Day 1 :
Keynote Forum
Sudeep Kumar
Unichem Laboratories Ltd, India
Keynote: Potential of recombinant protein (ULLB-0005) in different cancer
Time : 9:30-10:15
Biography:
Dr Sudeep Kumar did his Post Doc in Biotech from Valencia, Spain on purification, cloning and sequencing of Cellulase and Xylanase enzyme. He has more than 20 years of experience in Biopharma. He has worked from R&D to tech transfer and manufacturing of different molecules. He is dealing with different regulatory agencies for approval and faced WHO, USFDA and other regulatory audits. He also actively involved with clinical research team for Preclinical and clinical trials of recombinant proteins and vaccine. He established the VLP technology platform for different vaccine in India in collaboration with Novavax.
Abstract:
Recombinant protein (ULLB-0005), is derived from a natural fungal protein, which has high binding specificity toward the carbohydrate antigen (Galβ1–3GalNAc-α-O-Ser/Thr). The natural Amino acid sequence has been modified to make more stable and soluble protein. Modified sequence has been cloned and express in E.coli. The protein was purified through different column chromatography and was characterized as a single protein.
The present study evaluated the anticancer activity of Recombinant protein ULLB-0005 by determining in vitro cytotoxicity fingerprint, efficacy, mechanism and safety in human cell lines. Promising cytotoxicity was observed in 9 different cancer cell line, with a good safety profile in human PBMCs. The efficacy of the Molecule as antitumor agent was assessed in respective xenograft immuno-compromised mice models in vivo. As expected the molecule showed strong anti-cancer activity in immune-compromised mice model in various cancers which was observed in the reduction of tumor volume.
ULLB-0005 induced strong apoptotic signal by modulating Phosphatidyl serine (PS) externalization, mitochondrial membrane depolarization, cell cycle arrest, ultimately leading to death in cancer cells. Inhibition of proliferation and migration was observed in human endothelial cells, suggesting potential antiangiogenic effect.
Further studies to evaluate possible synergistic effect of the molecule with approved chemotherapeutic agents for Breast and Pancreatic cancers showed good synergy in In-vitro test. Detailed multi-arm mechanistic studies to investigate the effect of the molecule on multiple targets and signaling pathways involving kinases, GPCRs, Growth factor receptors, inflammatory markers and circulatory markers for metastasis are ongoing using multiplex platforms. The data for the same shall be presented.
Keynote Forum
Lingzhi Wang
Cancer Science Institute of Singapore, Singapore
Keynote: Novel autoantibody signatures in plasma exosomes as potential biomarkers for diagnostics and prognosis of non-small-cell lung cancer
Time : 10:15-11:00
Biography:
Dr. Lingzhi Wang is a Senior Research Scientist at the Cancer Science Institute of Singapore and an Assistant Professor in the Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore (NUS). Dr. Wang obtained his M.Med. in Medicinal Chemistry from Chongqing Medical University in 1993. He continued his postgraduate studies in NUS and obtained his M.Sc. in Pharmacy and Ph.D. in Pharmacology in 2003 and 2008, respectively. Dr. Wang received the Medical Research Scientist Award from the National Medical Research Council (NMRC Singapore) in 2005, and the PhD Graduate Research Excellence Award from the American Association of Pharmaceutical Scientists (AAPS) at its Annual Meeting in 2008 (USA).
Abstract:
Lung cancer has one of the highest cancer-related mortality rates due to lack of efficient diagnostic approaches. Although the National Lung Screening Trial (NLST) has now shown that screening with low-dose CT (LDCT) scanning results in fewer deaths from lung cancer, high false positive rate can lead to anxiety, additional cost and morbidity associated with cancer treatment. Therefore, the discovery of novel biofluid derived non-invasive exosomal biomarkers for lung cancer is urgently needed to reduce over diagnosis due to LDCT screening. Exosomes are small (30-120 nm) vesicles containing nucleic acid and protein cargo. There is currently a lack of information regarding the association between exosomal proteome and the pathological condition of lung cancer. We conducted studies to evaluate the utility of plasma exosomal proteins as circulatory biomarkers for early detection of non-small-cell lung cancer (NSCLC) using the Sengenics immunome protein array technology, which affords the simultaneous screening of over 1600 functional proteins selected based on their involvement in the immune system. It leverages on its use of a biotin carboxyl carrier protein (BCCP) folding marker, which ensures correct folding of every protein immobilized on the array. Preliminary data from this study revealed multiple biomarker signatures in both early and late stage patient cohorts when compared to healthy controls. With the use of sequential bioinformatics analyses which implements a penetrance fold change and a recursive feature elimination algorithm, we have modeled the correlation and classification of identified biomarker signatures with significant ROC-AUCs in differentiating NSCLC patients of different stages and the prognostic potential of exosomal autoantibody signatures is under investigation.
