bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-128: The aryl hydrocarbon receptor as driver of cancer immunity
Authors: Sherr David , Kenison-Whte Jessica , Wang Zhongyan 
Published: August 2018

Abstract
The Aryl Hydrocarbon Receptor (AHR) has been identified as a driver of cancer progression and cancer immunity in the tryptophan-IDO/TDO-kynurenine-AHR pathway. Over the last 10 years, studies from several laboratories have demonstrated that AHR ligand-mediated immunosuppression is effected, at least in part, through AHR regulation of inflammatory or inhibitory T cell subsets and immune suppressive MDSCs. These results suggest that the AHR is a driver of cancer immunity. To test this hypothesis, we used molecular and pharmacological approaches to regulate AHR activity in multiple murine cancer models and then measured multiple immune phenotypes. The resulting data indicate that a novel, non-toxic AHR inhibitor, HP163 (Hercules Pharmaceuticals), reduces tumor growth in orthotopic models of oral (MOC1), breast (4T1), and skin (B16) cancers in immunocompetent hosts. In the MOC1 model, HP163 significantly reduces the number of CD11b+PD-L1+ or CD11b+CCR2+ cells in the tumor draining lymph node. AHR knockdown in MOC1 cells with CRISPR/Cas9 decreases the percentage of CD11b+PD-L1+ tumor infiltrating cells and increases tumor infiltrating CD4+ and CD8+ T cells. This decrease in cells with an immunosuppressive phenotype is accompanied by a complete lack of orthotopic tumor growth. Furthermore, mice having received AHR- MOC 1 cells are resistant to a second challenge with wildtype AHR+ MOC1 cells several months after the primary inoculation. These data suggest that the presence of the AHR in the tumor itself is sufficient to induce immunosuppression. Preliminary data suggest that AHR+ myeloid cells mediate suppression of tumor immunity. These results collectively suggest that the AHR may be targeted for immunotherapy of several cancers and that HP163 may represent a novel approach to cancer therapy.
Citation Format: David Sherr, Jessica Kenison-Whte, Zhongyan Wang. The aryl hydrocarbon receptor as driver of cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-128.
Abstract LB-137: Integrated genomics: drug screening and personalized xenograft development approach to identify precision treatments for aggressive pediatric brain tumors
Authors: Tsoli Maria , Wadham Carol , Pinese Mark , Failes Tim , Joshi Swapna , Mould Emily , Yin Julia , Gayevski Velimir , Kumar Amit , Kaplan Warren , Ekert Paul , Franshaw Laura , Gifford Andrew , Weber Martin , Rodriguez Michael , Mayoh Chelsea , Cohn Richard , Arndt Greg , Lock Richard , Tyrrell Vanessa , Norris Murray , Haber Michelle , Lau Loretta , Quang Dong Anh Khuong , Wong Marie , Trahair Toby , Marshall Glenn M. , Cowley Mark J. , Ziegler David S. 
Published: August 2018

