Day :
- Cancer and Prevention
Location: Room 1
Session Introduction
Junjun Qiu
Obstetrics and Gynecology Hospital of Fudan University, China
Title: The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis
Biography:
Junjun Qiu has completed her PhD from Fudan University in 2014. She is now working at the Obstetrics and Gynecology Hospital of Fudan University. Her research mainly focuses on long noncoding RNA and ovarian cancer progression and was supported by funding from Shanghai Science and Technology Development Funds for the Talents (15YF1401400). She has published 8 SCI papers in recent three years
Abstract:
The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis: HOX transcript antisense RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) whose dysregulation correlates with poor prognosis and malignant progression in many forms of cancer. Here, we investigate the expression pattern, clinical significance, and biological function of HOTAIR in serous ovarian cancer (SOC). Clinically, we found that HOTAIR levels were overexpressed in SOC tissues compared with normal controls and that HOTAIR overexpression was correlated with an advanced FIGO stage and a high histological grade. Multivariate analysis revealed that HOTAIR is an independent prognostic factor for predicting overall survival in SOC patients. We demonstrated that HOTAIR silencing inhibited A2780 and OVCA429 SOC cell proliferation in vitro and that the anti-proliferative effects of HOTAIR silencing also occurred in vivo. Further investigation into the mechanisms responsible for the growth inhibitory effects by HOTAIR silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, these results highlight a critical role of HOTAIR in SOC cell proliferation and contribute to a better understanding of the importance of dysregulated lncRNAs in SOC progression.
Helene Castel
Université de Rouen, France
Title: Anti-VEGF ater cognitive functions and the CA1-CA3 hippocampal activity in mice: The first reported
Biography:
Hélène Castel started to develop different variants of the electrophysiological technique at the university of Rouen in the laboratory of Dr Vaudry (U413 Inserm) and biochemical approaches to give a comprehensive view of modulation of the GABAA receptor-channel function by interacting proteins. She received her PhD in Neurosciences, Molecular and Cell Biology at the Rouen University in 2000, and then spent 2 years on a post-doctoral position in Pr Colquhoun’s laboratory at University College of London, UK. There, she has developed fast-concentration-jump techniques to mimic electrical fast synaptic inputs on recombinant NMDA receptors and acquired expertise in molecular biology through mutagenesis of NMDA receptor subunits. In 2002, she obtained a permanent position as chargée de Recherche (CR) at the French National Institute of Health (Inserm) and University of Rouen. In 2010, she became group Leader “Astrocyte and Vascular Niche†and since 2015, she is co-head of the international platform “Cancer and Cognition†under the French North-West Canceropole. She develops projects based on vasoactive and chemokine G protein-coupled receptors (GPCRs) in tumor brain, brain vascular physiopathology and on cognitive dysfunctions induced by cancer and targeted therapies.
Abstract:
Cancer patients treated with chemotherapy may show impaired cognition (Chemofog) long-term after the treatment completion. Recently, targeted therapies have been developed and have been also associated with the appearance of leukoencephalopathy and major asthenia in cancer patients. Our previous work has identified a direct link between chemotherapy and impaired long-term behavioral flexibility associated with a decreased proliferation within the hippocampus and no cognitive dysfunctions after the cancer treatment everolimus in mice. In this study, we evaluated the impact of the systemic administration of an anti-VEGF antibody on cognitive function, hippocampal vascularization, cerebral metabolic activity and hippocampal synaptic activity in mice as well as on proliferation of neural stem and endothelial cells in vitro. Antibodies against the mouse VEGF (B20-4.1.1, MTA Genentech) and human VEGF (bevacizumab, Genentech, MTA, Roche) were administered to adult C57/Bl6 mice (1.5 mg/kg) every 4 days for 24 days. Note that B20-4.1.1 treatment caused a slowing of weight gain. During/or after treatment, emotional reactivity, spontaneous activity, learning and spatial memory, behavioral flexibility and object recognition memory were assessed. The selective cognitive impairments observed in B20-treated mice (spatial learning in the Morris water maze and memory consolidation in the object recognition test), were predictive of hippocampal dysfunctions. In addition, we detected modifications of the cytochrome oxidase activity in CA1-CA3 hippocampal area and markers involved in long term potentiation. However, proliferation of neural hippocampal precursors (BrdU labeling) and vascular density (Collagen IV) in vivo as well as neurosphere growth and Bend.3 endothelial cell proliferation in vitro were unaltered. Together, these data indicate that the inhibition of endogenous systemic VEGF levels does not drastically change the plasticity of the hippocampal vascular niche, but selectively alters the spatial learning dependent on the long-term potentiation in the hippocampus.
