bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4541: QL315, A CD3 bispecific antibody redirecting T cell activation to the tumor stroma antigen LRRC15
Authors: Jin Monica , Kurtzman Aaron , Prior Weiwei W. , Chan Allan , McClain Anna , Gu Shenda , Tang Irene , Cai Zijie , Schwimmer Lauren , Tran Hieu , Chen Shihao 
Published: September 2020

Abstract
Leucine-rich repeat containing 15 (LRRC15) antigen is highly expressed on both stromal fibroblasts of multiple solid tumors and on cancer cells of mesenchymal origin. As its expression is very low in normal tissues, targeting LRRC15 has shown therapeutic potential as an antibody-drug conjugate (Demetri, ASCO 2019), which could lead to significant tumor inhibition by solely targeting stromal LRRC15 expression. In this study, we have developed and rank ordered an array of IgG-based CD3 bispecific molecules based on biophysical and biologic attributes and anti-cancer efficiency through T-cell engagement and redirection/activation against LRRC15-expressing tumors. The selected lead, QL315, robustly and conditionally induced T cell activation and proliferation only in the presence of LRRC15-expressing cancer cells with an EC50 in a picomolar range in vitro but not in the coculture with LRRC15-negative cancer cells. Moreover, QL315 strongly induced tumor cell lysis in vitro and led to significant tumor regression and T cell expansion in a mouse xenograft model. Importantly, toxicologic evaluation of QL315 in cynomolgus monkeys showed antibody-like stability and half-life, and good tolerability with no changes of circulating blood cell homeostasis and organ damage. At highest levels, liver enzymes, as well as cytokine release, were transiently elevated but returned to normal within one week of treatment. In conclusion, these data demonstrate drug-like properties, promising anti-tumor capability and good tolerability of the anti-LRRC15/CD3 bispecific antibody, QL315, indicating its potential as a therapeutic option in the treatment of solid tumors of diverse origin by targeting either tumor stromal micro environment or patient cancers expressing LRRC15.
Citation Format: Monica Jin, Aaron Kurtzman, Weiwei W. Prior, Allan Chan, Anna McClain, Shenda Gu, Irene Tang, Zijie Cai, Lauren Schwimmer, Hieu Tran, Shihao Chen. QL315, A CD3 bispecific antibody redirecting T cell activation to the tumor stroma antigen LRRC15 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4541.
Abstract 4549: Evaluation of GUCY2c-CD3 bispecific targeting GI cancers in an orthotopic colorectal tumor model
Authors: Yao Johnny , Mathur Divya , Yang Sharon , Conant Roger , Kearney Jessica , Buklan Vlad , Golas Jonathan , Rosfjord Edward 
Published: September 2020

Abstract
GUCY2c is a tumor target expressed in &gt;90% of colorectal cancer (CRC). It is also expressed on the apical side of intestinal epithelial tight junctions, where it regulates intestinal fluidity. PF-07062119, a GUCY2c-CD3 bispecific antibody that recruits T cells to GUCY2c expressing gastrointestinal tumors, has shown anti-tumor efficacy in several subcutaneous colorectal cancer models without any signs of intestinal toxicity. Here we describe the effects of PF-07062119 in an intestinal orthotopic xenograft model, created surgically in NSG mice using LS1034 CRC cells expressing luciferase. To establish this model, LS1034-luc tumor fragments were sutured onto the cecum proximal to the colon. Tumor growth was monitored through detection of luciferin bioluminescence. PF-07062119 was administered at 0.03, 0.1 and 0.3 mg/kg iv weekly, along with an adoptive transfer of 2x106 human T cells the day after bispecific compound dosing. At 0.3 mg/kg dose, the bioluminescence signal was significantly reduced compared with the isotype control group. Necropsies at the end of study revealed complete tumor clearance, or residual calcified or fibrotic tissues, at the tumor implant site in all animals of the 0.3 mg/kg group, compared with tumor presence in 9 of 9 animals and liver metastases in 2 of 9 animals in the isotype control group. The average tumor weight of 0.1 mg/kg dose group decreased relative to the control group, but the difference did not reach statistical significance. The results of histological examination indicate enhanced T cell infiltration in the tumor tissues compared with the normal intestinal tissues in PF-07062119 treated animals. No body weight loss or other clinical signs were observed in all groups. These results demonstrate that PF-07062119 can eliminate LS1034 orthotopic tumors and potential metastasis with no observable toxicities. This supports our hypothesis that apical restriction of GUCY2c expression in normal intestine creates tumor-vs-normal differential for selective targeting of GUCY2c positive tumors, and the GUCY2c-CD3 bispecific antibody redirects T cells to lyse the CRC tumor cells.
