bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-034: MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in hepatocellular carcinoma
Authors: Hung Jung Hsien
Published: July 2017

Glycine N-methyltransferase (GNMT) is a tumor suppressor and frequently down-regulated in hepatocellular carcinoma (HCC). However, the mechanism is not fully understood. MicroRNAs are gene regulators and play important roles in tumorigenesis. In this study, we used both miRWalk and miRTar programs to search for microRNAs that may target at GNMT. Among several candidates, we found that microRNA-224 (miR-224) can bind to the GNMT transcript of the coding region. In addition, mutation of miR-224 seed sequences prevented its binding and subsequently repression activity in the reporter assay. The GNMT-MT plasmid containing GNMT mRNA with miR-224 seed sequence silent mutation can escape the suppression of miR-224 in HEK293T cells. Both exogenous and endogenous GNMT expression were suppressed by miR-224, while miR-224 inhibitors enhanced GNMT expression. In addition, miR-224 counteracts the effects of GNMT on the reduction of cell proliferation and tumor growth. We further demonstrated a significant inverse correlation of miR-224 and GNMT mRNA levels in HCC samples. In conclusion, miR-224 is the first reported miRNA that directly targets the GNMT mRNA coding sequence and plays an important role in GNMT suppression during hepatocarcinogenesis.

Citation Format: Jung Hsien Hung. MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in hepatocellular carcinoma [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-034. doi:10.1158/1538-7445.AM2017-LB-034
Abstract LB-036: Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity
Authors: Tanikawa Chizu , Matsuda Koichi
Published: July 2017

Recent proteome analyses have provided a comprehensive overview of various posttranscriptional modifications (PTM); however, PTMs involving protein citrullination remain unclear. Thus, we performed a proteomic analysis of citrullinated proteins and identified more than 100 PADI4 substrates, the majority of which are related to RNA processing and protein translation. Citrullination of RBMX (RNA binding motif protein, X-linked) inhibited the interaction with other hnRNP family members. RNA sequence analyses revealed altered splicing patterns in more than 300 genes in bone marrow cells in Padi4-/- mice. Approximately one-fifth of the PADI4 substrates contained an RG/RGG motif, and citrullination by PADI4 competitively inhibited the methylation of the RGG motif in FET proteins (EWS and TAF15). In addition, PADI4-mediated citrullination inhibited the aggregation of TAF15 proteins, which is a frequently-observed feature in neurodegenerative diseases, such as ALS. An antibody against citrullinated RGG motifs was observed in 11.5% (27 among 234) of serum samples from patients with HCV-related hepatocellular carcinoma, and female patients with high serum antibody exhibited poor prognosis. Our findings imply that PADI4-mediated citrullination plays a key role in RNA processing, protein aggregation and tumor immunogenicity, and suggest that PADI4 activation has potential therapeutic implications for neurodegenerative disease and cancer immunotherapy.

Citation Format: Chizu Tanikawa, Koichi Matsuda. Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity [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-036. doi:10.1158/1538-7445.AM2017-LB-036
Abstract LB-057: The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients
Authors: Bao Yongxing , Zhang Songan , Niyazi Huerdidan , Tuluwengjiang Gulixian , Zhang Lei , Zhang Yang , Su Weipeng
Published: July 2017

Cervical cancer is one of the most common gynecologic malignant tumors that threaten the health of women. Recently some researches have found that radiotherapy combined with anti-PD-1/PD-L1 drugs might improve anti-tumor efficacy. But there is few report about this issue on cervical cancer field. In order to testify the possibility and feasibility in cervical cancer patients, we collected 70 tissue samples of cervical squamous cell carcinoma and 70 tissue samples of cervical benign lesion, of which 24 cases of the cervical squamous cell carcinoma had matched peripheral blood samples, compared to 30 cases with matched peripheral blood samples of benign lesions. We used immunohistochemistry to detect the expression of PD-L1 in the tissues and flow cytometry to detect the proportion of CD4+PD-1+ and CD8+PD-1+ subsets in peripheral blood. Then Log-rank and COX regression were used to analyze the relationship among survival time, expression of PD-L1 and proportion of PD-1+ T cells. The results indicated that the proportion of CD4+PD-1+ T cells and CD8+PD-1+ T cells in peripheral blood positively correlated with the expression of PD-L1 in tissue samples of cervical squamous cell carcinoma patients (R2=0.734, P=0.000; R2=0.66, P=0.000), while there were less correlation in cervical benign patients (R2=0.138, P=0.043; R2=0.174, P=0.022). There were significantly differences in the proportion of CD8+PD-1+T cells and PD-L1+ tissue cells between cervical cancer group and cervical benign disease group (P=0.000, P=0.002). With the increase of tumor stage, the percentage of CD4+PD-1+ T cells and CD8+PD-1+ T cells increased correspondingly. With the increase of tumor diameter and stage, the expression of PD-L1 in tumor tissue also increased. The patients with small proportion of CD4+PD-1+ T cells and low expression of PD-L1 seemed to have longer survival time. Multivariate analysis showed that the PFS time was affected by the expression of PD-L1(B=1.844, P=0.019). Taken together, the cervical squamous cell cancer patients had more CD4+PD-1+ T cells in peripheral blood and PD-L1+ cells in tissues, which correlated to the grading of tumor and associated with prognosis.