Abstract
Brain tumors represent the most common solid tumors in childhood and account for significant morbidity and mortality. The lack of advances in treatment of the brain tumors is hindered by our lack of knowledge about the molecular pathogenesis of these malignancies as well as the availability of brain-permeable therapies. Personalised medicine approaches have the potential to enhance diagnostic, prognostic and / or therapeutic information. The TARGET study is a feasibility pilot study which focused on the development of genomic platforms, high throughput drug screening (HTS), and PDX models in order to identify personalised therapies for patients with aggressive pediatric tumors. In the pilot phase 59 patients were enrolled of which 28 were brain tumor patients (47%). In 28 curated cases molecular analysis identified a reportable somatic anomaly (SNVs, gene fusions, CNVs) in 82% (23/28), of which 78% (18/23) had actionable molecular aberrations. Four cases had a reportable germline predisposition variant and in 1 case, the genomic findings changed the primary diagnosis. Fresh tissue collection permitted in vitro HTS (112 single agents) in 58% of cases to date. Four PDX models have been established with additional 8 currently still being evaluated. This feasibility study demonstrates that an integrated approach based on genomic, in vitro and in vivo drug efficacy testing may be useful to guide the management of aggressive pediatric brain tumors.
Citation Format: Maria Tsoli, Carol Wadham, Mark Pinese, Tim Failes, Swapna Joshi, Emily Mould, Julia Yin, Velimir Gayevski, Amit Kumar, Warren Kaplan, Paul Ekert, Laura Franshaw, Andrew Gifford, Martin Weber, Michael Rodriguez, Chelsea Mayoh, Richard Cohn, Greg Arndt, Richard Lock, Vanessa Tyrrell, Murray Norris, Michelle Haber, Loretta Lau, Dong Anh Khuong Quang, Marie Wong, Toby Trahair, Glenn M. Marshall, Mark J. Cowley, David S. Ziegler. Integrated genomics: drug screening and personalized xenograft development approach to identify precision treatments for aggressive pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-137.
Abstract LB-179: The feasibility of delivering a cancer education program in correctional facilities
Authors: Valera Pamela , Mackey Daniel , Lian Zi , McLaughlin William 
Published: August 2018

Abstract
Introduction. Cancer 101, a cancer education program, is a critical resource to increase cancer knowledge, awareness, and cancer prevention activities to improve cancer health and survival rates. The purpose of this study was to test the feasibility of delivering the Cancer 101 curriculum to incarcerated adult males to improve cancer knowledge and increase cancer prevention activities.
Methods. Cancer 101 curriculum was pilot tested for adaptation with representatives from the target audience in a New York and Pennsylvania prison facilities and based on their feedback modifications were implemented. Three prison facilities participated in adapting Cancer 101 for this study; participation in the Cancer 101 educational intervention was limited to individuals who were current smokers or former smokers. Pre-test and post-test surveys were used to assess knowledge of, perceived attitudes regarding and benefits of cancer prevention activities at baseline and immediately after completing the Cancer 101 educational intervention. To determine whether cancer knowledge improved after participating in the Cancer 101 program, a paired t-test procedure was conducted; since improvement was expected, a one-tailed alpha of .05 was specified.
Results. The mean cancer knowledge scores differed prior to and after completing the Cancer 101 intervention, t(165) = -14.65, p &lt; .000. Mean cancer knowledge scores prior to the Cancer 101 intervention (M = 28.42, SD = 4.21) were significantly lower than after the intervention (M = 32.68, SD = 3.36). Therefore, the intervention had a positive effect on cancer knowledge. Participants also reported that the primary reasons for participating in the Cancer 101 intervention were to develop knowledge about cancer and the skills to participate in cancer prevention activities and to educate other inmates and family members about cancer. Participants demonstrated significant increases in cancer knowledge and interest in partaking in cancer prevention activities.
Discussion. A prison-based Cancer 101 educational intervention provides opportunities for inmates to increase cancer knowledge, as well as promote action for cancer control during incarceration.
Citation Format: Pamela Valera, Daniel Mackey, Zi Lian, William McLaughlin. The feasibility of delivering a cancer education program in correctional facilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-179.
Abstract LB-242: PTEN regulates mitotic checkpoint complex during mitotic progression
Authors: Choi Byeong Hyeok , Xie Steve , Dai Wei 
Published: August 2018

Abstract
PTEN is a well-known tumor suppressor through the negative regulation of the PI3K signaling pathway. Recently, it has been reported that nuclear PTEN plays an important role in cellular function. To understand the molecular basis by which PTEN mediates mitotic progression, we examined whether PTEN regulated the formation of mitotic checkpoint complex (MCC). Here we observed that arsenic trioxide, a mitotic inducer, stimulated nuclear translocation of PTEN in a time-dependent manner. PTEN physically interacted with Cdc20 and Mad2, two important components of MCC. Arsenic treatment diminished the physical association of PTEN with BubR1 and Bub3 but not with Cdc20 and Mad2. Our further studies revealed that downregulation of PTEN via RNAi enhanced formation of MCC during the cell cycle. Moreover, PTEN silencing induced chromosomal instability. Given the crucial role of PTEN in suppressing tumor development, our study strongly suggests that PTEN also functions to maintain chromosomal stability, partly through suppressing unscheduled formation of MCC.
Citation Format: Byeong Hyeok Choi, Steve Xie, Wei Dai. PTEN regulates mitotic checkpoint complex during mitotic progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-242.
Abstract LB-248: Chemically distinct class I HDAC inhibitors synergize to inhibit global lipid metabolism in cancer
Authors: Mahmud Iqbal , Garrett Timothy J. , Stowe Ryan , Roush William R. , Liao Daiqing 
Published: August 2018

