bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-062: Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles
Authors: Teesalu Tambet , Hedi Hunt , Simón-Gracia Lorena , Tobi Allan , Sugahara Kazuki N. , Sharma Shweta , Ruoslahti Erkki 
Published: July 2017

Abstract
Gastrointestinal and gynecological malignancies disseminate loco-regionally in the peritoneal cavity - a condition known as peritoneal carcinomatosis (PC). Intraperitoneal (IP) administration can be used to improve therapeutic index of anticancer drugs used for PC treatment. Activity of IP anticancer drugs can be further potentiated by encapsulation in nanocarriers and/or affinity targeting with tumor-specific affinity ligands, such as tumor homing peptides. Here we evaluated a novel tumor penetrating peptide, linTT1 (AKRGARSTA), as a PC targeting ligand for nanoparticles. We first demonstrated that the primary homing receptor for linTT1, p32 (or gC1qR), is expressed on the cell surface of peritoneal carcinoma cell lines of gastric (MKN-45P), ovarian (SKOV-3), and colon (CT-26) origin, and that peritoneal tumors in mice and clinical peritoneal carcinoma explants express p32 protein accessible from the IP space. Iron oxide nanoworms (NWs) functionalized with the linTT1 peptide were taken up and routed to mitochondria in cultured PC cells. NWs functionalized with linTT1 peptide in tandem with a pro-apoptotic [D(KLAKLAK)2] peptide showed p32-dependent cytotoxicity in MKN-45P, SKOV-3, and CT-26 cells. Upon IP administration in mice bearing MKN-45P, SKOV-3, and CT-26 tumors, linTT1-functionalized NWs showed robust homing and penetration into malignant lesions, whereas only a background accumulation was seen in control tissues. In tumors, the linTT1-NW accumulation was seen predominantly in CD31-positive blood vessels, in LYVE-1-positive lymphatic structures, and in CD11b-positive tumor macrophages. Experimental therapy of mice bearing peritoneal MKN-45P xenografts and CT-26 syngeneic tumors with IP linTT1- D(KLAKLAK)2-NWs resulted in significant reduction of weight of peritoneal tumors and significant decrease in the number of metastatic tumor nodules, whereas treatment with untargeted D(KLAKLAK)2-NWs had no effect. Our data show that targeting of p32 with linTT1 tumor-penetrating peptide improves tumor selectivity and antitumor efficacy of IP pro-apoptotic NWs. P32-directed intraperitoneal targeting of other anticancer agents and nanoparticles using peptides and other affinity ligands may represent a general strategy to increase their therapeutic index.
Citation Format: Tambet Teesalu, Hunt Hedi, Lorena Simón-Gracia, Allan Tobi, Kazuki N. Sugahara, Shweta Sharma, Erkki Ruoslahti. Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-062. doi:10.1158/1538-7445.AM2017-LB-062
Abstract LB-067: Design, synthesis and biological evaluation of novel selenocyanide histone deacetylase inhibitor as anti-triple negative breast cancer agents
Authors: Tang Chu , Du Yang , Tian Jie 
Published: July 2017

Abstract
Approximate 70-80% of breast cancers are estrogen receptor positive (ER+), and the ERα plays essential role in breast cancer growth. Therefore, many ERα ligands have been developed for hormone drugs, such as tamoxifen, which is the first line drug for the treatment of ER(+) breast cancer. Unfortunately, endocrine therapy is ineffective for triple-negative breast cancer (TNBC), which lacks of expression of ER, PR and HER-2, representing about 20% of breast cancers. Current treatment option for TNBC is still limited to cytotoxic chemotherapy, and histone deacetylase inhibitor (HDACi) was used as novel therapeutic strategy for TNBC. HDACi can induce functional ERα re-expression and re-sensitize cells of TNBC to estradiol activator and tamoxifen antagonist. More than ten clinical trials of HDACi are underway for the treatment of TNBC, and most of HDAC inhibitors have the hydroxamic acid moiety, a typical zinc-binding group. However, these inhibitors do not show significant anticancer effects on TNBC compared to SAHA, which is the first HDACi approved by FDA. Hydroxamic acids usually have pharmacokinetic and metabolic problems, and also SAHA shows considerable toxicity to healthy cells. Therefore, much effort has been undertaken to develop an “ideal HDACi”, more effective and less toxic. We recently found that zinc-binding group of HDACi is selenocyanide (named as SelA), which shows strong anti-HDAC1, HDAC6 and HDAC8. These three isoforms have been found to be critical for the invasion and migration of both ER(+) breast cancer and TNBC activities, with a nanomolar range of IC50, and demonstrate high selectivity for HDAC6; moreover, SelA also displays significant anti-proliferative effect on both ER(+) breast cancer and TNBC both in vitro and in vivo. In summary, selenocyanide compound represents a novel HDACi for the treatment of TNBC, and the structure-activity relation is pursuing.
Citation Format: Chu Tang, Yang Du, Jie Tian. Design, synthesis and biological evaluation of novel selenocyanide histone deacetylase inhibitor as anti-triple negative breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-067. doi:10.1158/1538-7445.AM2017-LB-067
Abstract LB-069: In vivo delivery of asymmetric gene-silencing RNAs targeting CTNNB1 and PD-L1 show a broad spectrum of potent antitumor activities in preclinical cancer models
Authors: Li Youzhi , Gao Yuan , Wang Yuxin , Su Jie , Hsu Eric , Wybieralska Ewa , Huang Janet , Gada Keyur , Oishi Jun , Dai Xiaoshu , Koga Erina , Li Wei , Sun Xiangao , Brooks Emily , Li Chiang J. 
Published: July 2017

