bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3390: Comprehensive analysis of tumor immunity by integrating transcriptome and methylome
Authors: Wang Xuefeng , Liang Cong 
Published: August 2018

Abstract
Immunotherapy has produced promising results in treating cancers. Further understanding of the crosstalk between tumor and its immune microenvironment is likely to have an immediate impact on therapeutic intervention as well as the development of markers of drug resistance. One main difficulty in quantifying the components of tumor microenvironment is that currently there are considerable technological and analytical barriers to assessing and measuring tumor immunity in situ. In this work, we propose to improve the prediction of cell mixtures by both gene expression and epigenetic information. The vast amount of DNA methylation data has been collected in public domain but remains under-analyzed and largely disconnected. No studies have yet investigated the value of using existing methylation panels for immune cell deconvolution in tumor tissues. In our preliminary data, we have observed a strong association between DNA methylation probes and immune signatures such as total TCR expression and tumor infiltrates estimation in melanoma and breast cancer. We have built a more rigorous prediction model based on methylation markers and to extend the analyses to all major cancer types. The results will be externally validated with pooled data from published studies with eligible methylation assay and immune signature measurements. We work closely with immunology scientists to perform a critical evaluation of the robustness and reproducibility of the predictive models. Results of the study, if validated, will have immediate clinical application in screening patient immunity, and will further support the hypothesis that the DNA methylome adds a new dimension to the pan-omic snapshot of cancer immunity and tumor microenvironment. Based on the proposed analytical framework, future prospective studies can be developed using newer methylation platforms—to compare patient groups with different immune conditions and patients in different stages of treatment.
Citation Format: Xuefeng Wang, Cong Liang. Comprehensive analysis of tumor immunity by integrating transcriptome and methylome [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 3390.
Abstract 3391: Comparison of gene copy number variations (CNV) in primary and metastatic lung cancers
Authors: Shi Yunfei , Mao Naiquan , Ding Xiao , Guo Jianji , Guo Gang , Chen Zheng , Gu Weiguang , Dai Lei , Wen Shiwang , Jia Hui , Tian Ziqiang , Shi Junping , Guo Taiyan , Yao Jicheng , Pang Fei , Chirn Gungwei , Yao Ming 
Published: August 2018

Abstract
Background: Characterization of genomic alterations that drive patient disease development is critical in cancer management. The genomic alteration and population characteristics between the primary tumors and metastases in patients with non-small cell lung cancer (NSCLC) is still unclear. Here we evaluated the frequency and distribution of all classes of genomic alterations in both primary and metastatic NSCLC by comprehensive genomic profiling approach.
Methods: FFPE tumor and matched blood samples of 1135 Chinese NSCLC patients (female:male is 670: 465), including 954 primary tumors and 181 metastases, were collected for next-generation sequencing (NGS) based panel assay. Gene copy number variations (CNV) including gene amplifications and deletions, short variants, and gene fusions were assessed.
Results: On average, 0.65 gene copy number variations were detected in the 181 metastatic lesions, which is higher than 0.43 CNVs per sample in the primary lesions (p value is 0.003). No significant difference was found in short variants (2.48 vs 2.31), fusions (0.27 vs 0.20) and germline mutations (0.26 vs 0.31) between the primary and metastatic NSCLC. In the top-ranked genes with copy number alterations, EGFR amplifications were detected in 11% of the primary and 15% in metastases. MET amplifications, CDKN2A/B deletions, and PMS2 deletions were more frequently found in metastatic lesions: MET (7.7% vs 1.7%, p=0.0001), CDKN2A (5.5% vs 1.5%, p=0.002), CDKN2B (5.0% vs 1.9%, p=0.0007), and PMS2 (3.9% vs 1.2%, p=0.016).
Conclusions: Copy number variations are common driver mutations in NSCLC. We reported here that the prevalence of copy number variations between primary and metastatic lung cancers was different, including driver genes MET, CDKN2A/B, and PMS2. No difference was observed in terms of frequency on short variants or gene fusions in NSCLC.
Citation Format: Yunfei Shi, Naiquan Mao, Xiao Ding, Jianji Guo, Gang Guo, Zheng Chen, Weiguang Gu, Lei Dai, Shiwang Wen, Hui Jia, Ziqiang Tian, Junping Shi, Taiyan Guo, Jicheng Yao, Fei Pang, Gungwei Chirn, Ming Yao. Comparison of gene copy number variations (CNV) in primary and metastatic lung cancers [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 3391.
Abstract 3458: Neurotensin increases breast cancer proliferation through activation of AMPK
Authors: Johnson Jeremy , Li Jing , Evers B. Mark 
Published: August 2018