Keynote Forum
Ming Liu
Guangzhou Medical University, China
Keynote: CHD1L promotes lineage reversion of hepatocellular carcinoma through open chromatin for key developmental transcription factors
Time : 11:15-12:00
Biography:
Ming Liu has received his PhD and Postdoctoral training at the Department of Clinical Oncology, the University of Hong Kong. He is currently a Professor at the School of Basic Medical Sciences, Guangzhou Medical University. He has been focusing on characterization of molecular pathogenesis of human hepatocellular carcinoma and has published more than 20 papers in reputed journals, such as Nature Medicine, Gastroenterology, Hepatology, etc.
Abstract:
High-grade tumors with poor differentiation usually show phenotypic resemblance with their developmental ancestral cells. Cancer cells that gain lineage precursor cell properties usually hijack developmental signaling pathways to promote tumor malignant progression. Oncogenic chromatin remodeling protein (CHD1L) might be important in this process. The association of CHD1L with HCC lineage reversion was systematically evaluated in cell line model, xenograft mouse model, genetically modified mouse model and HCC clinical samples. Chromatin immunoprecipitation followed by high-throughput deep sequencing was used to identify the potential molecular mechanisms. CHD1L was found closely associated with liver development and HCC tumor differentiation. Expression of CHD1L decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly-differentiated HCCs. ChIP-sequencing found that CHD1L could bind to genes related to development. Bioinformatics-aided network analysis indicated that CHD1L might regulate networks associated with embryonic development. Overexpression of CHD1L conferred ancestral precursor-like properties of HCC cells both in vitro and in vivo. Inhibition of CHD1L reversed the malignant phenotype and sensitized HCC cells to Sorafenib treatment. Mechanism studies revealed that CHD1L could maintain open chromatin architecture at promoter regions of key developmental transcriptional factors. Significant correlation of CHD1L with hepatic lineage differentiation markers was also found in HCC patients. We proposed a novel mechanism that oncogenic chromatin remodeler CHD1L might drive HCC lineage reversion and maintain a chromatin status suitable for liver ancestral precursor cells. Further, inhibition of CHD1L might down grade poorly-differentiated HCCs, sensitize tumors to Sorafenib treatment and provide novel therapeutic strategies for this deadly disease.
Keynote Forum
Yonghua Yang
Fudan University School of Pharmacy, China
Keynote: Pkc-δ phosphorylation of p62 is essential for VPS34-dependent breast cancer progression
Time : 12:00-12:45
Biography:
Yonghua Yang is currently a Professor in the Department of Biochemistry & Pharmacology of Fudan University, China. He has obtained his BS in Organic Chemistry from Jilin University and continued his Postgraduate studies in Shanghai Institute of Materia Medica, CAS and obtained his PhD in Pharmacy and Pharmacology, respectively. He is working with trainees in his laboratory on the characterization and development of novel molecules significant in breast tumorigenesis. He has published as first author and senior author in recognized peer-reviewed journals, including Nature Cell Biology, EMBO J, PNAS, Cancer Research and Oncogene, etc.
Abstract:
Among autophagy related proteins, two proteins have attracted immense interest. One is the class III phosphoinositide 3-kinase (PI3K) vacuolar protein sorting 34 (VPS34), which forms numerous complexes with the core components p150 (Vps15), Beclin 1 and ATG14L to function in a variety of cellular and physiological events. Another one is the well-known autophagic adaptor protein, sequestosome-1 (SQSTM1, also known as p62 in humans). VPS34 and p62 play important roles separately in vesicle nucleation and autophagy progression. Both of them may also contribute to the development and progression of human cancers. However, the mechanism of VPS34 coordinating p62 in tumorigenesis remains elusive. We found that the expression of VPS34, documented for the phosphorylation of MEK and ERK is strongly correlated with tumorigenic activity of human breast cancer cells. VPS34 augments PKC-δ to p62 for its phosphorylation at Serine 349, leading to transcriptional expression of p62 through its affinity with Keap1 (Kelch-like ECH-associated protein-1) and positive feedback on the Nrf2-dependent transcription of oncogenes. Moreover, ablation of PKC-δ or p62 expression in MCF-7 cells abrogates VPS34-dependent tumor growth. We will present data to show that VPS34 stimulates tumor development mainly through PKC-δ phosphorylation of p62 and all the results suggest that VPS34-p62-PKC δ machinery may be a useful target for cancer therapy.
- 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.