Citation Format: Johnny Yao, Divya Mathur, Sharon Yang, Roger Conant, Jessica Kearney, Vlad Buklan, Jonathan Golas, Edward Rosfjord. Evaluation of GUCY2c-CD3 bispecific targeting GI cancers in an orthotopic colorectal tumor model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4549.
Abstract 4597: 5-Hydroxymethylcytosine signatures in cell-free DNA as a potential biomarker for colorectal cancer andprecancerous adenoma
Authors: Xiao Zewen , Wu Jiayan , Wu Chunlong , Li Man , Sun Fuming , Zheng Lu , Liu Gaojing , Li Xiaoling , Yun Zhiyuan , Tang Jiebing , Yu Yang , Luo Shengnan , Sun Wenji , Feng Xiaohong , Cheng Qian , Tao Xue , Bai Jian , Wu Lin , Wu Shuangxiu , Tao Ji 
Published: September 2020

Abstract
Colorectal cancer (CRC) is a serious malignancy with the third incidence and second mortality throughout the world. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) is an important epigenetic mark linked with human cancer pathogenesis. Here we explored the genome-wide 5-hydroxymethylcytosine profiling in the plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 from plasma and 38 from tissues), collected from 21 CRC patients, 21 precancerous adenoma (AD) patients and 21 healthy control individuals (HC). 5hmC modifications exhibited distinct features in promoter and gene body regions in all 5 groups (3 groups from plasma and 2 groups from tissues), which offered a global overview of epigenetic changes of colon pathogenic statuses between early stage CRC and AD. Adenoma showed an independent property in the 5hmC profiles compared to cancer and healthy control. The 5hmC signatures in tumor were more comprehensive and could be divided into two clusters, one was similar to the healthy individuals and the other was similar to the AD patients. The results indicated that the candidate biomarkers to distinguish colorectal cancer from the blood-test population should be generated in two ways, one focused on the differential 5hmC features between CRC patients and healthy individuals; the other should detect the adenoma and tumor patients more extensive according to their precise pathological diagnosis and clinical information. Candidate cfDNA 5hmC biomarkers were further identified in the differential 5hmC modification regions between CRC and HC with a higher sensitivity than the classical CEA marker in non-invasive blood-based diagnosis. We suggested that the differentially enriched 5hmC regions in cfDNA were potential biomarkers to track colorectal cancer, even precancerous adenoma, with further large-scale follow-up studies.
Citation Format: Zewen Xiao, Jiayan Wu, Chunlong Wu, Man Li, Fuming Sun, Lu Zheng, Gaojing Liu, Xiaoling Li, Zhiyuan Yun, Jiebing Tang, Yang Yu, Shengnan Luo, Wenji Sun, Xiaohong Feng, Qian Cheng, Xue Tao, Jian Bai, Lin Wu, Shuangxiu Wu, Ji Tao. 5-Hydroxymethylcytosine signatures in cell-free DNA as a potential biomarker for colorectal cancer andprecancerous adenoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4597.