Didier Coquoz
Effimune, Copexis, Switzerland
Title: Evolution of cancer drug development and registration paradigms in light of the successes of immunotherapy
Biography:
Didier Coquoz has completed his PhD in Clinical Pharmacology. He has more than 20 years of experience as Pharma R&D Executive (VP R&D and CEO). He has been instrumental in the development/regulatory management from drug candidate up to phase III and registration of close to 30 biologics, monoclonal antibodies, peptides, cell-based therapeutics, NCEs of which 4 reached the market world-wide. He held positions as CEO and VP R&D on both sides of the Atlantic. He currently acts through Copexis S.A. as Chief Development Officer, Chief Regulatory Affairs and Chief Business Development Affairs for different biotechs/mid pharma in Europe, mostly in immunology.
Abstract:
For many decades, early and late stage drug development of anti-cancer drugs have been very much based on tumor sizes evolution. They registration was mostly based on survival increase, although the evolution of tumor sizes (PFS) were also taken into account. Early guidelines on anticancer drugs focused on conventional cytotoxic compounds. A first major revision was made in Europe in 2005 stressing on the PFS followed by a second in 2010 introducing among others, the notion of relative toxicity. In recent years, immunotherapy, especially anti immune-suppressive agents such as anti CTLA4 and anti PD1/ PDL-1 antibodies have shown remarkable increases in survival whereas they have relatively limited impact on the classical tumor size parameters. In addition to these improvements, not only increases in survival but increase in percentages of cures re more and more observed with recent anti-cancer drugs. Finally, combination of anticancer drugs such anti-immunosuppressive agents and other anti-cancer drugs may more and more prove to be very beneficial in the future. Consequently, the paradigms of drug development (efficacy criteria for phase II, for instance) as well as the regulatory and registration requirements will further evolve. Such probable evolutions will be discussed.
Fenglei Wu
Nanjing Medical University, China
Title: Effect of hENT1 polymorphism G-706C on clinical outcomes of gemcitabine-containing chemotherapy for Chinese non-small cell lung cancer patients
Biography:
Fenglei Wu has completed his PhD from Nanjing Medicine University. He is the Director of some projects of NSFC. He has published more than 5 papers in reputed journals and has been serving as an Editorial Board Member of repute.
Abstract:
Objective: To evaluate the association between a single nucleotide polymorphism (SNP) in human Equilibrative Nucleoside Transporter 1 (hENT1) and the therapeutic efficacy of gemcitabine-containing chemotherapy as well as the prognosis ofthe patients with Non-Small Cell Lung Cancer (NSCLC). Methods: Two hundred and twenty five patients with Stage III (A+B) or IV NSCLC who received gemcitabine-containing chemotherapy was recruited and genotyped for hENT1G-706C (rs61758845) using PCR–restriction fragment length polymorphism assays (RFLP). The association between hENT1G-706C and therapeutic efficacy of gemcitabine-containing chemotherapy was statistically evaluated. Results: Both genotype and allele frequency of hENT1G-706C polymorphism differed significantly between responders and poor-responders. To be more specific, the response rate in the patients carrying GG genotype was substantially higher than that in the patients with GC or CC genotype. Using logistic regression analysis, we found that GC or CC genotype presented higher risk of being poor-responders compared with the GG genotype (OR=2.34, 95% CI: 1.14–4.80; P=0.02). The overall survival in patients with GG genotype were significantly higher than those with GC or CC genotype (19.0 vs. 15.1 months, P<0.001). The hazard ratio for (GC+CC) genotype was 1.89 (95% CI: 1.23–2.90, compared with GG carriers, P=0.004). Conclusions: Our data revealed that hENT1G-706C polymorphism was significantly associated with the therapeutic efficacy of gemcitabine-containing chemotherapy as well as the prognosis in the patients with NSCLC, and it may represent a novel biomarker for the individualization of the treatment of NSCLC.
Wen Wen Xu
The University of Hong Kong, China
Title: Role of miR-29c in modulating the paracrine crosstalk between esophageal cancer cells and stromal fibroblasts in the tumor microenvironment
Biography:
Wen Wen Xu is a final year PhD student in the University of Hong Kong. She got her MPhil degree from The Chinese University of Hong Kong in 2012. Her current research interests include: 1) Role of Id1 in the regulation of tumor micro-environment and macro-environment; 2) Cellular and molecular mechanisms of tumor angiogenesis and potential targeted therapy. She was honored with many prestigious international and local awards and scholarships, including 2013 UK National Cancer Research Institute prize award, 21st Hong Kong International Cancer Congress Best Poster prize, Mary Sun Medical Scholarships, YS and Christabel Lung Postgraduate Scholarship.
