bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 958: MiR-196b is an epigenetically silenced tumor suppressor for lung cancer
Authors: Tellez Carmen S. , Juri Daniel E. , Do Kieu , Picchi Maria A. , Wang Teresa , Liu Gang , Spira Avrum , Belinsky Steven A. 
Published: July 2016

Abstract
Silencing of microRNAs by promoter hypermethylation could play a significant role in lung cancer initiation and progression. A pre-malignancy model using carcinogen transformed human bronchial epithelial cells (HBECs) treated with the demethylating agent 5-aza-2’deoxycytidine followed by next-generation sequencing identified miR-196b and miR-34c-5p as being epigenetically regulated. Bisulfite sequencing confirmed silencing via dense promoter hypermethylation that was commonly replicated in malignant cell lines and primary tumors. Functional studies of miR-196b revealed that it was epigenetically silenced by chromatin modification and DNA methylation during transformation of HBECs and re-expression modulated genes involved in cell cycle regulation. Stable re-expression led to a cell cycle arrest mediated in part through transcriptional regulation of the FOS oncogene that was replicated in vivo by a profound reduction in growth of tumor xenografts. Luciferase assays demonstrated that forced expression of miR-196b inhibits FOS promoter and AP-1 reporter activity. A case-control study showed that methylation of miR-196b in sputum was strongly associated with lung cancer (OR = 4.7, p&lt;0.001). These studies identify miR-196 as a tumor suppressor whose silencing early in lung carcinogenesis may provide a selective growth advantage to pre-malignant cells. Targeted delivery of this microRNA could benefit prevention and therapy for the management of lung cancer.
Citation Format: Carmen S. Tellez, Daniel E. Juri, Kieu Do, Maria A. Picchi, Teresa Wang, Gang Liu, Avrum Spira, Steven A. Belinsky. MiR-196b is an epigenetically silenced tumor suppressor for lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 958.
Abstract 963: Epigenetic silencing of miR-199a-3p is associated with increased cell survival, enhanced cell motility, and sensitivity to tivantinib through regulation of c-Met expression in hepatocellular carcinoma
Authors: Yasui Kohichiroh , Tomie Akira , Iwai Naoto , Kitaichi Tomoko , Dohi Osamu , Gen Yasuyuki , Itoh Yoshito 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and can act as tumor suppressors or oncogenes. To identify miRNA involved in the development of HCC, we performed a genome-wide miRNA gene expression analysis using the human miRNA microarray (Agilent) in paired tumor and non-tumor tissues from patients with primary HCC. The array-based miRNA expression profiles were validated by quantitative PCR. We also screened for genes with promoter DNA hypermethylation using a genome-wide DNA methylation microarray analysis (the Illumina HumanMethylation27 BeadChip) in primary HCCs. We found that miR-214-3p, miR-199a-5p, and miR-199a-3p were significantly down-regulated by aberrant promoter hypermethylation in HCC tumors. The c-Met gene was identified as the direct target of miR-199a-3p. Our study showed that reduced expression of miR-199a-3p was associated with increased cell survival through the c-Met/Akt pathway and enhanced cell motility through phosphorylation of FAK. The transfection of miR-199a-3p mimic reduced the expression of c-Met and enhanced the sensitivity to the c-Met inhibitor tivantinib in HCC cells. In conclusion, our results suggest that epigenetic silencing of tumor suppressor miR-199a-3p may be involved in hepatocarcinogenesis through regulation of c-Met expressionand and be associated with the sensitivity to tivantinib.
Citation Format: Kohichiroh Yasui, Akira Tomie, Naoto Iwai, Tomoko Kitaichi, Osamu Dohi, Yasuyuki Gen, Yoshito Itoh. Epigenetic silencing of miR-199a-3p is associated with increased cell survival, enhanced cell motility, and sensitivity to tivantinib through regulation of c-Met expression in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 963.