Abstract 4611: A multicenter clinical study of stool DNA test of methylated syndecan-2 for colorectal cancer detection
Authors: Wang Jianping , Liu Side , Wang Hui , Zheng Lei , Zhou Changchun , Li Guoxin , Huang Rongkang , Wang Huaiming , Li Chujun , Fan Xinjuan , Fu Xinhui , Wang Xinying , Guo Hongliang , Guan Jie , Sun Yanlai , Song Xilin , Li Zengjun , Mu Dianbin , Sun Jujie , Liu Xianglin , Qi Yan , Niu Feng , Chen Chunhua , Wu Xiaolin , Wang Xianshu , Song Xianrang , Zou Hongzhi 
Published: September 2020

Abstract
Study purpose: Previously, we had a pilot study to evaluate the feasibility of a stool DNA test of methylated Syndycan-2 (SDC2) for colorectal cancer (CRC) detection. The purpose of this continuing investigation was to assess the performance of this test in a multicenter hospital-based setting.
Methods: Each participant was required to undergo both a stool DNA test and a reference colonoscopy. The stool DNA test assesses the methylation status of a single target of SDC2 gene. Results of real-time methylation-specific PCR were dichotomized as positive and negative by a prespecified cut-off value. The main evaluation indexes were sensitivity, specificity, and kappa value, which was used to assess the diagnostic consistency between stool DNA test and colonoscopy. Tests were performed in blinded fashion and processed independently of the colonoscopic results.
Results: Among the 1110 participants from three hospitals included for analysis, 359 and 38 had CRC and advanced adenomas, respectively, according to colonoscopy findings. The sensitivity of the stool DNA test was 83.8% for CRC and 42.1% for advanced adenomas. For CRC at early stage confined to bowel wall (I to II), the sensitivity was 87.0%. Detection rate for CRC did not vary significantly according to age, tumor location, differentiation, and TNM stage, except for gender (P=0.041). The specificity of the stool DNA test was 98.0% among participants with nonadvanced colorectal neoplasia, non-neoplastic disorders, or negative results on colonoscopy. Diagnostic consistency for CRC assessed by kappa value was 0.84, indicating that the agreement in outcome between the stool DNA test and colonoscopy was excellent.
Conclusion: Noninvasive stool DNA test using methylated SDC2 as a molecular marker was a sensitive and accurate method for CRC detection.
Citation Format: Jianping Wang, Side Liu, Hui Wang, Lei Zheng, Changchun Zhou, Guoxin Li, Rongkang Huang, Huaiming Wang, Chujun Li, Xinjuan Fan, Xinhui Fu, Xinying Wang, Hongliang Guo, Jie Guan, Yanlai Sun, Xilin Song, Zengjun Li, Dianbin Mu, Jujie Sun, Xianglin Liu, Yan Qi, Feng Niu, Chunhua Chen, Xiaolin Wu, Xianshu Wang, Xianrang Song, Hongzhi Zou. A multicenter clinical study of stool DNA test of methylated syndecan-2 for colorectal cancer detection [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4611.
Abstract 4614: Genome-wide association analysis of pro-inflammatory cytokines and gene-lifestyle interaction for invasive breast cancer risk: The WHI Database for Genotypes and Phenotypes Study
Authors: Jung Su Yon , Scott Peter , Han Sihao , Pellegrini Matteo , Papp Jeanette , Sobel Eric , Yu Herbert , Zhang Zuo-Feng 
Published: September 2020

Abstract
Purpose: Pro-inflammatory biomarkers and their genetic variants may interact with obesity and obesity-related lifestyle factors, influencing breast cancer risk in postmenopausal women, but the interrelated metabolic pathways are incompletely understood.
Methods: We used data from the Women's Health Initiative Database for Genotypes and Phenotypes Study including 16,088 postmenopausal women, a population highly susceptible to obesity and increased risk for breast cancer. We conducted a genome-wide association (GWA) analysis in two steps: 1) with six GWA substudies, GWA meta-analysis of pro-inflammatory cytokines (Interleukin-6 [IL-6] and C-reactive protein [CRP]) for their gene-lifestyle interactions and 2) test for the association between identified single-nucleotide polymorphisms (SNPs) at the genome-wide level and breast cancer risk.