Abstract:
Esophageal cancer is the 8th most common cancer worldwide, with more than 480,000 new cases diagnosed every year. Angiogenesis is a major clinical feature of aggressive esophageal squamous cell carcinoma (ESCC). However, understanding of the cellular and molecular mechanisms of tumor angiogenesis remains poor. Our results demonstrated that insulin-like growth factor 2 (IGF2) secreted by ESCC cells could activate stromal fibroblasts in a paracrine manner, stimulating them to migrate and produce vascular endothelial growth factor (VEGF). Knockdown of IGF2 or neutralization of IGF2 using specific antibody greatly abrogated this effect. In silico target prediction algorithms and RT-PCR were used to screen for microRNAs that might mediate the regulation of IGF2 on VEGF. Amongst the potential candidates, miR-29c was found to satisfy the criteria of having conserved seed regions that perfectly matched with the 3’UTR of VEGF and being downregulated by IGF2. Gain- and loss-of-function studies showed that miR-29c negatively regulated the expression of VEGF in normal fibroblasts and mediated the regulation of IGF2 on VEGF. Results from luciferase reporter assay indicated direct binding of miR-29c to the 3’UTR of VEGF. More importantly, analysis of GEO datasets showed stromal VEGF to be a prognostic biomarker in breast cancer, and its potential in ESCC prognosis will be evaluated. Taken together, these data provide the first evidence showing that the IGF2/miR-29c/VEGF regulatory axis may have an important role in tumor progression.
Paula Bernardo
Brazilian National Cancer Institute, Brazil
Title: New synthetic anti-cancer compounds, LQB-118 and LQB-223, induce apoptosis by distinct mechanisms in glioblastoma cells
Biography:
Paula Sabbo Bernardo is a PhD student from Brazilian National Cancer Institute. She developed her PhD project at the Laboratory of Cellular and Molecular Hemato-Oncology, which is headed by Dr. Raquel Ciuvalschi Maia. She completed her Master´s degree in translational research in the field of anti-cancer drugs development for glioblastoma treatment.
Abstract:
Glioblastoma (GB) is the most common astrocytoma and a lethal human malignancy, with a median survival of 12 months. Therefore, our group is involved in the development of new anti-cancer drugs. This study evaluated the anti-tumoral activity of new synthetic compounds pterocarpans, LQB-118 and LQB-223 in human GB cell lines. Moreover, the relationship between microRNAs and Akt and ERK survival pathways underlying the compounds mechanism of action was investigated. LQB-118 and LQB-223 reduced cell viability to a greater extent than the first line chemotherapy, temozolomide (TMZ). The compounds also inhibited cell proliferation and induced apoptotic cell death demonstrated by caspases activation and annexin V labeling. Furthermore, the compound LQB-223 induced cell cycle arrest at G2/M phase, followed by DNA fragmentation. LQB-118 and LQB-223 reduced ERK1/2 expression and phosphorylation, while TMZ only slightly reduced ERK1/2 phosphorylation and did not significantly induce cell death. LQB-118 promoted an increase in miR-210 expression, while LQB-223 induced miR-7 expression. As miR-7 inhibits RAS in GB models, consequently, inhibiting Akt and ERK phosphorylation, we evaluated RAS expression. LQB-223 reduced RAS protein levels, suggesting an important role of this pathway in the compound mechanism. As LQB-118 showed the higher effect on cell viability, the association of LQB-118 with ionizing radiation was assessed by tripan blue exclusion assay. The association reduced cellular viability synergistically and a similar effect was observed in the combination of TMZ with ionizing radiation. Our results suggest that the compounds LQB-118 and LQB-223 are promising agents with distinct mechanisms of action for GB treatment.
Biography:
Sherry A Bradford completed her PhD at the New York State University at Buffalo Medical School/Roswell Park Cancer Institute Division. She is the Founder and Chief Scientific Director of AccuTheranostics, a premier biotechnology research and clinical laboratory service institute, located in the heart of Buffalo’s Medical Corridor. She has published many papers/book chapters and she has been invited as a speaker at many national and international meetings. She is currently serving as an Editorial Board Member of repute.