Abstract
Introduction. Neurotensin (NT), a thirteen amino acid peptide predominantly localized to enteroendocrine cells of the small intestine, is released after fat ingestion. While its major role involves regulating lipid metabolism and storage, NT, acting through its high-affinity receptor (NTR1), stimulates the growth and progression of a variety of NTR1-positive cancers. Proneurotensin—a stable precursor produced in equimolar amounts as NT—has been associated with breast cancer development in women, and prior work has implicated the NT/NTR1 axis in breast cancer progression; however, very little is known about the underlying NT signaling pathways that stimulate breast cancer growth. The purpose of this study is to elucidate mechanisms by which NT leads to increased proliferation and aggression of breast cancer—with particular emphasis placed on the role of AMP-activated protein kinase (AMPK). Methods. MCF-7 (estrogen-dependent) and MDA-MB-231 (triple negative) are breast cancer cell lines that express NTR1. (i) Proliferation assays were performed by treating both cell lines with NT (0 or 100 nM) in serum-free media for 24, 48, and 72 h and then counting the viable cells. (ii) Next, to assess signaling pathways mediating the effects of NT, both cell lines were treated with NT (0 or 100 nM) in serum-free media for 15 min, 30 min, 1 h, 6 h, 12 h, and 24 h; immunoblotting was performed for phosphorylated and total forms of AMPK and its downstream effector acetyl CoA carboxylase (ACC). Results. (i) Increased proliferation of MCF-7 cells treated with NT (100 nM) was observed after serum-starvation for 48 h. While MDA-MB-231 cells treated with NT demonstrated improved survival after serum-starvation for 48 h, the effects were not significantly different. (ii) NT induced activation of AMPK and ACC in MCF-7 cells after treatment for 6 and 12 h, but these effects were not observed in MDA-MB-231 cells. Conclusions. Our findings suggest a possible linkage between NT and increased proliferation of estrogen-dependent breast cancer cells through activation of AMPK and its downstream effector proteins. These effects were minimal in NTR1-expressing triple negative breast cancer cells, suggesting that the molecular classification of the tumor plays an important role in NT signaling and downstream effects. Further delineation of the differential effects of NT in specific breast cancer phenotypes has the potential to identify novel therapeutic targets in the treatment of this disease.
Citation Format: Jeremy Johnson, Jing Li, B. Mark Evers. Neurotensin increases breast cancer proliferation through activation of AMPK [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 3458.
Abstract 3493: Promoting role of AKR1B10 in HER2+ breast cancer at early stage
Authors: Khoshaba Ramina , Cao Deliang 
Published: August 2018

Abstract
Background:
Breast cancer is the second most common cause of female cancer-related death in the United States. Aldo-keto reductase 1B10 (AKR1B10) is a 35-kDa protein that is highly expressed in breast cancer in infiltrative and Ductal Carcinoma in Situ (DCIS) stages. Human epidermal growth factor receptor2 (HER2) is a tyrosine kinase receptor which is highly expressed in 15-20% of infiltrative breast cancer but over 60-70 % in DCIS.
Methods:
We targeted AKR1B10 and HER2 expression using AKR1B10 and HER2 expression lentiviruses in a panel of breast cancer cell lines that have different endogenous expression status of AKR1B10 or HER2, including MCF-7(AKR1B10-/HER2 low), ZR-75-1(AKR1B10-/HER2+), MDA-MB-468 (AKR1B10+/HER2-) and the normal human mammary cells MCF10A (AKR1B10-/HER2-). We investigated the effects of AKR1B10 or HER2 expression on cell proliferation, clonogenicity, adhesion, migration, and invasion. Western blots were performed to check integrin α5, δ-catenin expression and the phosphorylation of signaling proteins in Raf/MEK/ERK and AKT/P-mTOR pathways.
Results:
Our data showed that AKR1B10 promoted the proliferation of HER2+ human breast cancer cell. The results of colony forming and soft agar assays demonstrated that AKR1B10 stimulated clonogenic efficiency of HER2+ cells. Also, AKR1B10 promoted HER2+ cells adhesion to extracellular matrix, facilitated their migration and significantly increased their invasion capability. Moreover, it upregulated integrin α5, δ-catenin expression, and promoted HER2+ cells growth and invasiveness through the activation of AKT/mTOR and Raf/MEK/ERK pathways
Conclusion:
AKR1B10 promotes HER2+ human breast cancer cell proliferation and invasiveness.
Citation Format: Ramina Khoshaba, Deliang Cao. Promoting role of AKR1B10 in HER2+ breast cancer at early stage [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 3493.
Abstract 3497: Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma
Authors: Kim Young Saing , Lee Soon Il , Park Se Hoon 
Published: August 2018

