Day 2 :
Keynote Forum
David A Ligon
Oncology Fox LLC, USA
Keynote: Leading the global collaborative effort in epigenetics through a next generation search engine and portal for the oncology community
Time : 9:30 AM - 10:15 AM
Biography:
David A Ligon is the founder & CEO of Oncology Fox LLC. David established a global collaborative network of Education Technology Leaders. David Ligon brings more than 30 years of experience in Information Technology to the table, with a focus on Web and Systems design as well as Technical Documentation, Education, Grants and Leadership. Given David's passion for cutting-edge research and technology, it was only natural his direction would evolve in life to combine all these gifts into Epigenetically focused and Knowledge Management-based Cancer Research Portal of the 21st Century to foster communication and collaboration in the industry--all with the Goal of Saving Lives through Awareness and Knowledge-sharing.
Abstract:
Online networking and knowledge-sharing through application of the principles of knowledge management in development of the next generation cancer research portal is leading the global collaborative eff ort in epigenetics. Th e paradigm has fundamentally and profoundly changed in recent years on how we approach the understanding of cancer treatment and its latest breakthroughs. So much funding has been funneled to Cancer research that there is a big data problem coordinating and sharing those results. Further, Cancer research itself has outgrown previous search portal models in that they do not understand nor apply the principles of epigenetics or knowledge management to searching and sharing information. Top trophy announcements oft en get buried in the news, knowledge of new diagnostic markers, targeted therapies, clinical trials and CRISPR advances are not properly knowledge-shared. Oncology Fox addresses these problems in addition to providing a way for advanced cancer therapies service providers to market their wares to a targeted audience. Developing a sense of community amongst stakeholders fi rst is a key in achieving the level of collaboration needed globally to lead and forge a direction for epigeneticists in our common mission. Th e goal is to save lives through awareness and collaboration. By applying the principles of knowledge management toward a next generation cancer research portal and establishing a new content indexing and validation methodology for collaborative knowledge sharing in the 21st century we can achieve these goals. Th e global collaborative eff ort has pulled together the top researchers, doctors, institutions, donors and the infi rmed to provide a complete solution.
Keynote Forum
Atsushi Kaneda
Chiba University, Japan
Keynote: Induction of epigenetic alterations in gastric epithelium and their contribution to gastric tumorigenesis
Time : 10:15 AM - 11:00 AM
Biography:
Atsushi Kaneda has obtained his MD degree from University of Tokyo and became Assistant Professor at the Department of Gastrointestinal Surgery, University of Tokyo where he conducted genome-wide DNA methylation analysis in gastric cancer and acquired PhD degree. He has also studied at Johns Hopkins University and showed that accumulated epigenetic alteration could modify intestinal tumor risk using mouse model of IGF2 LOI. As an Associate Professor at University of Tokyo and as Professor at Department of Molecular Oncology, Chiba University since 2013, he has conducted projects to clarify epigenomic mechanisms in gastrointestinal carcinogenesis.
Abstract:
Cancer arises through accumulation of epigenetic and genetic alterations and therefore is stratifi ed into several molecular subtypes using comprehensive epigenomic and genomic information. We showed that accumulated epigenomic alteration could causally modify tumor risk. We also comprehensively stratifi ed gastric cancer into 4-5 DNA methylation epigenotypes, depending on pathogens. While the majority of gastric cancer is associated with Helicobacter pylori infection, a subset of gastric cancer, ranging 7-15%, is associated with Epstein-Barr virus (EBV) infection. EBV+ gastric cancer exhibits most severe DNA hypermethylation and EBV itself was shown to cause the extensive hypermethylation phenotype when infected into gastric epithelial cells, involving increased expression of DNMT1. Demethylating enzyme TET2 was found to function as a resistant factor against DNA methylation induction and hMeDIP-seq and MeDIP-seq analyses revealed that target regions of hydroxy methylation by TET2 signifi cantly overlapped with target regions of de novo DNA methylation by EBV infection. Th e repression of TET2 due to viral transcripts or up-regulated human miRNAs signifi cantly contributes to de novo methylation acquisition. Other epigenomic alterations are also involved in promoter regions, enhancer regions, etc., during EBV infection and cause aberrant regulation of critical genes e.g. proliferative genes or tumor suppressor genes. Another cancer subtype with DNA hypermethylation phenotype involves aberrant methylation of mismatch repair gene MLH1, leading to microsatellite instability (MSI) and gene hypermutation in gastric cancer. Th ese subsets of gastric cancer with hypermethylation phenotype, i.e., EBV+ subtype and MSI-high subtype, showed unique gene mutation patterns, which contribute to gastric tumorigenesis synergistically with DNA hypermethylation.