Results: In women overall and stratified by obesity status (body mass index, waist circumference, and waist-to-hip circumference) and obesity-related lifestyle factors (physical activity and high fat-diet), 88 loci were associated with pro-inflammatory phenotypes at genome-wide significance: 3 associated with IL-6 (1 index SNP in MAPK1 and 1 independent SNP in DEC1); 85 with CRP (3 index SNPs in CRP/CRPP1/HNF1A and 2 SNPs in APOE/APOC1, independently). Of those, 27 loci had significantly increased risk for breast cancer.
Conclusions: We found a number of novel genetic markers in relation to pro-inflammatory phenotypes, which interacted with obesity and related lifestyle factors. A substantial proportion of those SNPs' susceptibility influences breast cancer risk in the identical subgroup populations. Our findings may contribute to improved prediction accuracy for cancer and suggest intervention strategies for women who carry the risk genotypes, eventually reducing breast cancer risk.
Citation Format: Su Yon Jung, Peter Scott, Sihao Han, Matteo Pellegrini, Jeanette Papp, Eric Sobel, Herbert Yu, Zuo-Feng Zhang. Genome-wide association analysis of pro-inflammatory cytokines and gene-lifestyle interaction for invasive breast cancer risk: The WHI Database for Genotypes and Phenotypes Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4614.
Abstract 4642: Effects of soy protein diet on plasma isoflavones levels in obese DMBA-induced mammary tumor rat model
Authors: Hakkak Reza , Korourian Soheila 
Published: September 2020

Abstract
Obesity epidemic in the US and world grows as the number of overweight and obese adults continues to rise. Obese women have higher mortality rates from all cancers including breast cancer. Several studies have reported the protective effects of soy intake on breast cancer development, while other studies report the adverse effects of soy protein diet on breast cancer development. Soybeans contain isoflavones genistein, daidzein and glycitein, known as isoflavonoids, which are structurally similar to mammalian estrogens, have estrogenic properties and are potential anticarcinogens. Gut flora metabolizes daidzein into equol, a non-steroidal estrogen and has cancer chemopreventive property. The objective of this study was to determine the effects of obesity and a high isoflavones soy protein diet on plasma isoflavones; genistein, daidzein, glycitein, equol and O-Desmethylangolensin (O-MDA) levels using 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor model. Five-week-old female Zucker rats (45 obese fa/fa and 54 lean) were used. After one week of acclimation (age 42 days), rats were randomly assigned to the following diet groups; 1) Lean, casein; 2) Obese, casein; 3) Lean, soy and 4) Obese, soy. Rats had ad lib access to water and diet with either casein or soy protein isolate as source of protein. All rats were orally gavaged at age 50 days with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly and sacrificed 21 weeks post-DMBA treatment. Plasma was collected to measure genistein, daidzein, glycitein, equol and O-MDA levels using liquid chromatography−tandem mass spectrometry (LC-MS/MS). At end of the experiment, 69% of the Lean casein rats developed mammary tumors compared to 50% in lean soy group (p= 0.176). In the obese group, 76% of the soy-fed rats developed mammary tumors compared to 15% (P&lt;0.001) of obese casein- fed rats. Plasma daidzein and genistein concentration were not significantly different in lean vs obese soy-fed rats. However, O-MDA and equol concentration were significantly lower (P&lt;0.05) in obese soy-fed rats compared to lean soy rats. These data suggests that obese rats fed soy protein diet containing high isoflavone levels promoted DMBA-induced mammary tumor development compared to a casein-based diet. Also, obese soy-fed rats exhibited significantly lower plasma equol concentrations than those observed in lean soy-fed rats and this reduction may aid in explaining soy's impaired cancer chemopreventative effects in obese breast cancer model.