Abstract:
Chemotherapeutic treatment regimens tend to be deleterious and toxic to cancer patients. Thus, today many clinicians are changing their clinical practices opting for targeted and/or ancillary drug treatments that kill the tumor cell populations while sparing healthy cells. Greater than 70% of all cancer types rely on cytosolic aerobic glycolysis for energy production, an inefficient means of generating ATP rather than mitochondrial oxidative phosphorylation resulting in an acidic microenvironment conducive to their growth and proliferation. DCA inhibits Pyruvate Dehydrogenase Kinase (PDK) thereby increasing influx of pyruvate into the mitochondria, promoting glucose oxidation, reversing the suppressed mitochondria thus promoting apoptosis in cancer cells. Thus, it would be reasonable to propose that cancer cells would likely be sensitive DCA. Therefore, a prospective study of the efficacy of DCA as a potential chemotherapeutic agent was conducted.
Biography:
Didier Coquoz has completed his PhD in Clinical Pharmacology. He has more than 20 years of experience as Pharma R&D Executive (VP R&D and CEO). He has been instrumental in the development/regulatory management from drug candidate up to phase III and registration of close to 30 biologics, monoclonal antibodies, peptides, cell-based therapeutics, NCEs of which 4 reached the market world-wide. He held positions as CEO and VP R&D on both sides of the Atlantic. He currently acts through Copexis S.A. as Chief Development Officer, Chief Regulatory Affairs and Chief Business Development Affairs for different biotechs/mid pharma in Europe, mostly in immunology.
Abstract:
For many decades, early and late stage drug development of anti-cancer drugs have been very much based on tumor sizes evolution. They registration was mostly based on survival increase, although the evolution of tumor sizes (PFS) were also taken into account. Early guidelines on anticancer drugs focused on conventional cytotoxic compounds. A first major revision was made in Europe in 2005 stressing on the PFS followed by a second in 2010 introducing among others, the notion of relative toxicity. In recent years, immunotherapy, especially anti immune-suppressive agents such as anti CTLA4 and anti PD1/ PDL-1 antibodies have shown remarkable increases in survival whereas they have relatively limited impact on the classical tumor size parameters. In addition to these improvements, not only increases in survival but increase in percentages of cures re more and more observed with recent anti-cancer drugs. Finally, combination of anticancer drugs such anti-immunosuppressive agents and other anti-cancer drugs may more and more prove to be very beneficial in the future. Consequently, the paradigms of drug development (efficacy criteria for phase II, for instance) as well as the regulatory and registration requirements will further evolve. Such probable evolutions will be discussed.
Virendra N Pandey
Rutgers University, USA
Title: Fuse binding protein1 (FBP1) as antagonist of p53: A potential host target for drug development
Biography:
Virendra N Pandey has completed his PhD in 1985 from Bhabha Atomic Research Center (BARC), University of Mumbai, India. While working as a Senior Scientist at BARC, he was honored with the most prestigious Shanti Swaroop Bhatnagar Award in Life Sciences in 1991 by the Prime Minister of India. Currently he is a Senior Tenured Faculty in the Department of Microbiology at Rutgers New Jersey Medical School, New Jersey. He is on Editorial Board of several journals and has published over 80 papers in reputed journals.
Abstract:
FUSE binding protein1 (FBP1) is a transactivator of transcription of human c-myc proto-oncogene and expressed mainly in undifferentiated cells. Immunohistochemistry of archived hepatocellular carcinoma (HCC) tumors revealed abundant FBP1 expression in HCC tumors with chronic hepatitis C (CHC) background but absent in other HCC tumors with alcoholic or cryptogenic background. Hepatitis C virus (HCV) is a leading cause of CHC, liver cirrhosis, HCC and liver failure. Oncomine data analysis of normal liver versus HCV-HCC tumors indicated a 4-fold increase in FBP1 expression with a concomitant 2.5-fold decrease in the expression of p53. It is our novel discovery that FBP1, which is abundantly expressed in HCV-HCC tumors, is involved in the suppression of transactivation activity of p53 by physically interacting with p53 and inhibiting its DNA binding activity. The p53 transcription activity is enhanced in FBP-kd cells resulting in increased sensitivity of the cells to radiation. Knockdown of FBP1 expression activates p53-mediated response to cellular stress while transient expression of FBP1 restores the control phenotype in which 53-mediated response to cellular stress is strongly suppressed. FBP1 also promotes HCV replication by inhibiting p53, and also by regulating BCCIP and TCTP, which, respectively, are positive and negative regulators of p53. The severe inhibition of HCV replication in FBP1-knockdown cells is restored to control level by downregulation of either p53 or BCCIP. Since normal differentiated cells are devoid of, or poorly express FBP1, our studies indicate that over-expression of FBP1 in HCV-HCC tumors may have a potential role in promoting liver cancer by suppressing p53 activity, and thus, could be a potential target for drug development.
