Day 2 :
Keynote Forum
Polly Leilei CHEN
Cancer Science Institute of Singapore, Singapore
Keynote: Understanding RNA editing in human cancer: Causes and functional consequences
Biography:
Polly Leilei Chen is an Assistant Professor in the Department of Anatomy and Principle Investigator at the Cancer Science Institute of Singapore, National University of Singapore where she directs a research lab studying human cancers, particularly liver cancer. Her current focus is on the identification of key RNA editing events and translating these findings into diagnoses and even treatment. In addition, she has collaboration with local and international researchers to study the roles of RNA editing enzyme ADARs and their substrates in different types of human cancers, such as esophageal squamous cell carcinoma (ESCC), gastric cancer and acute myeloid leukemia.
Abstract:
Conventionally, cancer is driven by a clonal accumulation of somatic mutations, referred to as driver mutations, conferring a selective growth advantage to cancer cells. RNA editing, is an epigenetic mechanism, introduces changes in the RNA sequences encoded by the genome, contributing to editing/epigenetic mutations. In humans, the most frequent type of editing is the conversion of adenosine to inosine (A-to-I), which is catalyzed by ADAR (Adenosine Deaminase Acting on RNA) proteins, ADAR1 and ADAR2. Inosine (I) essentially mimics guanosine (G), therefore ADAR proteins actually introduce a virtual A-to-G substitution in transcripts. Such changes can lead to specific amino acid substitutions, alternative splicing, altered microRNA seeds or targets, or changes in transcript localization, expression and degradation. Up to now, changes in the information are being investigated almost exclusively at the DNA level. Using integrative genomic approaches, our previous study highlighted a link between a disrupted RNA editing balance and cancer development. We recently place focus on understanding the regulators of A-to-I RNA editing and their role in cancer development.
Keynote Forum
Lu-Hai Wang
China Medical University, Taiwan
Keynote: Transketolase regulates dynamic switch of glucose metabolism to control breast cancer cell metastasis via α-KG signaling pathway Cancer Cell Metastasis via α-KG Signaling Pathway
Biography:
Lu-Hai Wang has completed his PhD in Molecular Biology at University of California-Berkeley in 1976 and has been dedicated to the research in cancer biology. He holds the Professorship in The Rockefeller University and Mount Sinai School of Medicine since 1979 and 1988, respectively. He was recruited as the Distinguished Investigator and Director of the Institute of Molecular and Genomic Medicine at National Health Research Institute in 2008 and went back to Taiwan. In 2010, he was elected as the Academician, which is the highest honor in academia in Taiwan. In 2012, he was awarded Fellow of TWAS, The World Academy of Sciences. His research interests lie in the molecular mechanism for tumor progression and metastasis. His laboratory has identified several miRNAs involved in regulating, migration, invasion and metastasis of breast, ovarian, and oral cancer cells. He is currently the Vice President of the China Medical University (CMU) in Taiwan and a Chair Professor in the Graduate Institute of Chinese and Western Integrated Medicine, CMU.
Abstract:
Metabolic reprogramming including glucose metabolism is associated with progression of tumor growth. To identify the important players in such reprogramming, we employed 4T1/BALB/c syngeneic model to compare tumors of varying sizes. We identified the glycolytic enzyme transketolase (TKT) to be up-regulated in the bigger tumors. We found TKT expression levels were the highest in lymph node metastases compared with primary tumor and normal tissues of patients. Patients with higher TKT levels had poor overall survival. Reduced TKT attenuated cancer cell growth and metastatic behaviors by in vitro and in vivo assays. Depletion of TKT elevated the expression of alpha-ketoglutarate (α-KG), which was able to inhibit cancer cell growth and metastasis. Reduced TKT or addition of α-KG switched glucose metabolism from glycolysis to TCA cycle through the regulation of enzymes involved in those pathways. These results suggest that TKT-mediated α-KG signaling pathway may be exploited for anti-metastasis therapy in breast cancer.