- Cancer Epigenetics | Biomarkers and Bioinformatics Development in Epigenetics | Treatment and Therapy | Cell Free Biomarkers | Advances of Biomarker Testing | Predictive Cancer Biomarkers
Location: Japan
Chair
Atsushi Kaneda
Chiba University, Japan
Co-Chair
Safana Salim Al Saidi
Ministry Of Health, Muscat
Session Introduction
Glenn Deng
Stanford University School of Medicine, USA.
Title: Single-cell molecular analysis reveals a possibility of epithelial to circulating tumor cell transition when a tumor cell enters into the bloodstream
Biography:
Glenn Deng has completed his PhD from Tokyo University in Marine Science and Technology and Postdoctoral studies from Stanford University. He is the Professor of China Three Gorges University School of Medicine and the Senior Scientist of Stanford University School of Medicine. He has published more than 30 papers in reputed journals.
Abstract:
Circulating tumor cells are important biomarkers function as liquid biopsies for cancer diagnostics and therapeutics. However, traditional analyses of tumor cells and tissues are not suitable for circulating tumor cells due to the limited number of circulating tumor cells and the molecular analyses of a population of tumor cells that may miss crucial information such as single-cell heterogeneity. Th erefore, we have developed an automatic device that isolates live circulating tumor cells from a breast cancer patient's blood sample and performs a range of single-cell molecular analyses to determine tumor cell characteristics. Th e developed automatic device isolates live circulating tumor cells from patients' blood samples. Th is device is useful for the positive enrichment, negative enrichment or diff erent combinations of negative and positive enrichment of circulating tumor cells. Up to 100 gene expression analyses were performed on the isolated single circulating tumor cells with the profi le of the 100 genes showing great heterogeneity at the single-cell level on housekeeping genes expression and the molecular signatures of apoptosis, stem cell, transition, etc. About 1/3 of the analyzed CTCs lost housekeeping genes, suggests that these CTCs were already dead or lost the ability to continue growing. Th ere is also a large portion of CTCs that either does not express or have low levels of mesenchymal cell signatures, suggesting the current EMT hypothesis only happened in limited numbers of CTCs. Our single-cell molecular analysis results on breast cancer patients' CTCs reveals that there is a strong possibility that when an epithelial cell enters the bloodstream, its fi rst transition will be epithelial to circulating tumor cell transition (ECT), followed by the CTCs performing the circulating to mesenchymal cell transition (CMT) and fi nally the mesenchymal to epithelial cell transition (MET). Our results also suggest that the ECT transition may be very important for the survival of early CTCs in the bloodstream and may lead to more investigations about the survival ability and metastatic possibility of tumor cells at the DNA and RNA level.
Ladan Teimoori-Toolabi
Pasteur Institute of Iran, Iran
Title: Studying methylation status of p16, p14, MLH1, APC and UNC5C in the plasma as diagnostic biomarkers of colorectal cancer
Biography:
Ladan Teimoori-Toolabi has completed her MD, PhD and Postdoctoral studies from Pasteur Institute of Iran. She is an Associate Professor in Molecular Medicine Department of Pasteur Institute of Iran. She has published more than 35 papers in reputed journals in ISI and has been serving as an Editorial-Board Member of two journals.
Abstract:
Colorectal cancer, in spite of diff erent screening strategies is detected in late stages in Iranians patients. Hence, we aimed to study if diff erent epigenetic markers could be helpful in detecting colorectal cancer in any stages. We studied 50 patients (25 males and 25 females) aff ected with colorectal cancer. Plasma of patients was extracted before any surgical operations. Aft er extraction of free DNA in the plasma, the methylation status of P16, P14, MLH1, APC and UNC5C in the plasma of these patients in comparison with the plasma of normal controls was studied by High Resolution Melting Curve Analysis technique. It was shown that P14, P16 and MLH1 were not methylated in the palms of these patients. Th ree sites in CpG islands of P14, P16 and MLH1 were studied by this technique. Th ree sites of UNC5C were studied by HRM. It was shown that 15%, 32.5% and 12.5% of DNA plasma samples in patients with colorectal cancer were methylated from 12.5% to 75%. Also, three sites of APC gene were studied in these patients. In addition, three sites of APC gene were studied by HRM. In 50%, 75% and 70% of patients, APC was methylated in plasma samples. Plasma samples of normal controls was studied too and it was shown that none of the genes in the plasma samples of normal controls was methylated. Th is study shows that UNC5C and APC methylation can be considered as good candidates for diagnosis of colorectal cancer though more studies are needed before considering them as markers.