Abstract
Purpose: Muscle-invasive urothelial carcinoma (UC) has a poor prognosis and novel approaches to systemic therapy are required. Recent studies show that FGFR3 activation is an important contributor to tumor development and angiogenesis in UC. Therefore, FGFR3 is a potential therapeutic target in UC. The purpose of this study was to evaluate the rates and types of FGFR3 aberrations in invasive UC.
Methods: We analyzed primary tumor samples from 74 UC patients who had received radical cystectomy (n=40) or ureteronephrectomy (n=34). Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay were used to detect FGFR3 aberrations.
Results: Fifty-four patients (73%) had high-grade tumors, and 62% had lymph node involvement. Sixteen patients (22%) harbored FGFR3 alterations, the most common of which was FGFR3 mutations (n=13). These mutations included Y373C (n=3), N532D (n=3), R248C (n=2), S249C (n=2), G370C (n=1), A797P (n=1), and 746_747insG (n=1). In all three patients with FGFR3 rearrangement, the fusion partner was TACC3. The frequency of FGFR3 aberrations was higher in bladder UC (28%) than in UC of the renal pelvis and ureter (15%), but the difference was not statistically significant (P=0.183). Genes that were co-aberrant with FGFR3 included APC (88%), PDGFRA (81%), RET (69%), and TP53 (69%).
Conclusions: FGFR3 abnormalities are less frequently seen in upper tract UC than bladder UC. Patient selection could be critical in designing new approaches for anti-FGFR3 therapy in the perioperative setting.
Citation Format: Young Saing Kim, Soon Il Lee, Se Hoon Park. Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma [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 3497.
Abstract 350: Che-1/aatf-induced transcriptionally active chromatin promotes cell growth in multiple myeloma
Authors: Bruno Tiziana , Nicola Francesca De , Goeman Frauke , Pallocca Matteo , Sorino Cristina , Catena Valeria , Bossi Gianluca , Amadio Bruno , Cigliana Giovanni , Spugnini Enrico , Ricciardi Maria Rosaria , Petrucci Maria Teresa , Baldi Alfonso , Cioce Mario , Cortese Giancarlo , Mattei Elisabetta , Merola Roberta , Gianelli Umberto , Pisani Francesco , Gumenyuk Svitlana , Mengarelli Andrea , Hopker Katja , Benzing Thomas , Floridi Aristide , Passananti Claudio , Blandino Giovanni , Iezzi Simona , Fanciulli Maurizio 
Published: August 2018