Abstract
RNAi (RNA interference) technology has the potential to target any genes causing disease, including conventionally “undruggable” targets in cancer. We previously discovered aiRNA (asymmetric interfering RNA), a next generation of gene-silencing technology with improved gene silencing efficiency and reduced off-target effects in comparison with siRNA. We have recently developed a nanoscale formulation that encapsulates therapeutic aiRNAs targeting CTNNB1 and PD-L1, named BBI-801. Here we investigate the in vivo delivery and antitumor activity of BBI-801 encapsulating aiRNAs targeting CTNNB1 and PD-L1. CTNNB1 encodes undruggable β-catenin which is a cancer stemness gene that is broadly implicated in multiple cancer types PD-L1 gene encodes a key immune checkpoint factor that mediates cancer immune evasion. In our in vivo studies, we have achieved prolong silencing of β-Catenin/PD-L1 mRNA and protein in a dose-dependent manner in a wide variety of murine tumor models, including subcutaneous human tumor xenografts, orthotopic human liver and lung tumors, as well as syngeneic mouse colorectal, breast and lung tumors. Our biodistribution analysis of fluorescence-labeled aiRNA demonstrated that the delivery of BBI-801 to xenograft tumors happens within 5 minutes of aiRNA administration and lasts at least 8 hours. In all the models we examined, significant tumor growth inhibition by BBI-801 was achieved not only in β-Catenin over-expressed colorectal tumor models, SW480 and APCmin, but also in the rest of β-Catenin normal-expressed tumor models. Finally, BBI-801 is well tolerated and no signs of toxicity were observed after repeated dosing. These exciting data support further investigation of the anti-tumor potential of BBI-801 as an anticancer therapeutic in variety of tumor indications.
Citation Format: Youzhi Li, Yuan Gao, Yuxin Wang, Jie Su, Eric Hsu, Ewa Wybieralska, Janet Huang, Keyur Gada, Jun Oishi, Xiaoshu Dai, Erina Koga, Wei Li, Xiangao Sun, Emily Brooks, Chiang J. Li. In vivo delivery of asymmetric gene-silencing RNAs targeting CTNNB1 and PD-L1 show a broad spectrum of potent antitumor activities in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-069. doi:10.1158/1538-7445.AM2017-LB-069
Abstract LB-071: A facile strategy for exosome labeling and tracking
Authors: Kim Young , Lee Tae-Sup , Tung Ching H. 
Published: July 2017