Sang Hyun Lee
Duke-NUS Medical School, Singapore
Title: Dual Blockade of the Lipid Kinase and Mitotic Pathways Leads to Ras Activated Cancer-selective Lethality
Biography:
Achieving robust cancer-specifi c lethality is the ultimate clinical goal. Here we identify a compound with dual-inhibitory properties, named a131 that selectively kills cancer cells, while protecting normal cells. Th rough an unbiased CETSA screen, a proteome-wide drug-target engagement mapping, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological eff ects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally up-regulating PIK3IP1, a suppressor of the PI3K/Akt/ mTOR pathway via altering epigenettic regulation. Strikingly, Ras activation overrides a131-induced PIK3IP1 up-regulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131’s ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras|PIK3IP1|PI3K signaling network in Ras-pathway activated cancer cells and clinical samples from patients with colorectal and lung adenocarcinomas via epigenetic mechanisms.
Abstract:
Sang Hyun Lee is currently an Associate Professor in the Cancer & Stem Cell Biology Program at Duke-NUS. He is trained at Comprehensive Cancer Center, University of California-San Francisco with Professor Frank McCormick and at Keio Medical School in Tokyo with Professor Hideyuki Saya.
Jose Perez del Palacio
MEDINA Foundation, Spain
Title: Predictive biomarker discovery of treatment response in lung cancer: A metabolomic approach
Biography:
Jose Perez Del Palacio is a Scientist with 18 years of industrial experience in a leading pharmaceutical research company (Merck Sharp & Dohme), working mainly in biochemistry and drug discovery. He has broad knowledge of bioanalysis technologies and metabolomics. He has additional experience and specialization in analytical methods development for HPLC, LC/MS/MS, GC and GC/MS systems. He is the author of several papers, scientifi c posters and presentations at international conferences and congresses.
Abstract:
Although the broad range of chemotherapeutic agents approved in the late years, it is a challenge for oncologists to choose which drug or combination of drugs will represent the best option for each individual, since only a portion of patients will respond properly. In this regard a biomarker approach to predict patient response to treatment may be very helpful in the making decision process. Metabolomics, the unbiased identifi cation and quantifi cation of small molecule metabolites in biological samples, is particularly promising for biomarker development because altered metabolism is considered a hallmark of cancer. In this work, we have investigated the metabolome of 115 plasma samples from lung cancer patients by mean of liquid chromatography high resolution mass spectrometry. Th e obtained data matrix was analyzed according the clinical response to each therapy (Neoadjuvant and Inmunotherapy) in order to search for a predictive molecular signature in each group of patients.
Safana Salim Al Saidi
Ministry Of Health, Muscat
Title: Validity of prostate health index and percentage of [-2]pro-prostate-specifi c antigen as novel biomarkers in the diagnosis of prostate cancer fi rst reported Omani tertiary hospitals experience
Biography:
Safana Salim Al Saidi is a Chemical Pathologist and Specialist, working at the Directorate General of Quality Assurance Centre, Ministry of Health, Oman. She has graduated from Medical College, Sultan Qaboos University, Oman in 2003 as a Medical Doctor and completed her Residency training program in Clinical Biochemistry by Oman Medical Specialty Board (OMSB) in 2014. Presently she is a Fellow of the Royal College of Pathologist, UK. She has three publications to her credit and has great interest in conducting researches which are of help to the patients.
Abstract:
Statement of the Problem: Prostate cancer is the leading cancer in older men. When prostate cancer is detected early (organ defi ned), it is potentially curable by radical prostatectomy. As per the Ministry of Health (MOH) Oman Cancer Incidence Registry, cancer of prostate is the second most common cancer (in males) and seventh most common cancer (in both males and females), with 57 cases were diagnosed in 2011. Th erefore, early detection is important and prostate-specifi c antigen (PSA) is widely used as a laboratory test for this purpose. However, despite its wide use, its value in screening men particularly asymptomatic is controversial particularly in term of risks and benefi ts of early detection. Methods: Th is is an observational prospective study that included 136 male patients aged (mean±SD: 67±8.89; range 45-90) who were scheduled for prostate biopsy in two diff erent tertiary care teaching hospitals in Muscat, Oman. Blood specimens from these patients were collected at the same setting before obtaining the prostatic biopsy; the sera were stored at -200 °C until analysis. Laboratory measurements of the three prostate specifi c antigen (PSA) markers (tPSA, fPSA and [-2]proPSA) were processed using UniCell DxI 600 Access Immunoassay System (Beckman Coulter, USA). Calculation of