Keynote Forum
Shahana Pervin
National Institute of Cancer Research & Hospital, Bangladesh
Keynote: Primary malignant melanoma of the vagina in Bangladesh: Report of a case series and review of the literature
Biography:
Dr. Shahana Pervin is a surgeon at the National Institute of Cancer Research & Hospital, Bangladesh.
Abstract:
Objective: This study describes the characteristics of patients with primary malignant melanoma of the vagina and their treatment at National Institute of Cancer Research and Hospital in Dhaka, Bangladesh, from February 2013-January 2015.
Materials & Methods: Eight patients with primary malignant melanoma of the vagina were identified. Medical records were reviewed for demographic information, treatment and outcomes. This investigation was approved by the Ethics Committee of the National Institute of Cancer Research and Hospital.
Results: The median age was 48 years (Range: 35-65 years) and most patients were premenopausal. Seven of the eight patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage-2. Five patients had disease confined mainly to the upper and middle thirds of the vagina. One patient was diagnosed with stage-4 disease. In two patients, cervical metastases were present. Almost all patients received radiotherapy. Two patients with stage-2 disease developed local recurrences within eighteen months and one patient with stage-4 disease died ten months after diagnosis.
Conclusion: Primary malignant melanomas of the vagina are uncommon, highly aggressive tumors that are associated with poor overall survival. Surgery is the mainstay of treatment. Nearly 80% of vaginal melanomas will recur. Overall, 5 years survival ranges from 5% to 25%. The size of the tumor (>than 3 cm) and the presence of lymphadenopathy at diagnosis worsen the overall survival.
- Cancer Treatment and Therapeutics |Cancer Pharmacology | Gynaecologic Oncology
Location: Singapore
Chair
Yonghua Yang
Fudan University School of Pharmacy, China
Co-Chair
Ming Liu
Guangzhou Medical University, China
Session Introduction
Keith Potent
Monash University, Australia
Title: First in human report of intravenous infusion of Metavec (synthetic bacteriophage delivering genetic cargo) in a patient with metastatic ovarian cancer
Biography:
Dr Potent is currently a PhD candidate in Translational Research at Monash University. After completed undergraduate degrees in Mathematics and Chemistry, Dr Potent completed his medical degree. He is a practising doctor in Queensland. Today is presenting a small part of a significant body of research conducted by Dr Armand Sinclair, Novother Cancer Research.
Abstract:
We present a first in human case of a 50 year-old patient with end-stage metastatic ovarian cancer infused with a novel, intravenously administered, synthetically engineered bacteriophage-based gene therapy (Metavec) for metastatic solid malignancies. Compared to mammalian virus-based delivery vehicles, bacteriophage-based vectors bring many preferable features for treatment in humans. Their genomes have been extensively sequenced and with modern technologies, they are relatively malleable allowing them to be extensively modified. Unlike mammalian viruses, bacteriophages are not natural pathogens to humans yet their capsid can have equivocal cargo carrying capacity. To the authors’ best knowledge, no other bacteriophage-based applications have succeeded with intravenous administration. This advance in nanotechnology and novel approach could revolutionize medical care. The patient we discuss received a dose-escalating regime up to 1x1011 particles per dose, three times a week for three weeks. The infusions were very well tolerated. Symptoms include nausea, low-grade fever and also discomfort in areas where larger tumors were present. Post-infusion investigations included serum biochemistry, serum tumor markers and computed tomography. The paradigm shift, results and discussion will be presented.
Xiaoxiao Jiang
Fudan University School of Pharmacy, China
Title: Abrogation of LBH589-induced autolysosome maturation by Mevastatin promotes cell death in triple-negative breast cancer cells
Biography:
Xiaoxiao Jiang is a PhD student in the Department of Biochemistry & Pharmacology. She has received her Bachelor’s degree in Pharmacy from Shandong University and a Master’s degree in Tumor Pharmacology from Fudan University. Currently, her research project is on post-translational modification and development of anti-cancer drug screening assay. Her research interests include cancer immunotherapy and high-throughput genome sequencing.