Abstract
An increased rate of lipid production is a hallmark metabolic feature in cancer cells, which provides energy supplies, building blocks for membrane biogenesis, and signaling molecules for increased cancer cell proliferation. Current chemotherapeutic strategies targeting lipid metabolism have shown significant limitations, and as such, there is great interest in discovering novel therapies that effectively inhibit lipid production in cancer cells. Class I histone deacetylases (HDACs 1-3) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as novel anticancer drugs. Interestingly, HDAC inhibitors (HDACi) have been shown to decrease lipid production in different cells by modulating key genes in cholesterol synthesis, uptake, and efflux. However, effects of HDACi in lipid biosynthesis of cancer remains poorly studied. We have discovered a novel class of HDACi with a previously undescribed benzoylhydrazide scaffold. These new inhibitors are highly selective and potent to the class I HDACs (HDAC1, HDAC2, and HDAC3). Using global lipidomics approach by Ultra High-Performance Liquid Chromatography coupled High-Resolution Mass Spectrometry (UHPLC-HRMS), we found that a novel optimized analog, SR-4370, exhibits potent inhibition of lipid production in cells of diverse cancer types. Strikingly, SR-4370 in combination with entinostat, a benzamide analog of class I HDAC inhibitor currently in multiple clinical trials for treating breast cancer and other types of solid tumors, exhibits synergistic effects on inhibition of lipid production in cancer cells. We will present lipidomic profiling data from cells and xenograft tumors after treatment with SR-4370/entinostat, and discuss mechanisms of action for these distinct HDACi in inhibiting lipid production. In summary, our findings provide a rationale for inhibiting lipogenesis using isoform-selective HDACi in cancer therapy.
Citation Format: Iqbal Mahmud, Timothy J. Garrett, Ryan Stowe, William R. Roush, Daiqing Liao. Chemically distinct class I HDAC inhibitors synergize to inhibit global lipid metabolism in 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 LB-248.
Abstract LB-267: A small molecule mimic approach to the PEDF/LAMR1 interaction in prostate cancer
Authors: Edwards Daniel F. , Umbaugh Charles S. , Figueiredo Marxa L. 
Published: August 2018

Abstract
Pigment epithelium derived factor, or PEDF, is a well-known and potent inhibitor of angiogenesis. Our lab as well as others have examined PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, promotes tumor cell differentiation, and induces tumor apoptosis. PEDF has been identified as a binding partner for the cancer associated protein Laminin Receptor (LAMR1). LAMR1 has been shown to be overexpressed in several types of cancers including breast, colon, and prostate. It has been reported in the literature that the PEDF/LAMR1 interaction inhibits tumor migration and invasion. Recent work in the lab investigated whether we could mimic the PEDF/LAMR1 interaction using a small molecule approach.
Utilizing a 14,400 compound in-silico screen, we identified several small molecules as potential binders to the PEDF interaction interface of LAMR1. From those, we identified a hit compound with anti-proliferative capacity against several prostate cancer cell lines. In PC-3 cells, our hit compound showed activation of anti-tumor signaling and altered proteins associated with prostate cancer and DNA maintenance through LAMR1. We recently tested our hit compound as well as several structural analogs in PC-3 cells at 10 and 50 uM in a cell viability assay to compare the activity of the analogs with that of our hit compound. Several analogs showed activity comparable or superior to our hit compound at 50 uM, with at least a 95% reduction in cell viability after 48 and 96 hours.
We are currently working to identify medium-throughput in vitro functional assays that can be utilized for compound screening and profiling. Through an iterative screening, characterization, and optimization process, we hope to identify a lead-type compound to use in future preclinical studies. We are also investigating the mechanism of action downstream of the PEDF/LAMR1 interaction in prostate cancer, which will help us shed light on the therapeutic potential of LAMR1.
Support or Funding InformationCTSI Core Grant Purdue Cancer Research Center Department of Basic Medical Sciences
Citation Format: Daniel F. Edwards, Charles S. Umbaugh, Marxa L. Figueiredo. A small molecule mimic approach to the PEDF/LAMR1 interaction in prostate 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 LB-267.
Abstract LB-277: A small molecule compound targets mutant Ras driven cancers via changes in mitochondrial morphology and mTOR-dependent execution
Authors: Foo Jonathan C. , Iskandar Kartini B. , Pervaiz Shazib 
Published: August 2018