Abstract 969A: The histone methyltransferase EZH2 is a novel target of anticancer therapy in endometrial cancer
Authors: OKI SHINYA , SONE KENBUN , ODA KATSUTOSHI , NISHIJIMA AKIRA , TAKEUCHI MAKOTO , AGAPITI CHUWA , ASADA KAYO , MAKII CHINAMI , KAWANA KEI , OSUGA YUTAKA , FUJII. TOMOYUKI 
Published: July 2016

Abstract
Besides genetic disorders, dysregulation of epigenetic machinery has been proved to play a crucial role in human carcinogenesis, and the histone methylation/demethylation process has been considered as one of key regulators for this event. However, the roles of these alterations in cancer progression have not been well characterized in endometrial cancer. The aim of this study is to elucidate that one of methyltransferases, enhancer of zeste homolog 2 (EZH2) is a novel target of anti-cancer therapy in endometrial cancer.
We demonstrate that EZH2 plays pivotal roles in human endometrial cancer. To confirm these roles, we performed the expression profile of EZH2 in 11 endometrial cancer cell lines and 50 clinical endometrial cancer specimens, under informed consent and approval of our ethics committee. In addition, we performed the functional analysis of
EZH2 using endometrial cancer cell lines. The expression Quantitative real-time PCR revealed that EZH2 is aberrantly overexpressed in endometrial cancer cell lines and clinical samples compared with immortalized endometrial cell line and normal endometrial tissues (P&lt;0.05). The reduction of EZH2 expression by small interfering RNAS resulted in suppression of growth of cancer cells and caused apoptotic cell death in endometrial cancer cell lines.
Our results suggest that dysregulation of EZH2 plays an important role in the growth regulation of endometrial cancer cells, and further functional studies may affirm the importance of EZH2 as a promising therapeutic target for endometrial cancer.
Citation Format: SHINYA OKI, KENBUN SONE, KATSUTOSHI ODA, AKIRA NISHIJIMA, MAKOTO TAKEUCHI, CHUWA AGAPITI, KAYO ASADA, CHINAMI MAKII, KEI KAWANA, YUTAKA OSUGA, TOMOYUKI FUJII. The histone methyltransferase EZH2 is a novel target of anticancer therapy in endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 969A.
Abstract 988: A novel long non-coding RNA, TSA-LINC2, regulates cellular growth and is associated with poor prognosis in breast cancer
Authors: Pichler Martin , Cerk Stefanie , Stiegelbauer Verena , Schwarzenbacher Daniela , Ling Hui 
Published: July 2016

Abstract
Background: Long non-coding RNAs (LINCs) are an emerging class of molecules in cancer diagnosis and prognosis. The number of LINCs exceeds the number of protein-coding genes and their role in breast cancer is largely unknown.
Methods: In this study we used non-adherent growing tumor spheres (“mammospheres”) as a model system to identify tumor-sphere associated (TSA) gene expression patterns. We used microarrays to profile different breast cancer cell lines and selected the most up/down-regulated differentially expressed genes by RT-PCR. Clinical correlations including survival analysis of almost 900 breast cancer patients in two independent cohorts and experimental evaluation of the biological function were done.
Results: Among several TSA-genes, one novel not previously reported LINC, (that we termed TSA-LINC2) was significantly up-regulated in mammospheres (up to 50 fold, p&lt;0.05). In patient samples, TSA-LINC2 was significantly up-regulated in cancer tissue compared to normal breast tissue, and high expression was associated with poor survival in different molecular breast cancer subtypes (p&lt;0.05). Knock-down experiments of TSA-LINC2 in a panel of breast cancer cell lines led to significantly altered cellular growth, anchorage-independent growth and mammosphere formation in triple negative (p&lt;0.05). Molecular profiling with gene expression arrays shows that TSA-LINC2 regulates cell cycle-associated genes.
Conclusion: This novel long non-coding RNAis involved in breast cancer progression and might be useful as a prognostic marker in breast cancer patients.
Citation Format: Martin Pichler, Stefanie Cerk, Verena Stiegelbauer, Daniela Schwarzenbacher, Hui Ling. A novel long non-coding RNA, TSA-LINC2, regulates cellular growth and is associated with poor prognosis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 988.
