bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 899: High fat diet induced DNA methylation at transcription factor binding region and repressed gene expression of a metastasis suppressor E-cadherin in primary site of murine metastatic breast cancer (MBC), and promoted invasion of MBC cells to lung and liver
Authors: Zhang Yukun , Wang Wendan , Yang Xujuan , Helferich William G. 
Published: August 2015

Abstract
Breast cancer (BC) is the most prevalent type of cancer among women in the US. BC survival rate has long been compromised by metastasis. Consumption of a high fat diet (HFD) is associated with increased BC risk. However, the underlying molecular mechanisms remain inconclusive. E-cadherin (Cdh1) is a metastasis suppressor, the loss of which promotes tumor invasion. We aimed to examine the effects of a HFD containing 47% kcal from fat on metastatic breast cancer (MBC) using preclinical syngeneic mouse models. To access the dietary effect on metastatic mammary tumor, we injected MBC cells into the mammary duct of BALB/c mice. To evaluate the dietary effect on the spread of MBC from bone to lung and liver tissues, MBC cells were inoculated into tibia cavity of BALB/c mice. Growth of MBC at the injection and inoculation site, and invasion of MBC to other organs were monitored in real-time by the bioluminescence imaging (BLI) system. Three weeks post injection, animals were sacrificed and tissues samples were collected. In summary, our results showed that HFD promoted the invasion of MBC cells to lung and liver of mice. H&E staining showed that there were significantly more lung tumors in the HFD group than control group in the tibial injected animals (12.9±1.6, 8.9±1.1, P&lt;0.05), as well as more mice with liver tumors in HFD group (7 out of 16 mice with liver tumors in HFD group, 0 out of 17 mice with liver tumors in control group). Expression of Cdh1mammary tumor of mice was decreased by HFD. Intensity of methylation at the CpG-rich promoter region, where transcription factors bind, was increased by HFD in the mammary tumor. As the first to report that HFD induced DNA methylation and decreased the expression of Cdh1 in the metastatic mammary tumor, we proposed a mechanism by which HFD enhanced the invasiveness of MBC. Having laid a base and provided clues on HFD and MBC, this study also shed light on the intriguing interactions of nutrient epigenome and BC. Future studies are needed to further extrapolate our findings into the link between diet and disease in BC patients.
Citation Format: Yukun Zhang, Wendan Wang, Xujuan Yang, William G. Helferich. High fat diet induced DNA methylation at transcription factor binding region and repressed gene expression of a metastasis suppressor E-cadherin in primary site of murine metastatic breast cancer (MBC), and promoted invasion of MBC cells to lung and liver [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 899. doi:10.1158/1538-7445.AM2015-899
Abstract 94: Melatonin inhibits stemness of glioblastoma cancer stem-like cells via regulation of histone methylation
Authors: Lee Hyemin , Jung Ji Hoon , Lee Hyun Joo , Jeong Myoung Seok , Jung Deok-Beom , Kwon Hee Young , Kim Sung-Hoon 
Published: August 2015

Abstract
The pineal gland hormone melatonin (N-acetyl-5-methoxytryptamine) is well known as an anticancer effector. Recently, a variety of studies have shown that melatonin induces apoptosis in various cancer cell types such as colon cancer, Ewing sarcoma, hepatic cancer, prostate cancer and breast cancer cells. Glioblastoma cancer stem-like cells (GCSLC) are the most common and aggressive primary brain tumor in adults. In the present study, we found that melatonin significantly decreased the sphere formation of GCSLC, and attenuated the expression of c-Myc genes. Furthermore, melatonin suppressed expression of H3K4me3 and H3K79me3 around c-Myc promoter region by Western blotting and Chip assay. Of note, melatonin suppressed the expression of several stemness markers including nestin in GCSLC. Overall, our findings suggest melatonin as a potent anticancer stem cell agent for GCSLC.
Citation Format: Hyemin Lee, Ji Hoon Jung, Hyun Joo Lee, Myoung Seok Jeong, Deok-Beom Jung, Hee Young Kwon, Sung-Hoon Kim. Melatonin inhibits stemness of glioblastoma cancer stem-like cells via regulation of histone methylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 94. doi:10.1158/1538-7445.AM2015-94
Abstract 945: Synthetic lethal screen identifies Aurora A as a selective target in HPV driven cervical cancer
Authors: Gabrielli Brian G. , Bokhari Fawzi , Ranall Max , Oo Zay Yar , Stevenson Alex , Wang Weili , McKee Sara , Leggatt Graham , Leo Paul , Gonda Thomas J. , McMillan Nigel AJ 
Published: August 2015