Abstract:
There is a growing interest in the synergy of histone deacetylase inhibitors (HDACi) with other promising agents to achieve attractive therapeutic effects. We found that Mevastatin, a HMGCR reductase inhibitor, augments the antitumor efficacy of the HDACi LBH589 in triple-negative breast cancer (TNBC). The combination treatment with Mevastatin and LBH589 enhanced cell death of TNBC cells relying on a caspase-8 dependent apoptosis. Accompanied with the increased cell death, Mevastatin abrogated the autophagic flux triggered by LBH589, through activating LKB1-AMPK signaling and subsequently suppressing of mTOR, resulting in the blockade of VPS34/Beclin-1 complex formation and the inhibition of Rab7 prenylation, an active form of the small GTPase needed for autophagosome-lysosome fusion. In addition, our results indicate that disruption of autophagosome-lysosome fusion likely underlies Mevastatin-LBH589 synergistic anti-tumor effects. Furthermore, combinatorial treatment of metastatic TNBC with Mevastatin/LBH589 provoked a strong synergistic inhibition of tumor growth in MDA-MB-231 xenograft mice. These findings provide a potential therapeutic strategy for further clinical study and suggest that screening for novel autophagy modulators could be an efficient approach to strengthen the efficacy of HDACi in solid tumors.
Shahana Pervin
National Institute of Cancer Research & Hospital, Bangladesh
Title: Adjuvant hysterectomy after chemo radiation for residual disease of cancer cervix
Biography:
Dr. Shahana Pervin is a surgeon at the National Institute of Cancer Research & Hospital, Bangladesh.
Abstract:
Aim: The aim of the study was to see the disease-free survival and overall of post irradiated residual or recurrent cervical cancer patients who were treated with adjuvant hysterectomy.
Methods: Figo stage IIb-IIIb, 32 patients who received either concurrent chemo radiation with or without brachytherapy or induction chemotherapy+external beam radiotherapy with or without brachytherapy were treated by either radical hysterectomy or extra fascial hysterectomy. All these patients were treated in Delta Hospital and National Institute of Cancer & Hospital, Dhaka, Bangladesh. Progression free survival and overall survival of these patients were seen.
Results: From 2009-2012, all these patients were diagnosed as central residual or central recurrence on their follow-up (other than central recurrence was the exclusion criterion). During follow-up of these patients on routine clinical examination biopsy was taken for suspicion. Either radical hysterectomy or extra fascial hysterectomy was done after biopsy proof. Surgery was done after 10-12 weeks of their initial treatment. Outcome (disease free survival or overall survival) of radical hysterectomy was not better than extra fascial hysterectomy patients. But morbidity was more in radical hysterectomy patients. There were no severe complications during surgery. About 94% (30/32) of patients had complete remission after surgery and 2 patients had recurrence.
Conclusion: Surgery is the treatment of choice of post irradiated residual or recurrent cervical cancer patients. Extra fascial hysterectomy is sufficient for tumor regression.
- Cancer Cell Biology |Cancer Epidemiology | Anticancer Drugs and New Formulations | Oncology
Location: Singapore
Chair
Sudeep Kumar
Unichem Laboratories Ltd, India
Co-Chair
Lu-Hai Wang
China Medical University, Taiwan
Session Introduction
Kshama Pansare
Tata Memorial Centre Advanced Centre for Treatment Research & Education in Cancer, India
Title: Aspirin inhibition of a novel target upstream of COX pathway leads to tumor regression in oral squamous cell carcinoma
Biography:
Kshama Pansare has completed her PhD from Aston University, UK and is currently working as Postdoctoral Research Associate at ACTREC, TMC, India under the International Cancer Genome Consortium Project.