Antonina Khoruzhenko
National Academy of Sciences of Ukraine, Ukraine
Title: mTOR association with nucleoli and intermediate filaments in human breast cancer cells
Biography:
Antonina Khoruzhenko has great experience as clinical cytopathologist in thyroid neoplasm differential diagnostics, including Chernobyl caused cancer. From 2002-2003, she was a Fellow Researcher at the Medical Faculty of Reims University, France. She has completed PhD from Taras Shevchenko Kyiv National University and Postdoctoral studies from Institute of Molecular Biology and Genetics, Kyiv, NAS of Ukraine. She is team leader at the Department of Cell Signaling, Institute of Molecular Biology and Genetics. She delivers the course of lectures “Basic molecular diagnostics†in Taras Shevchenko Kyiv National University. She has published 23 review and experimental papers.
Abstract:
Kinase mTOR is one of the main links in signal transduction from the variety of growth factors and hormones into the cell. mTOR participates in the regulation of protein synthesis, cell growth, survival, proliferation and migration. Significant overactivation/overexpression of mTOR in numerous malignant neoplasms was demonstrated earlier. Its inhibitors are used as anti-cancer drug. Information about mTOR subcellular localization could clarify its role in tumor growth. So, mTOR subcellular localization was detected in breast cancer and normal tissues, and MCF-7 cells (originated from breast cancer) in monolayer and 3D cultures. For this the antibodies generated to C-, N-terminus and central sites of mTOR were used. Detection of mTOR subcellular distribution with antibodies to mTOR C-terminus in all cases revealed its diffuse cytoplasmic localization. Application of the antibodies to the central region of the kinase revealed its nucleolar (additionally to cytoplasmic) localization in breast cancer cells. Determination of mTOR localization with anti N-terminal antibodies uncovered a stained network inside the cells. Confocal microscopy, co-immunoprecipitation and PLA showed strong co-localization of mTOR and intermediate filaments (cytokeratins) in breast cancer and normal cells. Decrease of mTOR activity by rapamycin, as well as cytokeratin disassembly by sodium orthovanadate, did not disturb mTOR/cytoceratin association. Also in breast cancer cells the relocalization of rpS6K (mTOR target) was revealed. Besides, there was observed the effect of mTOR activation/inhibition on cell motility. So, for the first time the nucleolar localization of mTOR was demonstrated. Moreover, it was revealed the co-localization of mTOR kinase and intermediate filaments.
Biography:
Dimitrakopoulou Veronika is a student in the Department of Psychology in the Aristotle University of Thessaloniki in Greece. She has worked in the Association of the Women with Breast in Thessaloniki, Alma Zois. She is working on Palliative Care, which is not widely known in Greece.
Abstract:
The purpose of the current research is to study the different relationship between the social support from the social environment and social support from the partner to women with breast cancer, the interaction of the two forms of support and the differences compared with the general population of women. Specifically, 187 participants took part in the research, out of which, 89 women had breast cancer, 87 women were in general population and 16 were men partners of the women-patients. The questionnaires were given in paper and electronic form. The results showed that the positive and common dyadic coping is positively associated with the quality of life and relationship of women with breast cancer, while the negative dyadic coping is negatively related to the quality of life and relationship. With regard to partners, the negative dyadic coping is negatively associated with the life satisfaction and quality relationship. Moreover, it was found that social support from social environment is positively correlated with the quality of life of women, while the support interaction between others’ and partner’s support is a predictor of quality of life in women from general population. Finally, no differences were found between women with breast cancer and women from the general population.