Abstract
HPV has been identified as the definitive agent in cancers of the cervix, penis, vulva, vagina, anus, skin, eye, and head and neck, and is responsible for 5% of the total cancer burden worldwide. HPV oncogenes disable a number of tumour suppressor pathways, including p53 and Rb, contributing to the transformed phenotype. We have performed an siRNA screen using the kinome (779 genes) library to identify genes that when depleted are synthetically lethal with HPV transformation. The primary and validations screens have confirmed Aurora A kinase (AURKA) as a potential synthetic lethal target selective for HPV transformed cells. In vitro research using the investigational selective small molecule AURKA inhibitor alisertib found alisertib to be significantly more potent towards the HPV transformed cells, and selectively promoted apoptosis in the HPV cancers. The drug was shown to target the HPVE7 oncogene, the level of expression of this oncogene possibly influencing sensitivity. Apoptosis was sensitive to Mcl-1 but not Bcl-2 over expression, indicating that the mechanism is associated with the proteolytic destruction of Mcl-1 in the extended mitosis in the alisertib treated HPV cancer lines. Xenograft experiments with cervical cancer cell lines showed alisertib inhibited growth of HPV and non-HPV xenografts during treatment. The non-HPV cancer growth was delayed, but in two separate HPV cancers models, regression and no resumption of growth was detected at even 50 days post-treatment. A second transgenic model of premalignant disease driven solely by HPVE7 similarly demonstrated sensitivity to drug treatment. These findings provide preclinical evidnce that alisertib warrants evaluation as a potential targeted compound with activity in HPV-transformed cervical cancer and premalignant disease that may have application to other HPV driven cancers.
Citation Format: Brian G. Gabrielli, Fawzi Bokhari, Max Ranall, Zay Yar Oo, Alex Stevenson, Weili Wang, Sara McKee, Graham Leggatt, Paul Leo, Thomas J. Gonda, Nigel AJ McMillan. Synthetic lethal screen identifies Aurora A as a selective target in HPV driven cervical cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 945. doi:10.1158/1538-7445.AM2015-945
Abstract 964: GATA3 modulates chromatin structure to establish active enhancers in breast cancer cells
Authors: Takaku Motoki , Grimm Sara A. , Shimbo Takashi , Perera Lalith , Machida Shinichi , Kurumizaka Hitoshi , Wade Paul A. 
Published: August 2015

Abstract
Master transcription factors regulate cell-type-specific gene expression to define cellular identities. One such gene, GATA3, is a key regulator of multiple cellular programs, including T lymphocyte development, mammary luminal epithelial cell differentiation and trophoblast development. Recently, comprehensive genomic analysis has identified GATA3 as one of the most frequently mutated genes in breast cancer. It is also known that GATA3 expression levels directly correlate with favorable prognosis. These findings strongly suggest that GATA3 plays a critical role in tumorigenesis. However, the molecular mechanism(s) underlying GATA3-mediated gene regulation in breast cancer cells is not clearly defined. GATA3 participates in a complicated regulatory network with FOXA1 and ER-alpha, governing the transcriptional program in luminal tumors. Biochemical analyses indicate that: (1) GATA3 binds to chromatin in an estrogen-independent manner, (2) GATA3 acts upstream of FOXA1. These studies suggest GATA3 may act as a pioneer factor, which is capable of independently associating with closed chromatin and modulating chromatin structure to establish an active enhancer. In order to investigate GATA3 function as a pioneer transcription factor, we chose the MDA-MB-231 breast cancer cell line, which is GATA3, FOXA1 and ER-alpha negative, and established stable cell lines expressing wild-type GATA3 or GFP as a control. Consistent with previous results, GATA3-expressing cells represented an epithelial phenotype at the cellular and molecular level. To determine whether GATA3 can direct reprogramming of chromatin conformation, we performed genome-wide analyses of the chromatin binding activity of GATA3 and its impact on histone modifications and chromatin structure. We will present recent results describing how GATA3 licenses enhancer function to direct the luminal transcriptional program.
Citation Format: Motoki Takaku, Sara A. Grimm, Takashi Shimbo, Lalith Perera, Shinichi Machida, Hitoshi Kurumizaka, Paul A. Wade. GATA3 modulates chromatin structure to establish active enhancers in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 964. doi:10.1158/1538-7445.AM2015-964
Abstract 988: Triple negative breast cancer cells have higher dependence on mitophagy for their survival as compared to hormone positive breast cancer cells
Authors: Dikshit Bhawana , Rai Aakansha , Roy Soumya Sinha 
Published: August 2015