Note: This abstract was not presented at the meeting.

Citation Format: Yongxing Bao, Songan Zhang, Huerdidan Niyazi, Gulixian Tuluwengjiang, Lei Zhang, Yang Zhang, Weipeng Su. The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients [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-057. doi:10.1158/1538-7445.AM2017-LB-057
Abstract LB-079: Expression of evolutionarily novel genes in tumors
Authors: Kozlov Andrei , Krukovskaya Larisa , Samusik Nikolai , Makashov Andrei , Matyunina Ekaterina , Karnaukhova Julia , Kurbatova Tamara , Emelyanov Alexander
Published: July 2017

Several genes with dual specificity - evolutionarily novel and expressed specifically or predominantly in tumors (OTP, ESRG, PVT1, ELFN1-AS1, HHLA1, DCD, SPRR1A, PBOV1 and others), have been described in our lab. We suggested to call such genes Tumor Specifically Expressed, Evolutionarily Novel (TSEEN) genes.

We also described the evolutionary novelty of the whole classes of genes expressed predominantly in tumors, e.g. CT-X genes and genes of noncoding tumor specifically expressed RNAs.

We studied the phylogenetic distribution of the orthologs of genes expressed in tumors and found that different functional gene classes have different evolutionary novelty. Some of them are enriched with evolutionarily novel genes. We showed that phylogenetic distribution curves of oncogenes, tumor suppressor genes and differentiation genes almost coincide, i.e. their evolution proceeds in a parallel manner.

Using zebrafish transgenic inducible tumor model we discovered that some human genes which determine progressive traits originated in fishes and were first expressed in fish tumors.

Our data and the data published by other authors suggest that genes originated by gene duplication; from endogenous retroviruses; by exon shuffling; and de novo are expressed in tumors, sometimes with high tumor specificity.

The expression of evolutionarily novel genes in tumors may be a novel biological phenomenon with important evolutionary role.

Citation Format: Andrei Kozlov, Larisa Krukovskaya, Nikolai Samusik, Andrei Makashov, Ekaterina Matyunina, Julia Karnaukhova, Tamara Kurbatova, Alexander Emelyanov. Expression of evolutionarily novel genes in tumors [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-079. doi:10.1158/1538-7445.AM2017-LB-079
Abstract LB-102: Landscape analysis of the initial data release from AACR Project GENIE
Authors: Cerami Ethan , Baras Alexander S. , Guinney Justin , Lepisto Eva , Pugh Trevor J. , Schultz Nikolaus , Stricker Thomas , Sweeney Shawn M. , Veer Laura J. van't , Meijer Gerrit A. , Andre Fabrice , Velculescu Victor E. , Shaw Kenna R. , Levy Mia A. , Bedard Philippe L. , Rollins Barrett J. , Sawyers Charles L. ,   on behalf of the AACR Project GENIE Consortium
Published: July 2017

AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) is a multi-phase, multi-year, international data-sharing consortium whose goal is to generate an evidence base for precision cancer medicine by integrating and linking clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. The project fulfills an unmet need in oncology by providing the statistical power necessary to identify novel therapeutic targets, to understand genomic determinants of response to therapy, to design new biomarker-driven clinical trials and ultimately, to improve clinical decision-making and the care delivered to patients. Here we describe the goals, structure and data standards of the GENIE consortium and conclusions from a high-level analysis of the first public release of genomic and limited clinical data from approximately 19,000 patients treated at eight cancer centers obtained during this initial phase of the project. We also explore the clinical utility of these genomic data by examining rates of clinical actionability across multiple cancer types and by estimating patient enrollment rates to the NCI MATCH Trial. Based on yearly rates of sequencing at each of the eight founding institutions, together with the planned addition of new members, we estimate the GENIE database could grow to >100,000 samples within five years. Consistent with the goals of the proposed Cancer Moonshot National Cancer Data Ecosystem, GENIE is committed to the principles of generating interoperable, open access data that can be widely shared across the entire scientific community.

Citation Format: Ethan Cerami, Alexander S. Baras, Justin Guinney, Eva Lepisto, Trevor J. Pugh, Nikolaus Schultz, Thomas Stricker, Shawn M. Sweeney, Laura J. van't Veer, Gerrit A. Meijer, Fabrice Andre, Victor E. Velculescu, Kenna R. Shaw, Mia A. Levy, Philippe L. Bedard, Barrett J. Rollins, Charles L. Sawyers, on behalf of the AACR Project GENIE Consortium. Landscape analysis of the initial data release from AACR Project GENIE [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-102. doi:10.1158/1538-7445.AM2017-LB-102
Abstract LB-126: PPARgamma agonists sensitize PTEN-deficient lung cancer cells resistant to EGFR tyrosine kinase inhibitors
Authors: To Kenneth KW , Tong Wing Sum , Wu William KK , Loong Herbert HF
Published: July 2017

We aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of lung cancer. EGFR TKIs are approved for treating advanced lung cancer that harbors the sensitizing EGFR mutations. However, resistance to EGFR TKIs is almost inevitable for all patients due to multifactorial mechanisms. The PI3K/Akt/mTOR pathway is a major signaling pathway regulated by EGFR to drive cancer survival. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates PTEN to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to intrinsic resistance to EGFR TKIs. Therefore, PPARγ agonists are hypothesized to overcome EGFR TKI resistance. Using well defined human non-small cell lung cancer (NSCLC) cell model with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARγ agonists was demonstrated. PPARγ agonists were found to upregulate PTEN, subsequently inhibit the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI). Specific PPARγ inhibitor (GW9662) and genetic silencing of PPARγ were shown to prevent this potentiation of anticancer activity by PPARγ agonists, thus confirming the crucial role played by PPARγ activation. Interestingly, the tested PPARγ agonists were also found to induce autophagy, as evidenced by the increased expression of an autophagy marker LC3-II and the autophagic degradation of p62/SQSTM1. PPARγ agonists-induced autophagic cell death was believed to contribute to the circumvention of resistance in PTEN-deficient cells because the genetic silencing of ATG5 (an autophagy mediator) was found to eliminate the drug potentiation effect by the PPARγ agonists.

Our findings thus provide the basis for the rational and personalized use of PPARγ agonists in combination with EGFR TKIs in lung cancer patients with specific resistance mechanism.

Citation Format: Kenneth KW To, Wing Sum Tong, William KK Wu, Herbert HF Loong. PPARgamma agonists sensitize PTEN-deficient lung cancer cells resistant to EGFR tyrosine kinase inhibitors [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-126. doi:10.1158/1538-7445.AM2017-LB-126
Abstract LB-130: Tumor regression in novel triple therapy BRAF mutant metastatic melanoma patient-derived preclinical models
Authors: Harris Antoneicka L. , Thompson Michael , Markovic Svetomir , Durham William , Dawson Louis , Small Daniel , Copland John A.
Published: July 2017

Metastatic melanoma (MM) is the most aggressive type of skin cancer contributing to approximately 80% of all skin cancer related deaths. In 2016, it was estimated that more 76,000 cases would be diagnosed in the United States. The high metastatic potential and aggressive clinical behavior of this disease makes it a major health problem. As a consequence there has been notable development in for novel targeted (i.e. BRAF inhibitors) and immune therapies (i.e. anti-PD1 and CTLA4 inhibitors). However, despite improvements in patient outcomes, most patients develop resistance within 6-11 months on dual BRAF/MEK inhibition, and 5 months on immune therapy, highlighting the need to identify new therapies that improve disease management and patient survival. Increased expression of CyclinD1 has been reported to occur as a mechanism of resistance to BRAF inhibition, resulting in reactivation of the canonical activating pathway in melanoma, MAPK. Thus, we hypothesize that combined inhibition of CDK4/6 and MAPK signaling will provide a novel anti-tumor synergy drug combination superior to current standard of care in BRAF mutant patient-derived preclinical models. Using MM human tissue from patients we developed 3 BRAF mutant preclinical models investigating a novel triple therapy drug combination BRAFi/MEKi/CDK4/6i. Protein analysis and drug proliferation assays were used to design the novel combination. In vivo, we found statistically significant differences in tumor inhibition between the novel combination and the current standard of care. The triple therapy also showed promising results, in vivo, when assessed as a salvage therapy following tumor escape from BRAFi/MEKi combination treatment.

Citation Format: Antoneicka L. Harris, Michael Thompson, Svetomir Markovic, William Durham, Louis Dawson, Daniel Small, John A. Copland. Tumor regression in novel triple therapy BRAF mutant metastatic melanoma patient-derived preclinical 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-130. doi:10.1158/1538-7445.AM2017-LB-130
Abstract LB-142: Identification of STK33 as a cancer stemness kinase and regulator of Nanog function
Authors: Tran Susan L. , Furuta Yudai , Zhu Chen , Yang Ao , Sun Xiangao , Rogoff Harry A. , Li Chiang J.
Published: July 2017

In recent years evidence has accumulated in support of the cancer stem cell (CSC) model in cancer chemotherapy resistance, highlighting the urgency and necessity of identifying CSC targets for developing novel cancer therapeutics. A number of studies have suggested that Nanog is a crucial factor that can confer stemness properties to a portion of the heterogeneous cancer cell population. Although latent in normal somatic cells, aberrant expression of Nanog has been reported in many types of human cancers. Importantly, the expression levels of Nanog are often positively correlated with treatment resistance and poor survival of cancer patients. Various studies have shown that upregulation of Nanog expression enhances the tumorigenicity both in vivo and in vitro whereas repression or ablation of Nanog inhibits tumor initiation. Thus, expression of the stemness factor Nanog is linked to tumor progression, therapeutic resistance, relapse and metastasis.

However, Nanog is considered a non-druggable target. Here we provide data to support a role for STK33 (Serine Threonine Kinase 33) as a novel regulator of Nanog and as a potential therapeutic target. Ectopic STK33 expression promotes stemness phenotypes of cancer cells and increases expression levels of CSC drivers including Nanog, KLF4, and SOX2. On the other hand, knockdown of STK33 inhibits expression of Nanog and results in a reduction of the stemness phenotype. STK33 directly interacts with Nanog and appears to promote its stabilization through phosphorylation, resulting in increased Nanog transcriptional activity. Moreover, BBI-503 (Amcasertib), a first-in-class cancer stemness inhibitor, potently inhibits STK33, which led to inhibition of phosphorylation of Nanog. Collectively, our data demonstrate STK33 is a critical element in the signaling network that governs the stemness of cancer cells, and as a promising therapeutic target for cancer.