Prostate Health Index (phi) using Access Hybritech phi® soft ware was performed too. Th e histopathological report of the prostatic biopsy for each patient was obtained from the histopathology laboratory of the concerned hospital along with the clinical and laboratory data through the Hospital Information System (HIS). Results: Th e study showed that Phi has the best validity markers as compared with other prostate markers. It gave sensitivity and specifi city of 82.1% and 80.6%, respectively with AUC of 0.81 at cutoff value of 41.88. Th e remaining prostate markers showed sensitivities and specifi cities of 78.6% and 25.9% for tPSA; 35.7% and 92.6% for %fPSA; 64.3% and 82.4% for %p2PSA: and 75% and 35.2% for age-adjusted tPSA, respectively. Th eir AUCs at the best cutoff values were 0.67 at 10.1 μg/L for tPSA; 0.70 at 11.6% for %fPSA; 0.55 at 1.4% for %p2PSA and 0.50 for age-adjusted tPSA. Conclusion: Th e study has proved the usefulness of Phi and its component assays in predicting the diagnosis and prognosis in men who are suspected of having prostate cancer. Th e use of Phi outperforms other conventional prostate markers; tPSA and fPSA, when used alone or in combination. Phi appears to be more accurate than tPSA and fPSA in terms of excluding prostate cancer before biopsy; hence it helps the physicians to avoid unnecessary biopsies, particularly in patients with gray zone tPSA level. Phi is the strongest marker that also correlates proportionally with Gleason Score and therefore it is also useful in predicting the aggressiveness of the disease
In-Hye Jung
University of Ulsan College of Medicine, Seoul, South Korea
Title: EGF induces paradoxical growth arresting via the up-regulation of PTEN by activating Ref-1/Egr-1 in human NSCLC cells
Biography:
In-Hye Jung has completed her MSc from University of Ulsan College of Medicine. She is the Fellow in Department of Radiation Oncology of Asan Medical Center.
Abstract:
Epidermal growth factor receptor (EGFR) signaling promotes cell proliferation and survival in several types of cancer. Here, however, we showed that EGF inhibits proliferation and promotes apoptosis in non-small cell lung cancer (NSCLC) cells. In A549 cells, EGF increased redox factor-1 (Ref-1) expression and the association of Ref-1 with zinc fi nger-containing transcriptional regulator (EGR1) via activation of p22phox, RAC1 and an NOX subunit. EGF increased p22phox and RAC1 expression through activation of purinergic receptors (P2Y). Elevated Ref-1/EGR1 levels increased phosphatase and PTEN levels, leading to inhibition of the Akt pathway. EGF-induced PTEN up-regulation increased apoptosis and autophagy-induced damage in A549 cells, whereas Ref-1 knockdown blocked EGF-induced PTEN up-regulation in an NOX -p22phox subunitindependent manner. In addition, p22phox knockdown restored EGF-induced eff ects, implying that changes in P2Y activity caused by EGF, which activates NOX via RAC1, infl uenced Ref-1-mediated redox regulation. Finally, EGF similarly attenuated cell proliferation and promoted autophagy and apoptosis in vivo in a xenograft model using A549 cells. Th ese fi ndings reveal that EGF-induced redox signaling is linked to Ref-1-induced death in NSCLC cells.
Ho Gun Kim
Chonnam National University, Gwangju, South Korea
Title: DNA methylation of microRNA genes in gastric carcinoma and its clinicopathological association
Biography:
Ho Gun Kim is a Professor in the Department of Surgery and Pathology at Chonnam National University Medical School, Gwangju, South Korea.
Abstract:
Background & Aim: To explore the role of epigenetic mechanisms in the down-regulation of miRNA genes, we examined the presence of DNA methylation-associated silencing of miRNAs in gastric carcinoma and observed that aberrant methylation of these miRNAs is associated with expression of target gene products. Materials & Methods: Th e extent of promoter methylation of has-miR-9-1, has-miR-9-3, has-miR-129-2 and has-miR-137 was assessed using methylation-specifi c polymerase chain reaction in 100 gastric carcinoma tissues and corresponding non-tumor tissues. Th e potential target gene products of miRNAs were studied by immunohistochemistry and the relationship between methylation profi les of miRNAs. Results: Methylation of the has-miR-9-3 and has-miR-137 CpG island was frequently observed in tumor tissues (89% and 86%, respectively) and non-tumor tissues in 100 gastric carcinoma patients (70% and 78%). However, methylation level of the has-miR-129-2 did not shown signifi cant diff erence in tumor tissues (97%) compared with non-tumor tissues (90%) and normal gastric tissues (90%). Expression of NF-κB and SOX4 protein, which are has-miR-9 and has-miR-129-2 potential target respectively, were inversely correlated with methylation level of miRNAs. Conclusion: Th e results suggest that specifi c miRNAs methylation in gastric carcinoma could be an important molecular mechanism causing loss of control of its target and it may be correlated with the high transcriptional activity of target gene. Epigenetic silencing of some miRNAs may involve in the early stage of gastric carcinogenesis.