Abstract
Autophagy is a key pathway utilised by the cells to clear the dysfunctional cellular components and maintain homeostasis. However cancer cells having defective apoptosis, deploy autophagy as a survival mechanism by limiting tumor necrosis and metabolic stress. Autophagy has been reported to be upregulated in triple negative breast cancers which are categorized as the most aggressive breast cancers with poor prognosis. Nevertheless the exact mechanism of autophagic upregulation in TNBC is still elusive. Therefore analyzing pathways specifically altered in these tumors might provide better targets for therapeutic intervention.
Results:
In the present study we observed higher basal autophagy in TNBC cell line MDA MB 231 as compared to triple positive MCF7 cells as analyzed by the presence of higher number of GFP-LC3 puncta in the former. Treatment with 20μM of autophagy inhibitor chloroquine for 48 hrs led to significant cell death in TNBC cell line as compared to MCF7 whereas treatment with 20μM of PI3K inhibitor wortamannin did not significantly affected the survival of TNBC and MCF7 cells. Further the analysis of autophagy markers revealed higher LC3B and Beclin1 levels as compared to ATG5 and ATG7 levels in MDA MB 231 cells both at mRNA and protein levels as analyzed by qPCR and western blot. Also the knockdown of ATG7 by ATG7 shRNA did not significantly affected the survival of TNBC cells.
Conclusion:
Thus in this study we aim to highlight the difference in the expression of autophagy markers and the effect of autophagy inhibitors wherein only late phase of autophagy seems to significantly upregulated in TNBC. The difference can be attributed to the dependence of TNBC cells upon ‘late phase autophagy’ or particularly ‘mitophagy’ that is crucial for rapid clearance of misfolded proteins and dysfunctional mitochondria as has been reported in TNBCs. Further study to dissect the mechanism of selective upregulation of ‘late phase autophagy’or ‘mitophagy’ in TNBC might provide novel targets for treatment strategies in these breast cancers.
Citation Format: Bhawana Dikshit, Aakansha Rai, Soumya Sinha Roy. Triple negative breast cancer cells have higher dependence on mitophagy for their survival as compared to hormone positive breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 988. doi:10.1158/1538-7445.AM2015-988
Abstract 991: Role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity
Authors: Mohan Nishant , Shen Yi , Wu Wen Jin 
Published: August 2015

Abstract
Autophagy is basic catabolic cellular process which is essential for maintaining cellular homeostasis during nutrient starved and stress conditions. Even though autophagy is altered in various cardiovascular diseases including cardiomyopathy and heart failure, its precise role in heart conditions remains ambiguous. Trastuzumab is a humanized monoclonal antibody approved for treatment of HER2-positive breast cancer. Trastuzumab treatment has been shown to induce considerable cardiotoxicity. Molecular mechanism for trastuzumab-induced cardiotoxicity remains largely unclear. In this study, we investigated the role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity. We treated human primary cardiomyocytes with trastuzumab at different time points, and then examined the expression of prominent autophagic markers such as LC3A/B, Beclin 1 and Bcl-2 by western blotting. Results divulged that expression levels of LC3A/B were markedly decreased in cardiomyocytes after 24 and 48 h of trastuzumab treatment. Beclin 1 protein levels also significantly decreased, although Bcl-2 expression was increased. These results indicate that downregulation of Beclin 1 and upregulation of Bcl-2 after trastuzumab treatment could potentially impede the formation of autophagosomes resulting in inhibition of autophagy. Collectively, these data indicate that autophagy plays a beneficial role in normal cardiac tissues by preventing the accumulation of abnormal proteins or damaged organelles. However, trastuzumab treatment may inhibit the autophagy, resulting in cardiomyopathy.
Citation Format: Nishant Mohan, Yi Shen, Wen Jin Wu. Role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 991. doi:10.1158/1538-7445.AM2015-991
Abstract CT210: Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial
Authors: Chantrill Lorraine , Simpson Skye , Johns Amber , Martyn-Smith Mona , Chou Angela , Watson Clare , Nagrial Adnan , Chin Venessa , Sebastian Lucille , Yip Sonia , Simes John , Pavlakis Nick , Grimison Peter , Asghari Ray , Harvey Sandra , Biankin Andrew 
Published: August 2015