Citation Format: Susan L. Tran, Yudai Furuta, Chen Zhu, Ao Yang, Xiangao Sun, Harry A. Rogoff, Chiang J. Li. Identification of STK33 as a cancer stemness kinase and regulator of Nanog function [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-142. doi:10.1158/1538-7445.AM2017-LB-142
Abstract LB-143: Identification of STAT3-NRF2-hypoxia as a novel reinforcing mechanism for promoting cancer stemness
Authors: Tavera Luz Elisa , Simon Karen , Li Juying , Geromini Katherine , Zhang Zhuo , Keates Sarah , Rogoff Harry A. , Li Chiang J.
Published: July 2017

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively activated in many cancer types, and has been identified as a major mediator of cancer stemness (Li et.al., PNAS 2015). The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) is the reactive oxygen species (ROS) sensor and a master regulator of antioxidant gene expression. NRF2 has recently been implicated in contributing to cancer stem cell phenotypes, chemoresistance, and is associated with poor clinical prognosis. Hypoxia is considered a major feature of the tumor microenvironment as it can promote tumor progression, increased stemness characteristic, and resistance to conventional therapeutic intervention. Hypoxia can regulate a series of stress-sensor transcription factors, notably, the reactive oxygen species (ROS) sensor and response modulator NRF2.

We studied NRF2 transcript and protein levels in breast cancer cell lines MCF7 and AU565 cells under both hypoxic and normoxic conditions. Our data shows that in response to STAT3 pathway activators, NRF2 is upregulated at both mRNA and protein levels under hypoxia and this upregulation is STAT3 dependent. NRF2 ChIP-Seq experiments demonstrate that both hypoxia and STAT3 stimulation can modulate NRF2 binding in MCF-7 breast cancer cells. Surprisingly, under hypoxic conditions, STAT3 activation dramatically enhances (10 fold) NRF2 binding sites across the genome. Downstream analysis of NRF2 target genes revealed a significant change from stress response to activation of gene signaling pathways involved in stemness-high cancer cells and metastatic cells under both hypoxic and STAT3 stimulation. Finally, we investigated whether the stemness inhibitor BBI-608 (Napabucasin) could reduce chemotherapy-induced NRF2 upregulation. Our results indicate that STAT3 modulates NRF2 levels and transcriptional activity, and that stemness inhibitor BBI-608 can prevent this upregulation. Our data revealed STAT3-NRF2-Hypoxia as a novel reinforcing regulatory mechanism for promoting cancer stemness and chemoresistance.

Citation Format: Luz Elisa Tavera, Karen Simon, Juying Li, Katherine Geromini, Zhuo Zhang, Sarah Keates, Harry A. Rogoff, Chiang J. Li. Identification of STAT3-NRF2-hypoxia as a novel reinforcing mechanism for promoting cancer stemness [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-143. doi:10.1158/1538-7445.AM2017-LB-143
Abstract LB-155: Effects of alcohol consumption, cigarette smoking, betel quid chewing in upper digestive disease: A large cross-sectional study in Taiwan and meta-analysis
Authors: Chuang Yun-Shiuan , Wu Meng-Chieh , Lin Pi-i , Yu Fang-Run , Wang Yao-Kuang , Wu Deng-Chyang , Wu I-Chen , Wu Ming-Tsang
Published: July 2017

Alcohol drinking and cigarette smoking are well-known risk factors of upper digestive diseases, especially esophageal cancer. In Taiwan, betel quid chewing is another common risk factor. This study investigated the association between use of these three substances and upper digestive diseases. We collected data from 9,275 patients (>20 years) receiving esophagogastroduodenoscopy at four hospitals starting in 2008. Multiple imputation was used to handle missing questionnaire data and polynomial regressions were used to analyze the association between risk factors and clinical stage in the esophagus, stomach and duodenum. A random effects model was used to perform a meta-analysis and arrive at overall odds ratio and 95% confidence intervals. Participants who habitually smoked cigarettes, drank alcohol and chewed betel areca simultaneously had a 16.32-fold risk of esophageal cancer (95% CI =7.13-37.36), 2.93-fold risk of Barrette’s esophagus (95% CI =1.99-4.30), 1.59-fold risk of grade A-B erosive esophagitis (95% CI = 1.27-1.98), 1.97-fold risk of gastric ulcer (95% CI =1.50-2.59), 2.10-fold risk of duodenitis (95% CI =1.54-2.87) and 1.27-fold risk of duodenal ulcer (95% CI =1.00-2.69). Using more substances concurrently was associated with a significant trend at higher risk to develop those diseases. Meta-analysis also revealed the use of three substances came with a high risk of esophageal diseases. Our data concluded that cigarette smoking, alcohol drinking and betel quid chewing were associated with upper digestive tract disease. People who habitually used all three substances in Taiwan were at significantly higher risk of developing Barrette’s esophagus and esophageal cancer. This extremely high elevated risk of esophageal cancer alarms the clinical community and proper public health measures must be implemented in the clinical setting when identifying patients with exposure to the three risk factors.

