Gokita, Masahiro Kishikawa, Hidetoshi Hamamoto, Katsunori Kobayashi, Kyoko Fujiwara, Takahiro Asakage, Kazuyuki Kojima, Johji Inazawa. Therapeutic potential of the topical treatment of miR-634 ointment for cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2586.
Abstract 26: Development of potent lead compounds in multiple tumor types
Authors: Raj Ganesh V. , Liu Xihui , Ekoue Dede , Ahn Jung-Mo , Vadlamudi Ratna 
Published: August 2019

Abstract
Background: We had earlier reported a novel therapeutic agent, ERX-11, that modulates estrogen receptor coregulator interactions. For lead optimization, we designed, synthesized and tested over 500 analogs of ERX-11 in multiple models of BC. We also tested this library of compounds for activity against other cancer cell lines both in vitro and in vivo and against primary tumors ex vivo.
Methods: In vitro activity was tested using Cell titer glo, MTT, and apoptosis assays.The utility of the ERX analogs in treating therapy resistant ER-positive BC was evaluated using models with acquired resistance (Tamoxifen, Letrozole), and engineered models that express ER mutations. Xenografts were used for testing the utility of ERX analogs in vivo. Primary patient tumor derived explants were used for ex vivo testing of ERX analogs.
Results: Our screening studies identified several ERX analogs with potent activity against BC cells. Subtle changes in the ERX analogs appear to have significant ramifications on both their potency against ER+ BC cell lines and against other tumors types. Some analogs like ERX-41 were more potent than ERX-11 in their ability to block the proliferation of multiple ER-positive BC cell lines (IC50 ranging from 20-200nM). Other analogs like ERX-208 showed similar activity as ERX-11 against ER-positive BC cell lines (IC50 ranging from 100-500nM) but had potent activity against ovarian cancer cell lines. Through iterative changes, we have identified leads compounds with significant activity against other cancers, including in gliomas, ovarian and pancreatic cancers. Although all these compounds were designed to better target the ligand binding pocket of ER, these active compounds do not all target ER and appear to target other proteins, including other nuclear receptors. Some compounds for example have activity in ER-negative breast cancers. In several xenograft models, including pancreatic cancer and ER-negative, the activity of the compounds have been confirmed by oral administration of the ERX analog in vivo. We have also validated the activity of these analogs in patient-derived explants cultured ex vivoin multiple tumor types.
Conclusions: From our studies to develop a more potent ERX-11 lead analog, we have identified multiple analogs with distinct activities against multiple cancers. While the intended target of these analogs was ER, our library of analogs has potent activity against both ER-positive and ER-negative tumors. In collaboration, we are pursuing further leads in multiple cancers to further delineate the mechanism of action of these various analogs.
Citation Format: Ganesh V. Raj, Xihui Liu, Dede Ekoue, Jung-Mo Ahn, Ratna Vadlamudi. Development of potent lead compounds in multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 26.
Abstract 2600: Interaction of host cell factor-1 with the oncoprotein transcription factor MYC
Authors: Popay Tessa M. , Thomas Lance R. , Wang Jing , Liu Qi , Tansey William P. 
Published: August 2019

Abstract
Host cell factor (HCF)-1 is a highly-conserved epigenetic scaffolding protein that is essential for development, cell cycle progression, and cellular proliferation. Through integration into several chromatin modifying complexes, HCF-1 plays a critical role in regulating the activity of key transcription factors, such as the E2F family of proteins. HCF-1 is also linked to leukemogenesis, through its regulation by the BAP1 tumor suppressor and its incorporation into the oncogenic MLL complex. Despite its role in the cell cycle, presence at chromatin, and well-defined interactions, the function of HCF-1 in cancer remains under-studied and undetermined. Here we describe the role of HCF-1 in the context of its interaction with the transcription factor and oncoprotein MYC. MYC is overexpressed in most cancers and drives tumorigenesis by regulating the expression of genes involved in ribosome biogenesis, cell growth, and metabolism. The region of MYC responsible for interaction with HCF-1 is evolutionarily conserved in all vertebrate MYC family members, and we have previously demonstrated that mutations in MYC that selectively disable interaction with HCF-1 attenuate the tumorigenicity of MYC in vivo. This demonstrates that HCF-1 is an important co-factor for MYC-driven cancer. Using a battery of contemporary genomic approaches, including ChIP-seq, SLAM-seq, RNA-seq, and PRO-seq, coupled to a decisive CRISPR/Cas9 editing approach, we reveal the relationship of MYC and HCF-1 at chromatin and how this modulates the function of MYC as a transcription factor and oncoprotein.
Citation Format: Tessa M. Popay, Lance R. Thomas, Jing Wang, Qi Liu, William P. Tansey. Interaction of host cell factor-1 with the oncoprotein transcription factor MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2600.
Abstract 2603: Herbal extract SH003 suppresses tumor growth and metastasis of MDA-MB-231 breast cancer cells by inhibiting STAT3-IL-6 signaling
Authors: Choi Yu-Jeong , Kim Myeong-Sun , Kang SooYeon , Lee Seo Yeon , Kim Ji Hye , Choi Youn Kyung , Oh Sukjoong , Ko Seong-Gyu 
Published: August 2019