Abstract
In a recent report, we presented evidence that a small molecule compound selectively induces autophagy-associated execution of mutant RAS driven cancer cells via Akt-dependent mitochondrial ROS production (Iskandar, K. et al. Antiox. Redox Sig., 2016). During our efforts to explore the underlying mechanism of RAS dependent execution, we unraveled a novel mechanism of action involving changes in proteins responsible for maintaining mitochondrial morphology, Drp-1 and Opa-1. Exposure of cells to the small molecule, C1, results in specific phosphorylation of Drp-1 (serine 616) associated with mitochondrial fission as well as cleavage of the fusion associated protein Opa-1. Gene knockdown of KRAS significantly abrogated drug-induced phosphorylation of Drp-1 and rescued mitochondrial morphology. Interestingly, siKRAS also resulted in the complete inhibition of mitophagy induced upon exposure to the small molecule compound; mitophagy in this model is driven by the activation of Drp-1. We also provide evidence that KRAS is recruited to the mitochondria, upstream of Drp-1 activation and mitophagy induction in response to drug treatment. Furthermore, as Akt activation was linked to an increase in ROS production and knockout of Akt1/2 salvaged cells from the death inducing activity of C1, we studied the mechanism of Akt activation in this model. We present evidence that Akt activation might be downstream of Torin-sensitive but not Rapamycin-sensitive mTOR activation. Furthermore, a priori treatment with Torin completely blocked the effect of C1 on tumor colony forming ability. These data provide an interesting insight into the molecular mechanism(s) of a small molecule compound that triggers RAS dependent execution with potential therapeutic implications.
Citation Format: Jonathan C. Foo, Kartini B. Iskandar, Shazib Pervaiz. A small molecule compound targets mutant Ras driven cancers via changes in mitochondrial morphology and mTOR-dependent execution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-277.
Abstract LB-301: Inhibition of the co-inhibitory receptor KLRG1 reduces murine 4T1 breast cancer metastasis and MC38 colon cancer primary tumor growth and mortality
Authors: Greenberg Steven A. , Gulla Stefano V. , Thompson Evan 
Published: August 2018