Abstract
Exosomes are extracellular vesicles of endocytic origin with a size range of 40-150 nm and a lipid bilayer membrane. Though exosomes are known as dynamic mediators of intercellular communication, its characteristics and function have not been fully studied. In this report, we used a metabolic labeling method to prepare fluorescent exosomes to investigate the characteristics and the movement of exosomes derived from various breast cancer cells. MCF-7 and MDA-MB-231 cells were treated with three types of azido sugars, Ac4ManNAz, Ac4GalNAz, or Ac4GlcNAz (50 μM), for 3 days to produce the azide (-N3) containing exosomes through metabolic glycosylation. It is confirmed that the azido sugar decorated exosomes were able to maintain their original characteristics such as size, lipid bilayer morphology, and protein profile. The collected exosomes were labeled with Adibo-cy3 and Adibo-cy5.5 fluorescence dyes using copper-free click chemistry. The exosomes prepared with Ac4ManNAz have shown the highest labeling efficiency, in MCF-7 and MDA-MB-231 cells at 17.2% and 14.8%, respectively. To study their homing capability, the labeled exosomes from different origins were incubated with a panel of breast cancer cells, including MCF-7, MDA-MB-231, MDA-MB-468 and BT-549, and normal NIH/3T3 fibroblast cells for 24 hours. The cells were then evaluated by fluorescence microscopic imaging and flow cytometry. It was observed that exosomes from different origins have a different homing efficiency, suggesting that each exosome may have its unique navigation systems. Furthermore, the cells which have aggressive metastatic potential, such as MDA-MB-231, showed a higher uptake in all exosomes. Our development has demonstrated an effective labeling method that facilitates exosome research by providing a new way of quantification and tracking in vitro and potentially in vivo studies.
Citation Format: Young Kim, Tae-Sup Lee, Ching H. Tung. A facile strategy for exosome labeling and tracking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-071. doi:10.1158/1538-7445.AM2017-LB-071
Abstract LB-097: DNA methylation at enhancers distinguishes distinct breast cancer lineages
Authors: Fleischer Thomas , Tekpli Xavier , Mathelier Anthony , Wang Shixiong , Nebdal Daniel , Dhakal Hari P. , Sandberg Kristine Kleivi , Schliting Ellen ,   Oslo Breast Cancer Research Consortium (OSBREAC), Børresen-Dale Anne-Lise , Borgen Elin , Naume Bjørn , Eskeland Ragnhild , Frigessi Arnoldo , Tost Jörg , Hurtado Antoni , Kristensen Vessela N. 
Published: July 2017

Abstract
Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression we applied genome-wide expression-methylation quantitative trait loci (emQTL) analysis between 5meCpG and gene expression. We find that on a whole genome scale, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association, both in cis and in trans, which lead to identify distinct transcriptional networks and specific disease cell lineages deviating from the normal tissue. In three breast cancer cohorts (n=104, n=253 and n=330), we invariably identify enhancers whose DNA methylation tethers the binding of three key transcription factors in breast cancer in a lineage specific manner. Our emQTL analysis also identifies tumor infiltrating immune cell signatures. Using ChromHMM segmentation and ChIP-seq associated TF binding regions, we identify enhancers and TF binding sites around emQTLs-CpGs. We functionally validate the genes associated with these CpGs using knock-down by siRNA and applying GRO-seq analysis after transcriptional stimulation with estrogen. DNA methylation at TF binding regions is considered an early event during normal breast cell transformation into estrogen dependent breast cancer. Two distinct key gene regulatory networks reported here are prominently altered by DNA methylation.
Citation Format: Thomas Fleischer, Xavier Tekpli, Anthony Mathelier, Shixiong Wang, Daniel Nebdal, Hari P. Dhakal, Kristine Kleivi Sandberg, Ellen Schliting, Oslo Breast Cancer Research Consortium (OSBREAC), Anne-Lise Børresen-Dale, Elin Borgen, Bjørn Naume, Ragnhild Eskeland, Arnoldo Frigessi, Jörg Tost, Antoni Hurtado, Vessela N. Kristensen. DNA methylation at enhancers distinguishes distinct breast cancer lineages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-097. doi:10.1158/1538-7445.AM2017-LB-097
Abstract LB-098: Sequential azacitidine and histone deacetylase inhibition induces a potent antitumor response in Kras G12D mouse model of NSCLC
Authors: Topper Michael , Vaz Michelle , Chiappinelli Katherine , Shields Christina DeStefano , Wenzel Alyssa , Zahnow Cynthia , Strissel Pam , Strick Reiner , Baylin Stephen 
Published: July 2017