Citation Format: Yun-Shiuan Chuang, Meng-Chieh Wu, Pi-i Lin, Fang-Run Yu, Yao-Kuang Wang, Deng-Chyang Wu, I-Chen Wu, Ming-Tsang Wu. Effects of alcohol consumption, cigarette smoking, betel quid chewing in upper digestive disease: A large cross-sectional study in Taiwan and meta-analysis [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-155. doi:10.1158/1538-7445.AM2017-LB-155
Abstract LB-157: Association of aflatoxin and gallbladder cancer in Shanghai
Authors: Koshiol Jill E. , Gao Yu-Tang , Dean Michael , Egner Patricia , Nepal Chirag , Jones Kristine , Wang Bingsheng , Rashid Asif , Lou Wen , Dyke Alison Van , Ferreccio Catterina , Malasky Michael , Shen Ming-Chang , zhu Bin , Andersen Jesper , Hildesheim Allan , Hsing Ann W. , Groopman John
Published: July 2017

Background: Aflatoxin, which is a risk factor for developing hepatocellular carcinoma, may also cause gallbladder cancer (GBC). We hypothesized that GBC patients have higher aflatoxin exposure than gallstone patients.

Methods: We used samples and data from the Shanghai Biliary Tract Cancer Case-control Study conducted from 1997-2001. Of the 267 GBC and 730 gallstone participants with plasma available, 250 GBC patients and 250 controls with gallstones were randomly selected for measurement of aflatoxin B1 (AFB1)-lysine plasma adducts using isotope dilution mass spectrometry. In 54 GBC patients, tumor tissue was examined for the aflatoxin-related R249S TP53 mutation through targeted sequencing.

Results: We calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs), as well as the population attributable fraction (PAF). AFB1-lysine adduct detection was nearly 3-fold higher in GBC patients (OR, 2.96; 95% CI, 1.90 to 4.61). Among the 85 GBC patients (34%) with detectable AFB1-lysine adduct levels, the median was 4.6 pg/mg, compared to 1.2 pg/mg among the 37 gallstone-patient controls (15%) with detectable levels, and the OR was 9.97(95% CI, 2.73 to 36.44) for quartile 4 versus 1 in GBC compared to gallstone patients. The PAF for cancer related to aflatoxin was 22% (95% CI: 17%-27%). In 54 GBC patients, tumor tissue was examined for the aflatoxin-related R249S TP53 mutation through targeted sequencing, however, all patients were negative for the mutation.

Conclusions: Aflatoxin is significantly associated with GBC, although it does not appear to be correlated with the R249S TP53 mutation in the gallbladder. If aflatoxin is shown to cause GBC, it may have accounted for up to 22% of the gallbladder cancers in Shanghai during the study period and may account for an even higher proportion in high-risk areas. If verified, reducing aflatoxin exposure may reduce GBC incidence.

Citation Format: Jill E. Koshiol, Yu-Tang Gao, Michael Dean, Patricia Egner, Chirag Nepal, Kristine Jones, Bingsheng Wang , Asif Rashid, Wen Lou, Alison Van Dyke, Catterina Ferreccio, Michael Malasky, Ming-Chang Shen, Bin zhu, Jesper Andersen, Allan Hildesheim, Ann W. Hsing, John Groopman. Association of aflatoxin and gallbladder cancer in Shanghai [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-157. doi:10.1158/1538-7445.AM2017-LB-157
Abstract LB-167: A novel metabolite of citrus tangeretin epigenetically inhibits the growth of human prostate cancer cells
Authors: Chao Yen-Hsiang , Su Zheng-Yuan
Published: July 2017

Prostate cancer is the second leading cause of cancer death in men in the United States. Polymethoxyflavonoids (PMFs) such as tangeretin which exclusively exist in citrus fruit peels have been studied to have many bioactivities. In this study, we investigated the inhibitory effect of the metabolites of tangeretin in human prostate cancer LNCaP and PC3 cells. The results showed that PMF1 is a synthetic tangereitin metabolite can significantly inhibits the growth of LNCaP and PC-3 cells (IC50 14.0 and 13.5 µM, respectively) while PMF1 at 15 µM cannot affect the growth of human normal prostate epithelial RWPE-1 cells. The results of the anchorage-independent growth analysis indicated that PMF1 can suppress the colony formation in LNCaP and PC-3 cells as well as LNCaP and PC-3 stem-like cells which were isolated when the parent cells were cultured in the serum-free medium on the ultra-low attached dishes. Furthermore, PMF1 can induce apoptosis in LNCaP cells in which PMF1 increases protein expressions of Bax and Bad and decreases protein expressions of procaspases-3 and Bcl-2. We also found that PMF1 also decreases the protein levels of DNA Methyltransferase 1 and histone deacetylases 1, 2, and 4/5/9. These results suggested that PMF1 might effectively inhibit the growth of human prostate cancer cells as well as prostate cancer stem cells, which provides new insights in the prevention and treatment of prostate cancer.