Abstract
Introduction
Targeting of lymphocyte co-inhibitory receptors, such as CTLA-4, PD-1, Lag-3, and Tim-3, has gained intense interest for treatment of cancer. KLRG1 is also a lymphocyte co-inhibitory receptor, expressed predominantly on effector memory CD8+ T cells and NK cells, whose ligands E- and N-cadherin are differentially expressed during epithelial-mesenchymal transition. Targeting of KLRG1 in murine cancer models has not previously been published.
Methods
We constructed an anti-mouse KLRG1 antibody that neutralized the interaction of KLRG1 with its ligands. Anti-KLRG1 antibody was administered as a monotherapy in a murine metastatic tumor model (4T1 murine breast cancer) and as combination therapy with anti-PD-1 (clone RMP1-14) in a murine primary tumor growth model (MC38 murine colon cancer).
Results
In the 4T1 murine breast cancer model, anti-KLRG1 antibody reduced lung metastases compared to control antibody as measured by mean lung weights (0.28 g vs. 0.47 g; p=0.04) and nodule count (10.7 vs. 30.1; p=0.002). In the MC38 model, primary tumor growth was inhibited by anti-KLRG1 + anti-PD-1 antibody greater than anti-KLRG1 antibody or anti-PD-1 antibody or control antibody (day 13 tumor volume 582 vs. 1259 vs. 1279 vs. 1461 mm3, respectively). Combination therapy anti-KLRG1 + anti-PD-1 produced synergistic benefit significantly greater than that of anti-PD-1 alone for tumor volume (p=0.01) and survival (p=0.02; day 18 survival 60% of mice alive treated with combination therapy compared to 0% alive treated with anti-PD-1 alone). Ex vivo KLRG1 blockade with anti-human KLRG1 antibodies resulted in human CD8+ T cell proliferation and proinflammatory cytokine secretion.
Conclusions
Anti-KLRG1 neutralizing antibody demonstrates efficacy in inhibiting metastases in the murine 4T1 breast cancer model and reducing primary tumor volume and improving survival as synergistic combination therapy with anti-PD-1 in the murine MC38 colon cancer model. Anti-KLRG1 blockade with anti-human KLRG1 antibodies results in activation of CD8+ T cells. These data suggest that anti-KLRG1 treatment is a promising new approach for cancer immunotherapy.
Citation Format: Steven A. Greenberg, Stefano V. Gulla, Evan Thompson. Inhibition of the co-inhibitory receptor KLRG1 reduces murine 4T1 breast cancer metastasis and MC38 colon cancer primary tumor growth and mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-301.
Abstract LB-310: hnRNPM drives cell-state specific alternative splicing during EMT through combinatorial regulation with other RNA binding proteins
Authors: Harvey Samuel E. , Cheng Chonghui 
Published: August 2018

Abstract
The epithelial-mesenchymal transition (EMT) is a fundamental developmental program that is abnormally activated in cancer cells, resulting in therapeutic resistance and metastasis. Dramatic changes in alternative splicing occur during EMT, however the master regulators of this critical regulatory layer are poorly understood. We previously identified the ubiquitously expressed RNA binding protein hnRNPM as a causal driver of EMT and breast cancer metastasis whereby hnRNPM drives alternative exon skipping of the cancer stem cell marker CD44 in a mesenchymal-cell-state restricted manner. However, the scope of hnRNPM-mediated regulation of the EMT post-transcriptional landscape and the mechanisms by which hnRNPM functions in a cell-state specific fashion remain uncertain. By integrating breast epithelial and mesenchymal hnRNPM-depletion RNA-sequencing datasets coupled with individual nucleotide crosslinking and immunoprecipitation of hnRNPM, we identified cell-state specific hnRNPM target RNAs undergoing alternative splicing. hnRNPM cell-state specific targets enrich for distinct gene ontology terms where epithelial targets are enriched in genes critical for the cell cycle while mesenchymal targets cluster in pathways associated with cell migration and EMT. Strikingly, we found hnRNPM regulates splicing to oppose EMT in the epithelial state but then promotes EMT in the mesenchymal state. This unexpected regulatory switch where hnRNPM maintains the cell-cycle in epithelial cells while driving cell migration and metastasis in mesenchymal cells suggests a dual role for hnRNPM in sustaining epithelial and mesenchymal-type breast cancers. Motif analysis and regulon overlap of cell-state specific hnRNPM targets identify ESRP1 and other RNA binding proteins as putative mediators of hnRNPM cell-state specific activity during EMT. Together, this study extends our functional understanding of how hnRNPM regulates the EMT post-transcriptional program and functions in different subtypes of breast cancer.
Citation Format: Samuel E. Harvey, Chonghui Cheng. hnRNPM drives cell-state specific alternative splicing during EMT through combinatorial regulation with other RNA binding proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-310.