Abstract 996: STAT3 modulates HOTAIR transcription to influence HNSCC growth in vitro and in vivo
Authors: Zhou Xuan 
Published: July 2016

Abstract
Background
Squamous cell carcinoma is the most common cancer type of head and neck (HNSCC) with poor prognosis. Signal transducer and activator of transcription 3 (STAT3) activation is involved in HNSCC carcinogenesis as a transcript factor. A new class of transcripts, long noncoding RNAs (lncRNAs), has been recently found to be pervasively transcribed in the genome. HOTAIR, lncRNA Hox transcript antisense intergenic RNA, has been characterized as a novel hall marker to predict poor prognosis in HNSCC. HOTAIR regulates downstream target gene transcription by recruiting polycomb repressive complex 2 (PRC2) to the cell nucleus and triggers triple methylation of H3K27.
Methods
RNA sequencing, qPCR and CHIP assay were used to determine HOTAIR is a down-stream gene of STAT3. MTT and western blot were employed to examine the regulatory mechanism between STAT3 and HOTAIR in HNSCC cancers in vitro. Additionally, a cell derived xenograft tumor model was used to further validate the anti tumor effect of targeting STAT3/HOTAIR axis in vivo.
Results
STAT3 depleted HNSCC cell showed decreased HOTAIR expression by qPCR assay. CHIP assay indicated STAT3 bind to the promoter region of HOTAIR encoding gene. Combined inhibition of STAT3 and HOTAIR significantly inhibited cell proliferation, sensitive to cisplatin in HNSCC. Up-regulating HOTAIR partially compensated anti-tumor effect of targeting STAT3 in HNSCC.
Conclusion
Our data suggested that HOTAIR overexpression is depended on constitutive STAT3 activation in HNSCC and targeting STAT3/HOTAIR axis showed significant therapeutic potential in vitro and in vivo.
Citation Format: Xuan Zhou. STAT3 modulates HOTAIR transcription to influence HNSCC growth in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 996.
Abstract 997: Hotair promotes glioma cell cycle through a b-catenin mediated mRNA network
Authors: Wang Qixue , Huang Kai , Ren Yu , Wang Yunfei , Zhou Bingcong , Tan Yanli , Fang Chuan , Li Jie , Kang Chunsheng 
Published: July 2016

Abstract
Background:
LncRNA hotair is an oncogene that involves in the progression of several cancers. Previously we and others have reported that hotair promotes glioblastoma progression by regulating cell cycle. However, further mechanism still needs to be explored. The wnt/b-catenin signaling pathway is a crucial factor in the development of many cancers. B-catenin is a nuclear transcription factor that regulates multiple genes involved in cell proliferation, survival and EMT that contribute to glioma development.
Methods:
Positive correlation genes of hotair were picked up from CGGA (Chinese Glioma Genome Atlas) database by bioinformatics analysis. Real Time PCR is used to test the mRNA expression levels in U87 cells and astrocytes. Western blot is emplored to determine PKM2 expression after knocking down hotair. Further more, and nude mouse glioma intracranial model is employed to examine in vivo impact of hotair on GBM.
Results:
Hotair is a cell cycle related lncRNA as previously reported. Bioinformatics analysis indicated that various genes play important roles on cell cycle are positively correlated with hotair. Theses genes might be the executors of hotair on cell cycle regulating. We constructed a top 18 hotair-related genes network by connectivity. To test the hypothesis, we knock down hotair expression in U87 cells, and found out that FOXM1, CCNA2, CEP55, CENEP, CCNB2, HMMR, NCAPG, NUSAP were down-regulated significantly. In addition, overexpression of hotair in astrocytes could upregulate the mRNA of those genes. To further explore the regulatory mechanism, we analyed the promoter of these hotair-regulated genes and found out b-catenin/TCF4 binding site on all of them. This indicated that hotair might upregulate cell cycle associated genes through b-catenin/TCF4 pathway. FH535 is an inhibitor of wnt/b-catenin. The mRNA expression of these genes could be suppressed by FH535 treatment, which confirms the promoter analysis. It is reported that PKM2 could promote b-catenin nuclear translocation. Interestingly, we found out that binding site of miR-330 exists on both of hotair and PKM2 mRNA. Knocking-down of hotair inhibited PKM2 mRNA and protein expression in U87, U87vIII, U251 and LN229 cells. Further more, hotair siRNA could inhibit glioma growth in vivo.