Abstract
Tumor transformation is the result of genetic and epigenetic modifications that alter gene transcription, consequently producing a specific oncogenic program. Multiple myeloma (MM) is a neoplasia characterized by the accumulation of proliferating antibodies producing plasma cells in the bone marrow. This disease is the second most frequent haematological malignancy in the US and Europe. In this study we demonstrate that Che-1 plays a crucial role in the control of transcription and cellular proliferation by regulating the state of the chromatin and by increasing its accessibility, highlighting Che-1 as an essential component of the transcription machinery in MM. Che-1 loss induces a global transcription shut-off, by reducing RNA Pol II recruitment onto the DNA. Most importantly, transcriptional inhibition in Che-1 depleted cells could already be detected at pre-mRNA levels, leading to the hypothesis that Che-1 could regulate RNA pol II activity directly. Our study shows that Che-1 is required for the maintenance of open chromatin in MM cells, and is involved in general histone acetylation. Morever, we found that Che-1 downregulation further sensitizes MM cells to bromodomain and extra-terminal (BET) inhibitors. Indeed Che-1 silencing increased JQ1 sensitivity of MM cells. In summary, our findings identify Che-1 as a key player for maintaining the open chromatin structure required for sustaining MM growth. These findings support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.
Citation Format: Tiziana Bruno, Francesca De Nicola, Frauke Goeman, Matteo Pallocca, Cristina Sorino, Valeria Catena, Gianluca Bossi, Bruno Amadio, Giovanni Cigliana, Enrico Spugnini, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Alfonso Baldi, Mario Cioce, Giancarlo Cortese, Elisabetta Mattei, Roberta Merola, Umberto Gianelli, Francesco Pisani, Svitlana Gumenyuk, Andrea Mengarelli, Katja Hopker, Thomas Benzing, Aristide Floridi, Claudio Passananti, Giovanni Blandino, Simona Iezzi, Maurizio Fanciulli. Che-1/aatf-induced transcriptionally active chromatin promotes cell growth in multiple myeloma [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 350.
Abstract 3504: A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE inhibition
Authors: Mahoney Christopher , Pirman David , Chubukov Victor , Sleger Taryn , Padyana Anil , Gross Stefan , Hayes Sebastian , Fan Zi Peng , McDonald Gabrielle , Chen Yu , Murtie Joshua , Cianchetta Giovanni , Nagaraja Raj , Narayanaswamy Rohini , Choe Sung , Murray Stuart , Jin Shengfang , Biller Scott , Roddy Thomas , Smolen Gromoslaw A. 
Published: August 2018

Abstract
Numerous reports have described the differential metabolism of cancer cells as compared to their normal counterparts. However, only relatively few metabolic genes with cancer-specific mutations have been reported and the identification of cancer subsets with particular metabolic vulnerabilities remains a challenge.
To explore potential cancer-specific dependencies, we conducted a chemical biology screen utilizing a collection of small molecule inhibitors targeting diverse metabolic pathways in a large panel of cancer cell lines. A subset of neuroendocrine tumors, particularly small cell lung cancers (SCLC), displayed a striking dependence on squalene epoxygenase, SQLE, an enzyme in the cholesterol biosynthetic pathway. To develop further confidence in these findings, we have determined the first three-dimensional SQLE structure and further advanced a pharmacological toolbox for SQLE. Using these tools, we showed that the observed effects are on target and that the patterns of cellular sensitivity observed in vitro display excellent translation to in vivo xenografts studies. Interestingly, using a variety of orthogonal approaches, we demonstrated that SQLE sensitivity appears not to be related to overall inhibition of the cholesterol pathway but rather to specific and toxic accumulation of the SQLE substrate, squalene.
Collectively, these findings highlight the utility of chemical biology screens and identify SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly SCLC.
Citation Format: Christopher Mahoney, David Pirman, Victor Chubukov, Taryn Sleger, Anil Padyana, Stefan Gross, Sebastian Hayes, Zi Peng Fan, Gabrielle McDonald, Yu Chen, Joshua Murtie, Giovanni Cianchetta, Raj Nagaraja, Rohini Narayanaswamy, Sung Choe, Stuart Murray, Shengfang Jin, Scott Biller, Thomas Roddy, Gromoslaw A. Smolen. A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE inhibition [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 3504.
Abstract 3507: Targeting the insulin-like growth factor-1 receptor in MTAP-deleted renal cell carcinomas
Authors: Xu Jihao , Chang Wen-Hsin , Huang Carissa , Yang David , Chen Ching-Hsien 
Published: August 2018