Angel Garcia Martin
StemTek ,Therapeutics, Spain
Title: Drug development targeting cancer stem cells
Biography:
Angel G Martin obtained his PhD in 1999 at the Universidad Autonoma de Madrid (Spain) and the Centro de BiologÃa Molecular Severo Ochoa, focused on transcriptional regulation of T cell activation by citokines. In 2000 he moved to the National Cancer Institute at Frederick (NIH; USA) for Postdoctoral training in oncogene-induced apoptosis. He returned to Spain in 2005 as investigator for the genomic regulation of cancer group at Centro de Investigación PrÃncipe Felipe, Valencia. In 2006 he moved to the Bilbao area to work as a senior researcher at Proteomika SL. In March 2007 he joined Inbiomed to start the Regulation of Cell Growth Laboratory. His main research interest is to understand the role of stem cells in cancer through characterization of cancer initiating cells in order to find novel therapeutic and diagnostic/prognostic targets. Later that year he also became Director of Inbiobank, the biorepository of Fundacion Inbiomed dedicated to adult stem cell banking. In July 2013 he co-founded StemTek Therapeutics, a start-up biotech company dedicated to finding new drugs for cancer treatment based on understanding the biology of cancer stem cells and since then he is exclusively dedicated to StemTek Therapeutics serving as CSO and member of the Board. He has published more than 40 papers in reputed journals and has been serving as an editorial board member of repute.
Abstract:
Conventional anti-cancer treatment excels at tumor size reduction leading to clinically evident responses. However, these effects are frequently transient and are not associated with increased patient survival. Treatments are often too toxic to normal cells and they fail to selectively kill cancer stem cells (CSCs), which can survive treatment and, like the queen bee of a beehive, give rise to new malignant cells. Therefore CSCs are an underlying cause of tumor recurrence and metastasis. For truly effective treatments that can create a durable clinical response drugs that can target CSCs must be developed. Here we present data showing how functional assays for drug screening may be used to unravel compounds that target cancer stem cells, with a case study on drugs that inhibit activation of HIF dependent pathways
Roni Moya
CESPU University, Portugal
Title: Intravenous orthomolecular integrative treatment in oncology
Biography:
Roni Lara Moya has done master science in Molecular and Cellular Immunology and Biology from University of Coimbra, Portugal and also in Clinical Advanced Nutrition – University of Barcelona, Spain. She has completed PhD in Biomedicine and Immunology – Gulbenkian Institute of Science and Coimbra University. Currently she is Director of the Graduation Program in Orthomolecular Therapy - CESPU University, Portugal
Abstract:
Since 1970, Linus Pauling established that the C-Vitamin could potentially and selectively kill tumours by the induction of the hydrogen peroxide in the malignant cells, but not in the healthy cells. Afterwards, more scientific studies have been published concerning the use of intravenous antioxidants to combat cancer such as alpha lipoic acid, curcuma, selenium, glutathione, cysteine, magnesium, zinc etc. The actual scientific data combined with the clinical practice show positive results when intravenous nutrition is applied integrated with the chemotherapy or radiotherapy conventional protocols. Most of all, they may be developed to increase the patient’s quality of life and reduce the hard pharmaceuticals or radiation side effects such as nausea, dizziness, anaemia, fatigue, immune suppression and pain. The aim of this talk is to discuss the best and safest nutritional protocols in intravenous oncology and the possible anti-cancer mechanisms behind.
Biography:
MarÃa Elena Sales has completed his PhD in the School of Biochemistry at the University of Buenos Aires (UBA) Argentina in 1992, and Postdoctoral studies at UCSD in La Jolla California, USA and in the A.H. Roffo Oncology Institute, UBA. She is full Professor in Pharmacology and the Director of Tumor Immunopharmacology Laboratory (CEFYBO), in the Pharmacology Department of the School of Medicine, UBA. She has published more than 50 papers in reputed journals and serving as an Editorial Board Member of repute. She has supervised six PhD thesis and also thesis to obtain the graduation in biology of ten students.
Abstract:
We have demonstrated that muscarinic acetylcholine receptors (mAChR) are involved in breast cancer progression in different experimental models. In mice, we demonstrated that mAChR are expressed in three distinct spontaneous mammary adenocarcinomas, while they were absent in normal epithelial mammary cells. In humans, we detected the expression of mAChR in breast tumor homogenates as well as, in two different tumor cell lines MDA-MB-231 and in MCF-7. The latter exhibits a marked expression of 3 and 4 subtypes. To analyze the role of mAChR in human breast oncogenesis, we transfected the non tumorigenic mammary cell line, MCF-10A, which does not express mAChR with these receptors, and obtained three stable clones: MCF-10A-mAChR3, MCF-10A-mAChR4 and MCF-10A-mAChR3 & 4, the latter one resembled to MCF-7 cell line. These clones formed spheroid structures in vitro, and responded to the stimulation with carbachol. Clones grew to form tumors in NUDE mice, while MCF-10A cells were unable to form spheroids in culture or to grow in vivo. Taking into account these previous results, as well as the fact that the addition of a combination of paclitaxel plus carbachol at low concentrations to murine breast cancer cells promotes tumor cell lysis, mainly via apoptosis, we analyzed the role of mAChR as therapeutic targets in human breast cancer. We confirmed that this combination was equally useful to trigger cell death in MCF-7 and MDA-MB-231 human adenocarcinomas, while it was innocuous in MCF-10A cells. These results let us speculate, about the possibility of using of this type of therapy in breast cancer.