Abstract
Background: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial is designed to exploit results from whole genome sequencing of pancreatic cancer collected under the auspices of the ICGC in Australia. Results showed that small subsets of patients had actionable changes in their tumor genome that could be druggable with currently available therapies. Only 7% of cases were found to be KRAS wildtype, and this phenotype may enrich for susceptibility to EGFR inhibition. Her2 positivity occurs in 2% and may confer sensitivity to Her inhibition. Tumors displaying defects in the DNA damage repair pathway (∼5%) respond to DNA damaging chemotherapy.
Trial Design: The IMPaCT trial has recently been amended to a single arm pilot study of first line molecularly guided therapy for advanced pancreas cancer. Patients are permitted to begin their first cycle of chemotherapy with gemcitabine with or without nab-paclitaxel while awaiting molecular results.
We screen potential patients for the three molecular targets: Her2 amplification: trastuzumab + gemcitabine; KRAS wildtype: erlotinib + gemcitabine; and DNA damage: platinum-based chemotherapy.
In our initial cohort of patients who underwent resection with curative intent, 70% recurred. Recurrence occurred 16m after initial surgery. Collection of tissue commenced in 2009. The first site to open was in April 2013 by which time, only 8 patients for whom we had complete sequence data and actionable mutations were still alive, so we changed the trial to screen de novo metastatic patients.
Using the WGS data, we constructed a custom sequencing panel to use DNA extracted from FFPE core biopsies to screen in real time for mutations in KRAS, BRCA2, BRCA1, PALB2 and ATM. Her2 screening is undertaken with IHC and FISH.
We have screened 89 cases in 18m, 8 have relevant molecular targets. The average time from biopsy to delivery of results is 21d. 2 of the 8 eligible cases have commenced precision therapy on trial.
Citation Format: Lorraine Chantrill, Skye Simpson, Amber Johns, Mona Martyn-Smith, Angela Chou, Clare Watson, Adnan Nagrial, Venessa Chin, Lucille Sebastian, Sonia Yip, John Simes, Nick Pavlakis, Peter Grimison, Ray Asghari, Sandra Harvey, Andrew Biankin. Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT210. doi:10.1158/1538-7445.AM2015-CT210
Abstract CT219: Clinical and immunological analysis in a phase II trial of the glypican-3 peptide vaccine for patients with ovarian clear cell carcinoma
Authors: Suzuki Shiro , Shibata Kiyosumi , Kikkawa Fumitaka , Nakatsura Tetsuya 
Published: August 2015