Abstract:
Aspirin is an anti-inflammatory, anti-thrombotic and cardioprotective drug has been clinically reported to be effective in colorectal, esophageal, breast, lung, prostrate, liver and skin cancers. Here we report the chemopreventive and chemotherapeutic effect of Aspirin on oral squamous cell carcinoma-Gingivobuccal sulcus (OSCC-GB) and its underlying molecular mechanism. We have identified that Aspirin inhibits a novel phospholipase (PLA), upstream of the arachidonic acid metabolism pathway and thereby inhibits the downstream components of COX pathway. Binding of aspirin to PLA2 enzymes may partly contribute to its anti-inflammatory action, however the exact mechanism by which this occurs has not been shown. The inhibitory effect of Aspirin on OSCC-GB cell lines (ITOC-03 and ITOC-04) was shown by MTT and clonogenicity assay. Further, the inhibition of arachidonic acid metabolism (AAM) pathway components was confirmed at transcript level by qPCR and at protein level by Western blot and Immunofluorescence. Wound healing assay showed the decreased migratory potential of OSCC cell lines while the cell cycle analysis showed an increase in G0/G1 phase and a reduction of S phase on treatment with Aspirin. Following the in vitro findings we performed in vivo studies on NOD-SCID mice. Tumor regression was seen in both the OSCC cell line (ITOC-03 and ITOC-04) induced tumors. We further validated our findings with immunohistochemistry. We have established a novel mechanism of tumor inhibition by Aspirin in OSCC-GB.
Samira B A Sesay
Zhengzhou Medical University, China
Title: GSTM1 and GSTT1 genetic susceptibility and interaction with chemical exposures in childhood acute lymphoblastic leukemia: A systematic review and meta-analysis
Biography:
Samira B A Sesay is a Researcher in the Department of Epidemiology and Health Statistic, college of Public Health, Zhengzhou University with a passion for childhood health and improving health of susceptible populations like women, newborns etc. Prior to pursuing a MPH degree she grew interest and gained experience in evaluation, maternal and child health evidence-based research campaigns. With this interest, she did a comparative study on healthcare practices in community health facilities in her home country and her goal is to build innovative models for improving health care. Presently, she is working on a research in China to evaluate effect of environmental exposures in Henan on childhood leukemia incidence.
Abstract:
Background: The glutathione s-transferase genes play an important role in the detoxification of carcinogenic substances and null mutations of these genes are linked to increase in acute Lymphoblastic Leukemia (ALL) due to an increase in susceptibility to environmental exposures of toxins and carcinogens and chemical exposures like tobacco smoke and pesticides are common carcinogenic substances that children could be vulnerable to as risk of developing childhood ALL.
Aim: The aim of this study is to analyze the effect of glutathione s-transferase mu1 (GSTM1) and theta1(GSTT1) genetic susceptibility and interaction of chemical pesticide and tobacco smoke exposures on childhood ALL.
Method: A total of 22 published case-controls were included in the meta-analysis of over 40,000 participants with 14,974 cases and 25,841 controls.
Result: Overall, the meta-analysis of these studies showed increase risk of ALL among children (random-effect, OR: 1.36, 95% CI: 1.18-1.57). Subgroup analysis showed that the GSTM1 and GSTT1 null genotype has association to childhood ALL (random-effect, OR: 1.36, 95% CI: 1.05-1.76) and chemical pesticide in comparison with tobacco smoke exposures did have an increased association with childhood ALL (random-effect, OR: 1.40, 95% CI: 1.10-1.78) and (random-effect OR 1.38, 95% CI 1.20-1.58), respectively.
Conclusion: In this study, the GSTM1 null genotype is significantly associated with susceptibility to childhood acute Lymphoblastic Leukemia in Asians and chemical pesticides also showing increase associations. The GSTM1 and GSTT1 null genotypes show increase interaction with chemical pesticides in childhood ALL as compared to tobacco smoke exposures.
Danmaigoro Abubakar
Universiti Putra Malaysia, Malaysia
Title: pH-responsive Doxorubicin-loaded cockle shell-derived nanoparticles: Release kinetics and pharmacokinetics in canine
Biography:
Danmaigoro Abubakar is currently a PhD student at Universiti Putra Malaysia. He is also a Lecturer at the Usmanu Danfodiyo University, Nigeria in the Department of Veterinary Anatomy.