Abstract
Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.
Citation Format: Yu-Jeong Choi, Myeong-Sun Kim, SooYeon Kang, Seo Yeon Lee, Ji Hye Kim, Youn Kyung Choi, Sukjoong Oh, Seong-Gyu Ko. Herbal extract SH003 suppresses tumor growth and metastasis of MDA-MB-231 breast cancer cells by inhibiting STAT3-IL-6 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2603.
Abstract 2604: Constitutive activation of the human aryl hydrocarbon receptor in mice promotes hepatocarcinogenesis independent of its coactivator Gadd45b
Authors: Lu Peipei , Cai Xinran , Fang Zihui , Xie Wen 
Published: August 2019

Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared to the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Peipei Lu, Xinran Cai, Zihui Fang, Wen Xie. Constitutive activation of the human aryl hydrocarbon receptor in mice promotes hepatocarcinogenesis independent of its coactivator Gadd45b [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2604.
Abstract 2608: EGF signaling activates a TAZ-driven oncogenic program in glioblastoma
Authors: Gao Minling , Fu Yi , John Laterra , Ying Mingyao 
Published: August 2019

Abstract
Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor in humans. Hyperactivation of the signaling pathway driven by the epidermal growth factor (EGF) and its receptor (EGFR) are commonly occurring in GBM. The oncogenic transcriptional program driven by EGF signaling is still incompletely understood in GBM. Here, we found that EGF induces the upregulation and nuclear translocation of TAZ, an oncogenic transcriptional co-activator. TAZ and its paralog gene YAP are commonly known as downstream mediators of the Hippo signaling pathway. TAZ has been found as a driver of mesenchymal transition in GBM cells and promotes GBM radioresistance. Our results support that EGF induces TAZ transcription and the activation of TAZ gene targets, through the signaling axis including EGFR, STAT3 and ERK. EGFRvIII is the most frequently occurring EGFR mutation in GBM causing constitutively active EGFR. We found that EGFRvIII causes EGF-independent activation of TAZ and its downstream oncogenic targets. Next, we used next-generation sequencing to establish a genome-wide map of TAZ gene targets in GBM cells after EGF stimulation. The results suggest that EGF signaling activates a TAZ-driven oncogenic program including autocrine and paracrine factors that promote GBM growth, angiogenesis, stemness and immunoescape. Moreover, we found that TAZ targeting by shRNAs or the FDA-approved drug Verteporfin effectively inhibits the TAZ-driven oncogenic program activated by EGF stimulation or the EGFRvIII mutant. TAZ targeting also inhibits GBM cell growth and xenograft formation. In contrast, enforced TAZ induces the TAZ-driven oncogenic program and promotes GBM cell growth and xenograft formation. In conclusion, our results reveal a novel TAZ-driven oncogenic program that is activated by EGF signaling in GBM. Our discoveries strongly support TAZ as a therapeutic target for GBM and likely other human cancer with hyperactivation of EGF signaling. Our preclinical studies also provide a clinically translatable strategy for GBM therapy based on using the FDA-approved drug Verteporfin.
Citation Format: Minling Gao, Yi Fu, Laterra John, Mingyao Ying. EGF signaling activates a TAZ-driven oncogenic program in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2608.