Conclusion:
Our data indicated that hotair promotes glioma cell cycle through a b-catenin mediated mRNA network, and hotair could be a a biomarker and therapeutic target in glioblastoma. Meanwhile, there are still a lot of work to be done.
Citation Format: Qixue Wang, Kai Huang, Yu Ren, Yunfei Wang, Bingcong Zhou, Yanli Tan, Chuan Fang, Jie Li, Chunsheng Kang. Hotair promotes glioma cell cycle through a b-catenin mediated mRNA network. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 997.
Abstract CT016: Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies
Authors: Aggarwal Rahul , Thomas Scott , Grabowsky Jennifer , Harb Armand , Leng Jim , Reinert Anne , Mastroserio Ilaria , Truong Thach-Giao , Munster Pamela N. 
Published: July 2016

Abstract
Background: PAZ is a tyrosine kinase inhibitor of VEGFR, PDGFR, and c-KIT approved for use in renal cell carcinoma (RCC). ABX is a potent pan-HDAC inhibitor (HDACi). Pre-clinical models suggest that HDACi-mediated epigenetic modulation of VEGF expression prevents PAZ resistance and potentiates efficacy. We therefore designed a Phase I clinical trial combining ABX with PAZ in pts with advanced solid tumors with an expansion cohort in RCC.
Methods: The primary endpoint was the maximal tolerated dose (MTD) of PAZ plus ABX. Secondary endpoints included pharmacokinetics (PK) and efficacy. PAZ was dosed days 1-28 and ABX days 1-5, 8-12, and 15-19 of 28-day cycle (schedule A) with at a starting dose of 400 mg/day and 45 mg/m2 orally twice daily respectively. An alternate ABX dosing schedule days 1-4, 8-11, and 15-18 was investigated (schedule B) due to toxicity of Schedule A.
Results: 52 patients (pts) (RCC; N = 23) with advanced solid tumors were enrolled (N = 22 schedule A; N = 30 schedule B). There were six dose-limiting toxicities including fatigue (N = 2), thrombocytopenia (N = 2), and elevated AST/ALT (N = 2). The most common grade ? 3 related adverse events observed were fatigue (13%), thrombocytopenia (12%), and diarrhea (10%). The MTD was PAZ 800 mg/day + ABX 45 mg/m2 BID on schedule B. 8 evaluable pts (19%) (N = 6 RCC; 2 thyroid; median number of prior lines of therapy = 3) achieved partial tumor response (PR), with median duration of response of 9.2 months (1-33.2+). 7/9 (78%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. 15 out of 48 evaluable pts (31%) experienced stable disease or better for ? 6 months, and two previously PAZ-refractory pts with PRs remain on study for &gt; 20 and 37 mos respectively. PK analyses did not reveal drug-drug interaction. Degree of histone acetylation and metabolomic profile are being evaluated.
Conclusion: The combination of PAZ + ABX was well tolerated and durable tumor control (&gt; 3 yrs) was observed in RCC and thyroid cancer. Tumor regressions observed in majority of PAZ-refractory tumors preliminarily support the potential of ABX to reverse therapeutic resistance. A randomized phase 2 study with cross-over design is planned to further evaluate the combination of PAZ + HDACi.
Citation Format: Rahul Aggarwal, Scott Thomas, Jennifer Grabowsky, Armand Harb, Jim Leng, Anne Reinert, Ilaria Mastroserio, Thach-Giao Truong, Pamela N. Munster. Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT016.
Abstract CT077: PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission): a phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer
Authors: Braunstein Lior Z. , Taghian Alphonse G. , Harris Jay R. 
Published: July 2016

Abstract
Background: Radiation therapy (RT) following breast conserving surgery (BCS) is well-known to improve outcomes for patients with invasive breast cancer. However, RT poses an inconvenience to patients and confers a small, yet real, risk of long-term adverse effects. In addition, reports have suggested that not all patients stand to benefit equally from RT, with certain disease features portending an excellent prognosis regardless of the adjuvant treatment approach. Specifically, favorable luminal A cancers exhibit a 10-year locoregional recurrence (LRR) rate of 2% following BCS and RT, suggesting very low putative risk in the absence of RT. While luminal A breast cancers are the most favorable among subtypes, robustly distinguishing them from luminal B tumors is a challenge. This trial seeks to employ a molecular profiling approach to identify favorable-risk, early-stage breast cancer patients who may feasibly omit RT following BCS.