Citation Format: Reza Hakkak, Soheila Korourian. Effects of soy protein diet on plasma isoflavones levels in obese DMBA-induced mammary tumor rat model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4642.
Abstract 466: Epigenetic drug profiling in diffuse intrinsic pontine glioma
Authors: Tolson Hannah 
Published: September 2020

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and universally fatal form of childhood brain cancer. As prognosis has improved little over the last 40 years, exploring alternate drug therapies remains paramount. Roughly 80% of DIPG patients harbor mutations that result in the substitution of a lysine for a methionine at position 27 of histone variants 3.1 and 3.3 (H3.1K27M and H3.3K27M). This hallmark mutation causes global epigenetic changes in DIPG patients by dysregulating methylation and acetylation of histones, thus making the epigenome a potential therapeutic target. We explored vulnerabilities in 10 DIPG models (8 of which were H3.3K27M and 2 of which were H3.1K27M) to HDAC inhibitors (TSA and Panobinostat) and an LSD1 inhibitor (SP2577) both alone and in combination using drug dose response assays. As expected, Panobinostat showed high potency in each DIPG cell line, with 7 of the 9 lines having IC50 values less than 10 nM. In contrast, all 10 lines had no response to SP2577 apart from cytotoxic reactions in higher concentration ranges. SP2577 will thus be interesting to test in combination with Panobinostat with the intention of increasing its sensitivity. We also evaluated the efficacy of epigenetic drugs when used in combination with drugs targeting transcriptional pathways including TGN1076, a novel reversible CDK7 inhibitor. We found that TGN1076 shows marginal synergy with TSA, an HDAC inhibitor, and good synergy with JQ1, a BET inhibitor in the cell line DIPG6. Though equilibrating the epigenome remains a necessary objective in DIPG research, elucidating the mechanisms underlying extreme epigenetic shifts could provide important insight into disease pathogenesis. For this reason, we also focused on the histone methyltransferase protein PRC2 which is commonly implicated in epigenetic dysregulation in DIPG. Because the catalytic subunit of PRC2, EZH1/2, is allosterically regulated by another subunit, EED, in a “write and read mechanism,” we are testing the efficacy of the drug EED226 which binds to EED and modulates the function of PRC2. Analyzing the effects of this drug alone and in combination will provide a novel approach to managing PRC2 dysregulation and will potentially reveal future therapeutic strategies. Through screening novel drugs and testing their efficacies in combination with drugs that are commercially available, we intend to provide future therapeutic options for DIPG patients.
Citation Format: Hannah Tolson. Epigenetic drug profiling in diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 466.
Abstract 4689: Co-treatment of MEKi and BRD4 inhibitors lead to synergistic repression of MYC-associated enhancer RNAs
Authors: Azofeifa Joseph , Basken Joel , Lai Maria , Langendorf Ryan , Norris Laura , Read Tim , Robbins-Pianka Adam 
Published: September 2020

Abstract
Recent evidence suggests that co-treatment with BRD4 and MEK inhibitors can lead to synergistic suppression of MAPK signaling, however, little is known about the mechanism of action of this synergy. In a triple negative breast cancer cell line model, we harvested nascent RNA at 45 minutes following repression of BRD4 and MEK via a variant of the precision run-on followed by sequencing (PRO-seq) assay. We noted dose-dependent repression of enhancer RNAs over MYC binding sites as well as enhancer RNAs upstream known ERK targets such as DUSP6. Using new machine learning techniques, we were able to link synergy-specific enhancer RNAs to their target genes. This work will inform on new methods for patient stratification and biomarker selection of the BETi and MEKi treatment regimes.
Citation Format: Joseph Azofeifa, Joel Basken, Maria Lai, Ryan Langendorf, Laura Norris, Tim Read, Adam Robbins-Pianka. Co-treatment of MEKi and BRD4 inhibitors lead to synergistic repression of MYC-associated enhancer RNAs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4689.