Abstract
Renal cell carcinoma (RCC) has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes. Patients with metastatic RCC have an unusually poor prognosis and near-universal resistance to all current therapies. To ultimately improve cancer treatment and survival rate, there is an urgent need to reveal the mechanisms by which metabolic enzymes and aberrant pathways regulate oncogenic signaling. Through an integrated two-step analysis of RCC metabolic pathways, we previously identified dysregulated expression of methylthioadenosine phosphorylase (MTAP) in aggressive RCC. An accumulation of cellular methylthioadenosine has been observed in MTAP-deleted cancer cells. Interestingly, we found a decreased of protein-methylation level with concomitant with an increase in tyrosine phosphorylation after MTAP knockout. Next, we performed a phospho-kinase antibody array screen and identified the type 1 insulin-like growth factor-1 receptor (IGF1R) as the top-one candidate with upregulated tyrosine phosphorylation in response to MTAP loss. IGF1R phosphorylation acted upstream of Src and STAT3 signaling in MTAP-knockout RCC cells. Reduction of phospho-IGF1R by a selective inhibitor of IGF-1R, linsitinib, inhibited the cell migration and invasion capability of MTAP-deleted cells. Data from cell viability assays showed that MTAP loss enhanced linsitinib-mediated cytotoxicity in RCC cells. Our data suggest that IGF1R signaling is a driver pathway to confer aggrieves nature of MTAP-deleted renal cell carcinomas.
Citation Format: Jihao Xu, Wen-Hsin Chang, Carissa Huang, David Yang, Ching-Hsien Chen. Targeting the insulin-like growth factor-1 receptor in MTAP-deleted renal cell carcinomas [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 3507.
Abstract 3518: Piperlongumine, a novel treatment option to overcome BRAF inhibitor resistance in melanoma
Authors: Ramachandran Sharavan , Fofaria Neel , Srivastava Sanjay 
Published: August 2018

Abstract
Tumor cell metabolism is a hallmark of chemoresistance and its role has been well-defined in BRAF inhibitor resistance in melanoma. Melanoma cells are highly proliferative and are shown to develop addiction towards the metabolic pathways like glycolysis and mitochondrial respiration to meet energy demands. Melanoma cells predominantly utilize cytosolic aerobic glycolysis or Warburg effect to develop resistance towards BRAF inhibitors (vemurafenib and dabrafenib). Our observations indicated that vemurafenib resistant cells possessed 1.5 fold higher extra-cellular acidification rate (ECAR), an indicator of glycolysis when compared to sensitive cells. We also observed that STAT3, a known regulator of glycolysis was up-regulated in A375 and SKMEL28 BRAF inhibitor resistant cells when compared to the parental cell line. In addition, LDH-A, a key glycolytic enzyme was significantly overexpressed in A375 vemurafenib resistant cells when compared to its parental counterpart. Consequently, we observed that vemurafenib and dabrafenib treatment induces the expression of STAT3 in A375 and SKMEL-28 melanoma cells. Our results showed that piperlongumine inhibits the survival of A375 vemurafenib resistant (A375VR) melanoma cells. Our observations indicated that the combination of piperlongumine with vemurafenib and dabrafenib shows synergistic effects by suppressing 75% - 85% of cell survival when compared to vemurafenib/dabrafenib and piperlongumine (25% - 45%) treatment alone in A375 and SKMEL-28 BRAF inhibitor resistant melanoma cells. Moreover, the combination of piperlongumine with vemurafenib or dabrafenib induced 2-8 fold apoptosis when compared to vemurafenib/dabrafenib and piperlongumine treatment alone in A375 and SKMEL-28 BRAF inhibitor resistant melanoma cells. Piperlongumine treatment reduced the ECAR (glycolysis) in a concentration dependent manner after 12h of treatment in A375VR cells and suppressed nearly 50% of ECAR parameters glycolysis and glycolytic capacity. Treatment of A375VR cells with piperlongumine for 48h inhibited the expression of LDH-A and its upstream regulators pSTAT3 (Y705), β-catenin, c-Myc and HIF-1α as evaluated by western blot. In addition, oral administration of piperlongumine and vemurafenib combination suppressed 86% of tumor growth when compared to vemurafenib treatment. Taken together, our study thus indicate that piperlongumine potentiates the effects of BRAF inhibitors by inhibiting Warburg effect and its upstream regulators. [Supported in part by R01 grant CA129038, awarded to (S.K.S) by the National Cancer Institute.
Citation Format: Sharavan Ramachandran, Neel Fofaria, Sanjay Srivastava. Piperlongumine, a novel treatment option to overcome BRAF inhibitor resistance in melanoma [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 3518.