Jiss Maria Louis
Rajiv Gandhi Center for Biotechnology, India
Title: TGF-β regulates recurrence by inducing self-renewal ability in cancer cells
Biography:
Jiss Maria Louis has done her Post Graduation from University of Calicut in Biotechnology. Presently she is working as Junior Research Fellow in Cancer Research Program with Dr Tessy for the past 16 months at Rajiv Gandhi Centre for Biotechnology, Kerala, India.
Abstract:
Recurrence after chemotherapy often hampers the treatment outcome of oral cancer which is believed to be due to the selection of cancer stem cells that recreate tumor after the withdrawal of the drug. Emerging evidences suggest the involvement of a tumor niche in recurrence by inducing CSC properties like self-renewal ability in cancer cells escaping chemotherapy. Here, we used model systems using tumor cells and growth–arrested fibroblasts, isolated from OSCC samples to generate short-term co-culture, long term 3D-co-culture on alginate matrix and xeongrafts. Our results show that TGF-β secreted by stromal elements of tumor niche is regulating recurrence by inducing self-renewal property. We also show that this induction is independent of Smad4-mediated canonical pathway. It is mediated by another transcription factor, TIF1γ which was identified as a regulator of hematopoesis. Collectively, our results show that recurrence is regulated by tumor niche-mediated, TGF-β-induced self-renewal that depends on TIF1γ.
Tessy Thomas Maliekal
Rajiv Gandhi Centre for Biotechnology, India
Title: TIF1γ is a central player in the regulation of self-renewal ability in cancer cells
Biography:
Tessy Thomas Maliekal has completed her PhD in 2002 from Kerala University and Postdoctoral studies from National Centre for Biological Sciences. She is a Scientist in Rajiv Gandhi Centre for Biotechnology, a premier research organization in India. She has published more than 14 papers in reputed journals like Cancer Research, Oncogene and J Boil Chem.
Abstract:
Recurrence is a major reason for mortality in many forms of cancer including oral squamous cell carcinoma (OSCC). It is explained as a continuing process in which cancer cells possessing self-renewal ability and resistance to therapy survive the treatment and recreate tumor after the withdrawal of the treatment. Our results show that tumor micro environment induce self-renewal property in cells surviving chemotherapy which enhances recurrence. We identified a transcription factor, TIF1γ which was previously known as a regulator of hematopoiesis as a regulator of self-renewal ability. We show that this molecule is indispensible for the induction of self-renewal by important pathways regulating cancer stem cells. Further we identified intermediate molecules regulating the function of TIF1γ using proteomic analysis. The role of TIF1γ in self-renewal ability and the various down-stream molecules and pathways regulating the function of this molecule will be discussed.
Biography:
Summya Rashid submitted her PhD thesis at Jamia Hamdard University New Delhi. She has research experience of more than four years in the field of cancer and chemoprevention. The area of herresearch is modulation of kidney cancer and anti cancer drug toxicity by natural compounds targeting inflammatory, apoptotic and proliferation signaling pathways at preclinical stage. She has published four first author papers in internationally reputed journals with good impact factors and PubMed indexed. She has 15 co-authored papers which in total makes 19 internationally accepted publications to her credit. She has been awarded by her university, a cash prize and a certificate for publishing in high impact factor journal in 2013. She has qualified National Eligibility Test (NET), University Grants Commission, Govt. of India.
Abstract:
5-Fluorouracil (5-FU) is an effective anti-cancer drug commonly used for the treatment of various malignancies. It has varied undesirable effects such as hepatotoxicity, nephrotoxicity and cardio toxicity which limit its broad and widespread clinical practice. It is found to result in remarkable organ toxicities along with increased oxidative stress and apoptosis. Chrysin (CH) is a natural flavonoid having anti-oxidative, anti inflammatory and anti-cancerous activities. It is found in many plant extracts, blue passion flower, honey and propolis. The present study was designed to investigate the efficacy of CH against 5-FU induced renal toxicity in Wistar rats by biochemical, histopathological and immunohistochemical approaches. Rats were subjected to prophylactic oral treatment of CH for 21 days at lower dose of 50 mg/kg b.wt. and a higher dose of 100 mg/kg b.wt. against renal toxicity induced by single intra peritoneal injection of 5-FU (150 mg/kg bwt). The probable mechanism of 5-FU induced renal toxicity is the generation of free radicals resulting in oxidative stress; activation of apoptotic pathway by upregulation of p53, bax, caspase-3 and down regulating Bcl-2. On the contrary, prophylactic treatment of CH decreased renal serum toxicity markers, increased renal anti-oxidant armory as well as regulated apoptosis in kidneys of wistar rats. Histopathological alterations further confirmed the biochemical and immunohistochemical data. Hence, results of the present finding suggest that CH may be a positive modulator in alleviating 5-FU induced renal toxicity and may be used in combinational therapy before further pre clinical and clinical testing.