Abstract:
Nanoparticles with stimuli-responsive release mechanism have received great interest in nanomedicine. Doxorubicin-loaded pH-responsive nanocarriers could enable selectivity and specificity by reducing premature drug release in the plasma following an intravenous administration. Doxorubicin-load cockleshell-derived nanoparticle (CSNP-DOX) was prepared via ball-milling method. Apart from the analysis of CSNP drug release kinetics at pH 4.8 and 7.4, a high-performance liquid chromatography (HPLC) bioanalytical method was developed for the detection of Doxorubicin. For the pharmacokinetics of CSNP-DOX, animal ethics approval was sought. Six canines were divided into two groups to receive intravenous CSNP-DOX and free Doxorubicin at 30 mg/m2, respectively. At predetermined time interval, blood was sampled and processed before analyzed by HPLC. The pharmacokinetic parameters were determined based on the plasma Doxorubicin concentration in the canines. An excellent bioanalytical method with high acceptable extraction yield and linearity of 89.87% and 0.997 within the range limit of 0.25-4 µg/mL was revealed from the method developed. At pH 7.4, 13.7% of DOX was released from CSNP-DOX after 96 hours while 52.6% of Doxorubicin was recorded in the free Doxorubicin alone. However, the amount of Doxorubicin released from the nanocarriers doubled in acidic condition. CSNP-DOX increases the t1/2, Tmax and AUC0-t of Doxorubicin. The plasma concentration of Doxorubicin rapidly becomes lower versus time when compared to the plasma concentration of CSNP-DOX. CSNP-DOX exhibited pH-triggered and sustained-drug release properties. The pharmacokinetic parameters confirmed that CSNP has the ability to regulate and delay the release of doxorubicin in blood circulation.
Suganya Sakthivel
Tzu Chi University, Taiwan
Title: EBNA2/c-Myc dependent regulation and adaptor function to LMP 1 in NF-κB signaling: MCT 1 and EBV- A first approach
Biography:
Suganya Sakthivel is currently a Master’s degree student at Tzu chi University, Taiwan and has received her Bachelor’s degree from SRM University, India. She has been the District Head-Honcho for a social organization during her graduation. Currently, she is gaining acuity on viral oncology and trying to investigate the interaction between the virus and a host gene.
Abstract:
Epstein Barr Virus, a ubiquitous virus discovered 50 years ago as a first human tumor virus is implicated to latently infect B cells and epithelial cells. In vitro, EBV could transform B cells into immortalized lymphoblastoid cell lines (LCLs). LCLs expresses six nuclear antigens (EBNA 1, 2, 3A-3C, LP) and three latent membrane proteins (LMP1, 2A-B) creating a cellular milieu for proliferation and survival. This growth transformation program is referred as Latency III. A recent study suggests the role of activated Warburg metabolism in EBV transformed lymphoblastoid cells. Also, previous studies indicate Monocarboxylate Transporter-1 (MCT 1) which is essential in post stages of Warburg metabolism, to be a direct Wnt target. Of importance, the nuclear protein EBNA-2 expressed only at Latency III is a multiple regulator involved in β-catenin accumulation, c-Myc regulation and LMP1 transactivation. Herein we identify MCT-1 regulation is EBV associated and their role with LMP1 in NF-κB signaling. Immunoblotting and quantitative PCR verified the overexpression of MCT-1 in EBV infected cells as compared to EBV negative cells. In cell-based reporter assays, EBNA-2 and c-Myc regulate MCT-1 expression and the combined effects of MCT-1 and LMP1 in the down-regulation of NF-κB signaling which was absent when cells were transfected with MCT-1 alone. Taken together, our study supports a model for EBNA-2 and c-Myc dependent expression of MCT-1 and the role of MCT-1 as an adaptor to LMP1 in NF-κB signaling.