Abstract
Combination epigenetic treatment as a therapeutic approach holds much promise. However, to unlock the true potential of these combinatorial paradigms, further optimization is required. We have elucidated in our current study, a treatment schedule combining Azacitidine with Histone Deacetylase Inhibition (HDACi) which considers both schedule and isoform specificity. We have deployed a sequential schedule with HDACi administered post Azacitidine in a chronic low dose manner. This schedule takes advantage of two key parameters altered by Azacitidine: dsRNA induced immune signature and MYC depletion. In our system, HDACis amplify an existing immune signature and the MYC depleted environment acts as a potent sensitizer. HDACi induced augmentation of immune gene transcription seems driven predominantly through the inhibition of HDAC1/2 and HDAC6 isoforms, with broad spectrum HDACi inhibitors demonstrating the greatest potency. While the combination treatment induced perturbation of proliferation is driven by inhibition of HDAC1/2/3 isoforms. Applying this concept to a genetically engineered mouse model of NSCLC we observe a potent anti-tumor response as evidenced by a reduction in tumor burden, progression and proliferation. These phenotypic parameters are correlated with modification of both immune and proliferative gene signatures as well as alteration of key immune populations in the tumor microenvironment. We propose that this combinatorial alteration of both immune and proliferative parameters holds the promise to be a more robust treatment for NSCLC.
Note: This abstract was not presented at the meeting.
Citation Format: Michael Topper, Michelle Vaz, Katherine Chiappinelli, Christina DeStefano Shields, Alyssa Wenzel, Cynthia Zahnow, Pam Strissel, Reiner Strick, Stephen Baylin. Sequential azacitidine and histone deacetylase inhibition induces a potent antitumor response in Kras G12D mouse model of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-098. doi:10.1158/1538-7445.AM2017-LB-098
Abstract LB-099: BET bromodomain proteins are essential for the oncogenic EWS-fusion driven Ewing Sarcoma
Authors: Gollavilli Paradesi N. , Pawar Aishwarya , Wilder-Romans Kari , Engelke Carl , Dommeti Vijaya L. , Krishnamurthy Pranathi M. , Nallasivam Archana , Apel Ingrid A. , Xu Tianlei , Qin Zhaohui S. , Feng Felix Y. , Asangani Irfan A. 
Published: July 2017

Abstract
Ewing sarcoma (EWS) is a lethal pediatric small, round, blue cell tumor defined by the characteristic fusion between EWSR1 and a member of the ETS family transcription factor, mostly FLI1 and ERG. Bromodomain and extra-terminal domain (BET) proteins play an essential role in transcription as an epigenetic reader of acetylated histones and transcription factors, and recent studies of inhibitors against these proteins have demonstrated therapeutic potential in various cancers. In this study, we investigated the importance of BET proteins BRD2, BRD3, and BRD4 in EWS-fusion driven transcription program required for maintenance and progression of EWS. Similar to EWS-FLI1 and EWS-ERG, knock-down of BET proteins severely impaired the proliferation and invasion of EWS cells. Gene expression profiling by RNA-Seq showed a common set of genes altered in EWS-FLI1 and BRD2/3/4 knockdown cells implicating a direct role of BET proteins in the transcriptional regulation of EWS-fusion targets. Importantly, BET inhibitor, JQ1, induces apoptosis in EWS cells through an MYC-independent mechanism, and without affecting the EWS-fusion levels. Rather, evidence suggested that BRD4 exists in a complex with EWS-ETS fusion proteins and that its inhibition abrogates the fusion transcriptional program. In vivo, JQ1 inhibited the metastases in chicken CAM model of EWS as well as displayed anti-tumor and anti-metastatic activity in mouse xenograft models of EWS. Together, these results indicate that BET proteins, especially BRD4 interacts with EWS-ETS fusion proteins and this interaction is necessary for the EWS-fusion mediated oncogenesis. Moreover, this study provides a clear rationale for the clinical utility of BET inhibitors in treating metastatic Ewing sarcoma patients.
Citation Format: Paradesi N. Gollavilli, Aishwarya Pawar, Kari Wilder-Romans, Carl Engelke, Vijaya L. Dommeti, Pranathi M. Krishnamurthy, Archana Nallasivam, Ingrid A. Apel, Tianlei Xu, Zhaohui S. Qin, Felix Y. Feng, Irfan A. Asangani. BET bromodomain proteins are essential for the oncogenic EWS-fusion driven Ewing Sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-099. doi:10.1158/1538-7445.AM2017-LB-099
Abstract LB-109: PDeX (Patient Derived eXplant) models to determine the basis for response to targeted agents in prostate cancer
Authors: Shafi Ayesha A. , Schiewer Matthew J. , Leeuw Renee de , McCue Peter A. , Gomella Leonard G. , Lallas Costas D. , Trabulsi Edouard J. , Hickey Theresa , Shah Neelima , Cukierman Edna , Butler Lisa M. , Tilley Wayne , Raj Ganesh , Knudsen Karen E. 
Published: July 2017