Citation Format: Yen-Hsiang Chao, Zheng-Yuan Su. A novel metabolite of citrus tangeretin epigenetically inhibits the growth of human prostate cancer cells [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-167. doi:10.1158/1538-7445.AM2017-LB-167
Abstract LB-172: Chemotherapy impact on the gut microbiota: clinical trial on patients
Authors: Pensec Cindy , Martino Alessandra De , Serres Laure-Anne ,   IMODI consortium, Amouzou Yao , Leuillet Sebastien , campone Mario , Carton Thomas , VACON Françoise LE
Published: July 2017

The French Consortium IMODI (Innovative MODels Initiative) aims to develop predictive preclinical mouse models for new chemotherapeutic treatment discovery, to progress toward personalized medicine. In this consortium, Biofortis Merieux NutriSciences issue is to better understand the relation between gut microbiota and cancer, particularly during chemotherapeutic treatment. Because chemotherapy can lead to disruption in microbiota composition and several side effects, our purpose is to identify and track the impact of chemotherapy treatment on the gut microbiota.

To this aim, we coordinate a clinical study to recruit patients with four types of cancer (breast, ovary, liver and prostate) from 7 clinical centers. Gut microbiota composition is assessed by targeted metagenomic, from patient stool samples, collected before, during and after chemotherapy. The 16S rDNA sequences will be analyzed using an in-house bioinformatic pipeline based on mothur software.

Interestingly, preliminary results from preclinical studies showed that some chemotherapeutic treatments could have an effect on gut microbiota composition associated with weight loss. These results support that microbiota is an important additional parameter for evaluating the efficacy and the toxicity of pharmacological treatments. The clinical study is ongoing to better understand the effect of chemotherapy on the gut microbiota. This approach may lead to beneficial intervention for cancer patients, particularly to minimize side effects and infectious complications.

Note: This abstract was not presented at the meeting.

Citation Format: Cindy Pensec, Alessandra De Martino, Laure-Anne Serres, IMODI consortium, Yao Amouzou, Sebastien Leuillet, Mario campone, Thomas Carton, Françoise LE VACON. Chemotherapy impact on the gut microbiota: clinical trial on patients [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-172. doi:10.1158/1538-7445.AM2017-LB-172
Abstract LB-176: Extracts of Psidium guajava (guava) and Syzygium samarangense (wax apple) leaves and teas with Nrf2 induction activity protect mouse AML12 hepatocytes from tumor-initiating acetaminophen-induced damage
Authors: Su Zheng-Yuan , Chan Yen-Fan , Chen Pei-Chun , Sung Ping-Hua , Lin Zi-Han
Published: July 2017

The liver is the primary organ responsible for the major detoxifications and metabolic functions in the human body; however, liver carcinogenesis can be triggered by acetaminophen (paracetamol, APAP), a tumor-initiator. Nrf2 is a master regulator to induce the expression of phase II detoxification/antioxidant enzymes. Some of fruit plant leaves in Taiwan have hepatoprotective potential, including Psidium guajava (guava) leaves (GL) and Syzygium samarangense (wax apple) leaves (WAL) as well as the processing guava tea (GT) and wax apple tea (WAT). In this study, we found that water extracts (WE), including GL-WE (250 μg/mL), WAL (250 μg/mL), GT (500 μg/mL), and WAT (500 μg/mL) without cytotoxicity can active Nrf2 pathway at 24 hrs in HepG2-C8 cells which are stably transfected with an antioxidant response element (ARE)-luciferase construct. These extracts also effectively recovered the cell viability of mouse liver AML12 cells with APAP-induced injury when the cells were pretreated with the extracts for 24 hrs and then co-treated with extracts and APAP for another 48 hrs. A better understanding of the mechanisms how these extracts inhibit oxidative stress/inflammation related to APAP-induced liver carcinogenesis in the future would open new avenues of approaches for the prevention of liver cancer in human.

Citation Format: Zheng-Yuan Su, Yen-Fan Chan, Pei-Chun Chen, Ping-Hua Sung, Zi-Han Lin. Extracts of Psidium guajava (guava) and Syzygium samarangense (wax apple) leaves and teas with Nrf2 induction activity protect mouse AML12 hepatocytes from tumor-initiating acetaminophen-induced damage [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-176. doi:10.1158/1538-7445.AM2017-LB-176
Abstract LB-177: Chemopreventive effect of aged citrus peel (Chenpi) extracts against tumor initiator acetaminophen-induced hepatotoxicity through regulating Nrf2 pathway
Authors: Lin Zi-Han , Luo Wan-Tzu , Chan Yen-Fan , Su Zheng-Yuan
Published: July 2017

The liver is a critical organ responsible for the major detoxification and metabolism in the human body. Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but it has been demonstrated to be a cancer-initiating agent to induce liver cancer. Aged Citrus peel (Chenpi, CP) is a Chinese herb with hepatoprotective potential to be usually used as foods in Taiwan. Three extracts of CP were prepared in this study, including water extract (CP-WE), ethanol extract (CP-EE), and water extraction residue ethanol extract (CP-WREE). Among these extracts, we found CP-WREE (100 μg/mL) can effectively enhance the Nrf2-ARE pathway in HepG2-C8 cell line which is stably transfected ARE-luciferase construct. CP-WREE (50 μg/mL) also exhibit a significant protective effect on the mouse AML12 hepatocytes from APAP-induced damage. We further find that CP-WREE enhances the activity of some glutathione-related enzymes and inhibits lipid peroxidation in AML12 cells. Furthermore, CP-WREE can also increase the expressions of Nrf2 and Nrf2 downstream enzymes while the expressions of some epigenetic modifying enzymes are regulated. Therefore, CP-WREE may have beneficial effects to protect liver carcinogenesis caused by APAP-induced damage through the regulation of Nrf2/antioxidant pathway as well as epigenetic modification.