Methods: To identify a low-risk, luminal A cohort of breast cancer patients, we will employ well-characterized clinicopathologic parameters in addition to molecular profiling. Eligible patients will be 50-75 years of age and must have invasive breast cancer ?2 cm (T1), that is estrogen receptor positive, low- or intermediate-grade, without HER2 amplification, and with negative margins (no ink on tumor) following BCS. Following resection, tumor samples will undergo prediction analysis of microarray 50 (PAM50) profiling via the NanoString Prosigna assay to characterize intrinsic biologic subtype. Patients with tumors classified as luminal A (low-risk score) will be eligible for the omission of RT. The trial is a single-arm prospective cohort study designed to assess the viability of RT omission in this favorable population. The primary endpoint will be LRR at 5 years and a rate of &lt;5% will be considered of interest. Projected accrual will be 345 patients to be enrolled over 4 years. Using this design, the study has 90% power to distinguish a 5-year LRR rate of 1% from 5% using a one-sample exponential test with one-sided type I error of 0.025. Secondary endpoints include 5- and 10-year recurrence rates of any type (local, regional and/or distant), disease-free survival, invasive-disease-free survival and overall survival, in addition to rates of salvage mastectomy and radiotherapy. (ClinicalTrials.gov: NCT02653755)
Citation Format: Lior Z. Braunstein, Alphonse G. Taghian, Jay R. Harris. PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission): a phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT077.
Abstract CT114: Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results
Authors: Tagawa Scott , Chatta Gurkamal S. , Pal Sumanta K. , Goel Sanjay , Mazhari Reza , Heaton Callie , Benaim Ely , Agarwal Neeraj 
Published: July 2016

Abstract
Background: RX-0201, a novel, oligonucleotide that binds native AKT-1 mRNA, prevents downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth in vitro and is in development for the treatment of metastatic clear cell renal carcinoma
Methods: The phase Ib/II proof of concept, multicenter, open label study is conducted in 2 phases. The phase Ib was a dose-escalation study of RX-0201 administered in combination with everolimus. RX-0201 was administered as a continuous intravenous infusion for 14 days followed by 7 days of rest; everolimus was administered at a starting dose of 10mg once daily. Subjects were enrolled at increasing doses of RX-0201 in a modified 3+3 design. Plasma concentrations were measured in phase Ib and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. The dose of RX-0201 identified in phase Ib is being studied further in phase II, which is the randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone.
Results: In the Phase Ib, seven males and 3 females, (median age 61 years) were treated with 125 mg/m⁁2/day (n = 3), 200 mg/m⁁2/day (n = 4), and 250 mg/m⁁2/day (n = 3) RX-0201 in combination with 10 mg everolimus. They received 1-3 lines of therapy prior to study entry (median = 1). The most common toxicities attributed to the combination were rash, mouth ulceration, weight loss, thrombocytopenia, facial edema, fatigue, and pruritus. No significant events were attributed to RX-0201 alone. Most events (81%) were mild or moderate in severity. Based on the tolerability, 250 mg/m⁁2/day RX-0201 dose was declared the recommended phase II dose. Three subjects in the phase Ib have experienced stable disease for 383, 191, and 122 days; a tumor burden reduction of 16 and 36% was seen in 2 subjects. RX-0201 PK demonstrated a dose proportional exposure.
Conclusions: RX-0201, in combination with everolimus, appears to be safe and well tolerated in patients with metastatic renal cancer at doses up to 250 mg/m⁁2/day. Randomized phase II of this trial is currently ongoing.
Citation Format: Scott Tagawa, Gurkamal S. Chatta, Sumanta K. Pal, Sanjay Goel, Reza Mazhari, Callie Heaton, Ely Benaim, Neeraj Agarwal. Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT114.