Abstract
Prostate cancer (PCa) is the most common non-cutanenous cancer and the third leading cause of cancer-related death in American men. Androgen receptor (AR) is a hormone-activated transcription factor that plays an important role in both the development and progression of PCa. Androgen deprivation therapy is a common first-line therapy for disseminated disease. However, virtually all tumors become resistant to such therapy and the tumor recurs. Thus, there is a vital need for the development of novel, more effective drugs. One major hurdle in this aspect is the lack of adequate preclinical models. Current models do not effectively recapitulate the heterogeneity and the microenvironment of human PCa tumors, significantly hindering the ability to accurately predict therapeutic response. Our collaborative group has utilized and characterized a method to culture patient tumors ex vivo, termed Patient Derived eXplant (PDeX). This approach maintains the integrity of the native tumor microenvironment, tumor tissue morphology, and molecular signaling. Importantly, our PDeX model can be manipulated both chemically (drugs/compounds) and genetically (shRNA) in order to determine specific reactions and mechanisms of response on individual tumor growth. Furthermore, with this model we can quantitatively assess drug efficacy on numerous parameters (i.e. AR levels, Ki67 staining, apoptosis screening, and desmoplasmic indices). Data to be discussed will assess the variances in response to AR-directed therapeutics and underlying mechanisms of action, while also utilizing TME characteristics as a means to predict response to therapy. In addition, we can potentially identify clinically relevant subpopulations of patients and molecularly profile their cultured tissue to uncover new pathways for therapeutic intervention. Thus, the PDeX model allows for a comprehensive evaluation of individual tumors in their native microenvironment to ultimately develop more effective therapies. This study will have transformative clinical impact discerning novel metrics for the inclusion of precision medicine for advanced PCa.
Citation Format: Ayesha A. Shafi, Matthew J. Schiewer, Renee de Leeuw, Peter A. McCue, Leonard G. Gomella, Costas D. Lallas, Edouard J. Trabulsi, Theresa Hickey, Neelima Shah, Edna Cukierman, Lisa M. Butler, Wayne Tilley, Ganesh Raj, Karen E. Knudsen. PDeX (Patient Derived eXplant) models to determine the basis for response to targeted agents in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-109. doi:10.1158/1538-7445.AM2017-LB-109
Abstract LB-119: Targeting DNA-PK via small molecule inhibitors of the Ku-DNA interaction
Authors: Turchi John J. , Gavande Navnath , VanderVere-Carozza Pamela , Vernon Tyler , Pawelczak Katherine 
Published: July 2017

Abstract
DNA-PK, the DNA-dependent protein kinase, is a validated target for cancer therapeutics that drives the DNA damage response and plays a critical role in the nonhomologous end joining (NHEJ) DNA repair pathway.
Inhibition of DNA-PK activity can elicit anticancer activity and also sensitize cancer cells to DNA damaging therapy. NHEJ is responsible for the repair of DNA double strand breaks (DSB), particularly those induced by ionizing radiation (IR). The generation of DNA DSBs is the mechanism of clinical efficacy of radiation therapy and numerous DNA damaging chemotherapeutic drugs used to treat various cancers. Modulating the pathway responsible for repairing these breaks has been shown to have a profound impact on the efficacy of IR or chemotherapy in the clinic. We have taken a completely unique and novel approach to inhibiting DNA-PK that is based on extensive knowledge regarding DNA-PK kinase activation and affords considerable advantages to current approaches in DNA-PK inhibition. DNA-PK activation and NHEJ pathway engagement requires binding of the Ku70/80 heterodimer to DNA ends and we are targeting this protein-DNA interaction. We have discovered and developed a series of highly potent and selective DNA-PK inhibitors that act via blocking the binding of Ku70/80 to DNA ends. The lead compound from this series of molecules inhibits DNA-PK catalytic activity at nanomolar concentrations, has single-agent anticancer activity in cancer cell lines, and potentiates cellular sensitivity to IR treatment and DSB-producing chemotherapeutic agents. These data demonstrate the utility of inhibiting DNA-PK via targeting the Ku-DNA interaction.
Citation Format: John J. Turchi, Navnath Gavande, Pamela VanderVere-Carozza, Tyler Vernon, Katherine Pawelczak. Targeting DNA-PK via small molecule inhibitors of the Ku-DNA interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-119. doi:10.1158/1538-7445.AM2017-LB-119