Citation Format: Zi-Han Lin, Wan-Tzu Luo, Yen-Fan Chan, Zheng-Yuan Su. Chemopreventive effect of aged citrus peel (Chenpi) extracts against tumor initiator acetaminophen-induced hepatotoxicity through regulating Nrf2 pathway [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-177. doi:10.1158/1538-7445.AM2017-LB-177
Abstract LB-191: Combination checkpoint inhibitor therapy: Anti-PD1 and Beta-alethine lead to complete responses of melanoma in a syngeneic mouse model
Authors: Taub Floyd E. , Wright Suzin , Guth Amanda
Published: July 2017

Previously we reported that the combination of anti-PD1 and β-alethine completely stopped cancer growth in a syngeneic mouse melanoma model even under conditions when neither of the drugs had statistically significant effects as a single agent. In order to further examine this dramatic result, we extended the studies, evaluated immune parameters and tested if long-term immunity to re-challenge occurred. Surprisingly, three low doses of anti-PD1, spread over 9 days, were sufficient to allow concurrent and continuing weekly dosing of β-alethine to not only halt tumor growth, but to reverse it. The established melanoma regressed over the subsequent 4-6 weeks. Even more striking was that the short course of anti-PD1, which failed to reduce cancer growth as a single therapy, altered the immune system such that subsequent treatment with β-alethine was effective. β-alethine therapy, beginning eight days after the conclusion of anti-PD1 therapy, when tumors averaged 40 mm2, was sufficient to cause at least stabilization of cancer in all animals and complete response (no palpable tumor on repeated measurements) in the majority of animals. Statistical comparisons of all animals receiving combination therapy (either concurrently or sequentially) with controls resulted in significant differences using ANOVA for tumor size (p=0.005) or X2 tests for tumor presence (p <0.000). No toxicity was noted in treated animals. This is consistent with previous animal and GLP toxicity studies and the completed human Phase I/II trial. The human trial showed that β-alethine, as a single agent, caused no drug-related adverse events and lead shrinkage or stabilization in all patients with lymphoma who were not anergic to recall antigens pre-trial. The final result of re-challenging the mice with the original Cloudman melanoma at a higher dose than the initial cancer inoculation level will be presented.

Citation Format: Floyd E. Taub, Suzin Wright, Amanda Guth. Combination checkpoint inhibitor therapy: Anti-PD1 and Beta-alethine lead to complete responses of melanoma in a syngeneic mouse model [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-191. doi:10.1158/1538-7445.AM2017-LB-191
Abstract LB-202: A novel neoepitope screening platform for generating effective and safe neoantigen-based vaccines and immunotherapeutics in a hepatocellular carcinoma model
Authors: Chao Cheng-chi , Yuan Fengjiao , Liu Geng , Li Guanglei , Li Bo , Lu Lian , Tian Yaomei , Li Dongli , Zhou Bailing , An Ting , Fan Yingzi , Jiang Chongming , Shu Yang , Lin Honggang , Xu Heng , Yang Hanshuo , zhang Rui , Zhang Xueyan , Cheng Zhen , Huang Rong , Dean Michael , Men Ke , Zhang Xiuqing , Yu Chaoheng , Wang Jian , Cheng Shuang , Yang Huanming , Wang Yantai , Hou Yong , Wei Yuquan , Yang Li
Published: July 2017

Immunotherapy has emerged as a novel and promising strategy for cancer treatment, while available markers for immunotherapy have poor effectiveness and safety. The advance of next-generation sequencing (NGS) technology enables us to identify tumor-specific neoantigen which could be more effective and safer for personalized immunotherapy. In this study, we demonstrated a novel workflow for the development of liver cancer personalized vaccine. Xenograft models for liver cancer were built in mice using Hepa1-6 cell lines. Tumor-specific candidate neoantigen were determined by performed whole exome sequencing (WES) and used a comprehensive bioinformatics pipeline integrating multiple factors such as MHCI-binding affinity fold change (FC), variant allele frequencies (VAFs) of somatic mutation, mRNA expression and hydrophobicity of peptides. The results showed that peptide vaccine of Gpr55 neoantigen not only triggered striking neo-antigen specific CD8+ T cell response, but also significantly inhibited the growth of tumors in both prophylactic and therapeutic models. Moreover, our results demonstrated that VAFs and FC were the effective and safety property for immunogenicity. The identified Gpr55 neoantigen was an ideal vaccine for Hepa1-6 induced xenograft models considering the immunogenicity, anti-tumor effect and safety evaluation. It was also possible to identify and develop highly effective personalized cancer vaccine by our workflow within 13 weeks. The results illustrated huge potential of tumor-specific neoantigen as a potent vaccine for clinical tumor therapy and the workflow built in this study could be used to develop more specific, safer, more effective treatments to all types of cancer patients.

Note: This abstract was not presented at the meeting.