Abstract
Compared with other epithelial ovarian carcinoma subtypes, ovarian clear cell carcinoma (OCCC) is associated with a poorer prognosis and increased chemoresistance. Therefore, new treatment modalities are urgently required for patients with OCCC refractory to chemotherapy. Glypican-3 (GPC3) is useful not only as a novel tumor marker, but also as an oncofetal antigen for immunotherapy. It is specifically overexpressed in hepatocellular carcinoma (HCC). Previous studies demonstrated that GPC3 was also overexpressed in several malignant tumors, including OCCC. We previously reported the safety of and immunological and clinical responses to a GPC3-derived peptide vaccine in a phase I clinical trial of patients with advanced HCC. Although the efficacy of the GPC3-derived peptide vaccine against HCC patients was evaluated, other GPC3-positive cancer patients have not yet been investigated. Therefore, we conducted a phase II trial to evaluate the clinical outcome of OCCC patients treated with a GPC3-derived peptide vaccine (UMIN-CTR: 000003696).
In this study, we describe the effect of vaccination with the HLA-A24 or A2-restricted GPC3 peptide on patients with OCCC. The patients were divided into three groups such as adjuvant therapy group, combined therapy group (combined to second-line chemotherapy) and recurrence or advanced group (single of vaccine treatment). The dose of GPC3 peptide injected was 3 mg per body. Patients received the intradermal injection of GPC3 peptide emulsified with incomplete Freund's adjuvant. Vaccinations were carried out biweekly from the first until the 6th and repeated at 6-week intervals after the 7th. Immunological responses were analyzed by ex vivo IFN-γ enzyme-linked immunospot assay (ELISPOT).
Seventy OCCC patients were entered into clinical trial until the end of October 2014. In adjuvant group, twenty-nine of thirty-five patients have no recurrence. Recurrence pattern of all 6 patients was peritoneal metastasis. Three of twenty-nine patients with refractory OCCC achieved a significant clinical response. Ex vivo IFN-γ ELISPOT analysis in most OCCC patients revealed vaccine-induced immune reactivity against the GPC3 peptide. Our current data provide preliminary evidence of clinically meaningful benefit for GPC3 peptide vaccines in OCCC and support further evaluation of this approach in these patient populations.
Citation Format: Shiro Suzuki, Kiyosumi Shibata, Fumitaka Kikkawa, Tetsuya Nakatsura. Clinical and immunological analysis in a phase II trial of the glypican-3 peptide vaccine for patients with ovarian clear cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT219. doi:10.1158/1538-7445.AM2015-CT219
Abstract CT311: Results of a phase I/IIa dose-escalation study of the combination of decitabine and genistein against advanced solid tumors
Authors: Raynal Noël J. , Kassouf Elie , Daigneault Luc , Colin Patrick , Plante Isabelle , Lassonde Guylaine , Momparler Richard , Charbonneau Michel , Blais Normand 
Published: August 2015

Abstract
Background: Epigenetic aberrations, including DNA hypermethylation of tumor suppressor genes are a common feature in solid tumors. Thus, targeting epigenetic pathways is a promising approach for cancer chemotherapy. However, only occasional proof-of-principle responses can be seen in solid tumors. The activity of hypomethylating drugs, such as decitabine could be improved by a treatment combination. Preclinical studies have suggested that adding genistein, a natural isofavone may synergize with demethylating drugs and improve treatment results.
Methods: Here, we describe a phase I/IIa dose-escalation study of decitabine with a fixed dose of genistein. Primary objective of the phase I trial was to determine the Maximum Tolerated Dose (MTD) and to evaluate pharmacokinetic parameters in patients with advanced solid tumor. The objective of the phase IIa was to assess its efficacy in lung cancer. Decitabine was administered over 10-hours at increasing doses (60, 120, 240 mg/m2) with continuous administration of genistein 300 mg/day orally. Treatment was repeated every 4 to 6 weeks.
Results: For the phase I, ten patients with advanced solid tumors were recruited. The recommended dose of decitabine (for the phase IIa) was 120 mg/m2 with neutropenia as limiting side effect. Decitabine at 120 mg/m2 and genistein produced plasma levels of 0.62 ± 0.06 μM and 8.5 ± 5.6 μM, respectively. The drug combination was well tolerated and produced stable disease for more than 7 months (7-14 months) in 50% of the patients. One patient had a 50% reduction in tumor burden after 6 months of therapy. In the phase IIa trial against advanced lung cancer, patients progressed rapidly, within 2 months of treatment mainly because of the apparition of new lesions in the liver.
Conclusion: The combination of decitabine and genistein is well-tolerated in advanced solid tumors and shows interesting anticancer effects. This study on decitabine and genistein warrants future investigations to address this issue of liver metastasis in advanced lung cancer.
Citation Format: Noël J. Raynal, Elie Kassouf, Luc Daigneault, Patrick Colin, Isabelle Plante, Guylaine Lassonde, Richard Momparler, Michel Charbonneau, Normand Blais. Results of a phase I/IIa dose-escalation study of the combination of decitabine and genistein against advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT311. doi:10.1158/1538-7445.AM2015-CT311