Citation Format: Cheng-chi Chao, Fengjiao Yuan, Geng Liu, Guanglei Li, Bo Li, Lian Lu, Yaomei Tian, Dongli Li, Bailing Zhou, Ting An, Yingzi Fan, Chongming Jiang, Yang Shu, Honggang Lin, Heng Xu, Hanshuo Yang, Rui zhang, Xueyan Zhang, Zhen Cheng, Rong Huang, Michael Dean, Ke Men, Xiuqing Zhang, Chaoheng Yu, Jian Wang, Shuang Cheng, Huanming Yang, Yantai Wang, Yong Hou, Yuquan Wei, Li Yang. A novel neoepitope screening platform for generating effective and safe neoantigen-based vaccines and immunotherapeutics in a hepatocellular carcinoma model [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-202. doi:10.1158/1538-7445.AM2017-LB-202
Abstract LB-247: Early detection of gastric cancer using global and gene-specific promoter DNA methylation in endoscopic biopsies
Authors: Pirini Francesca , Noazin Sassan , Arias Martha Jahuira , Rodriguez-Torres Sebastian , Friess Leah , Michailidi Christina , Cok Jaime , Combe Juan , Vargas Goria , Prado William , Soudry Ethan , Perez Jimena , Yudin Tikki , Mancinelli Andrea , Unger Helen , Ili Carmen , Brebi Priscilla , Berg Douglas , Hayashi Masamichi , Sidransky David , Gilman Robert , Guerrero-Preston Rafael E.
Published: July 2017

Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings. We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Perú, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, genome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC. We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean= 5.74, 95% CI, 4.97-6.50), gastritis patients with metaplasia (mean= 4.81, 95% CI, 3.77-5.84), and gastric cancer cases (mean=3.38, 95% CI, 2.82-3.94), respectively (p<0.0001). Promoter methylation of IRF4 (p <0.0001), ELMO1 (p <0.0001), CLIP4 (p <0.0001), and MSC (p <0.0001), is also associated with increasing severity from gastritis with no metaplasia to gastritis with metaplasia and gastric cancer. Our findings suggest that promoter methylation of IRF4, ELMO1, CLIP4 and MSC and a GDMI > 4, is a useful molecular tool for gastric cancer risk stratification in endoscopic biopsies.

Citation Format: Francesca Pirini, Sassan Noazin, Martha Jahuira Arias, Sebastian Rodriguez-Torres, Leah Friess, Christina Michailidi, Jaime Cok, Juan Combe, Goria Vargas, William Prado, Ethan Soudry, Jimena Perez, Tikki Yudin, Andrea Mancinelli, Helen Unger, Carmen Ili, Priscilla Brebi, Douglas Berg, Masamichi Hayashi, David Sidransky, Robert Gilman, Rafael E. Guerrero-Preston. Early detection of gastric cancer using global and gene-specific promoter DNA methylation in endoscopic biopsies [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-247. doi:10.1158/1538-7445.AM2017-LB-247
Abstract LB-277: Four noval activating and resistance mutations of EGFR drug response targets were discovered in northern Chinese patients
Authors: Tian Geng
Published: July 2017

Background and Objective: Lung cancer is the most rapidly developed cancer in terms ofmorbidity and fatality rate. The presence of EGFR mutations is a useful tool to determine NSCLC patients' prognosis. But there are differences in Eastern Asian and European and American. The aim of this study is to discoveryand validate the new EGFR drug targets in Northern Chinese patients with non-small cell lung cancer (NSCLC) via bioinformatics analysis, molecular biology experiments and clinical outcomes, and raise new possibilities for designing personalized treatments for patients carrying specific mutations.

Methods: In this study, a new computational method and drug model was firstly established by referring to the HotSpot3D[1], which was applied to process mutagenesis data and identify new drug targets. We subsequently applied the computationaltool to more than 500 tumors of NSCLC patients in North China.The captured target DNAs were analyzed by next-generation sequencing using a nine gene lung cancer panel to find somatic variations. We then validated our predictions in cell-line-based experimental combining the results of the clinical follow-up.

Results: We used a new computational tool to analyze more than 500 tumors data of NSCLC patients in North China, discovering several rarely reported druggable mutations, including EGFR mutations (p.Val742Ile, p.Ile789Met, p.Asn842His) with erlotinib, gefitinib, lapatinib and EGFR mutations (p.Ser811Cys) with afatinib. Furthermore, we performed an experiment examining the sensitivity of the EGFR proteins with these variants to the target drugs mentioned above. We found that EGFR with the p.Ile789Metvariant was sensitive to gefitinib, consistent with a previous report [1]. In parallel, of the 500NSCLC patients, 200 were treated with the above targetdrugs, and clinical outcomes of treated patients were collected. The results were consistent with the cell-line-based experiments. Verification of other EGFR variants is still in progress.

Conclusion: In this study, severalnew EGFR druggable mutations were for the first time found and validated in NorthernChinese patients with non-small cell lung cancer (NSCLC). Our results will provide better treatment options for patients carryingthese specific mutations. [1] Niu B, Scott A D, Sengupta S, et al. Protein-structure-guided discovery of functional mutations across 19 cancer types[J]. Nature Genetics, 2016, 48(8).

Citation Format: Geng Tian. Four noval activating and resistance mutations of EGFR drug response targets were discovered in northern Chinese patients [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-277. doi:10.1158/1538-7445.AM2017-LB-277