- Oncology & Treatment Therapies
Location: Room 1
Session Introduction
Jan Stevang
University of Copenhagen, Denmark
Title: Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines
Biography:
Jan Stenvang has completed his PhD in 2003 from the University of Copenhagen. He has worked as group leader in both academia and biotech. Currently, he is Associate Professor in a translational research group focusing on resistance to chemotherapy, and implementation of research into clinical trials. He has published 46 publications in peer-reviewed journals and has 2 patents.
Abstract:
Studies in taxane and/or anthracycline refractory metastatic breast cancer patients have shown approximately 30% response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the ground work for development of predictive biomarkers for irinotecan treatment in breast cancer. We established breast cancer cell lines with acquired or de novo resistance to SN-38 by exposing human breast cancer cell lines (MCF-7 and MDA-MB-231) to either stepwise increasing concentrations over six months or an initial high dose of SN-38 (the active metabolite of irinotecan). The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers, Top1 and Top2a protein expression, and inhibition of the ABCG2 encoded breast cancer resistance protein (BCRP) drug efflux pump. The resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan.
Andrea Alimonti
Oncology Institute of Southern Switzerland (IOSI), Switzerland
Title: Enhancing Chemotherapy Efficacy in Pten-Deficient Prostate Tumors by Activating the Senescence-Associated Antitumor Immunity
Biography:
Andrea Alimonti is Head of the Molecular Oncology laboratory of the Institute of Oncology Research, the research branch of the Oncology Institute of Southern Switzerland (IOSI), and privat- docent in the Faculty of Biology and Medicine at the University of Lausanne. He received a Bachelor’s degree in Medicine from the University of Rome in 2000, and a Residency in Oncology from the University of Rome in 2004 working as Clinical Oncology at the Italian National Cancer Institute of Rome. He has later worked at the Memorial Sloan Kettering Cancer Center in New York as Post-Doctoral Research Fellow. Subsequently he spent two years at Beth Israel Cancer Center at Harvard Medical School in the laboratory of PP Pandolfi. In 2010 he has joined the IOSI. He has won several awards including the Swiss Bridge Award and the prestigious ERC starting grant in 2010. He has published several peer reviewed papers, including papers in Nature, Cell, Nature Genetics, JCI and JCO either as main or Co-Author. Alimonti is full Member of the European society of medical oncology and of the Yang Academy of Europe.
Abstract:
Pro-senescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the Senescence-Associated Secretory Phenotype (SASP) of senescent tumor cells can have pro- as well as anti tumorigenic effects. Here in, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemo resistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the down regulation of the protein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Herethe author will discuss how immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments. Finally the author will provide evidence that novel immunotherapies can be used in combination with chemotherapy to enhance the anti-tumor response in the treatment of prostate cancer
Biography:
Didier Coquoz has completed his PhD in clinical pharmacology, he is a 20+ years seasoned Pharma R&D executive (VP R&D and CEO). He has been instrumental in the development/regulatory management from drug candidate up to phase III and registration of close to 30 biologics, monoclonal antibodies, peptides, cell-based therapeutics, NCEs of which 4 reached the market world-wide. He held positions as CEO and VP R&D on both sides of the Atlantic. He currently acts through Copexis S.A. as Chief Development Officer, Chief Regulatory Affairs and Chief Business Development Affairs for different biotechs/mid pharmas in Europe, mostly in immunology.
Abstract:
For many decades, early and late stage drug development of anti-cancer drugs have been very much based on tumor sizes evolution. They registration was mostly based on survival increase, although the evolution of tumor sizes (PFS) were also taken into account. Early guidelines on anticancer drugs focused on conventional cytotoxic compounds. A first major revision was made in Europe in 2005 stressing on the PFS followed by a second in 2010 introducing among others, the notion of relative toxicity. In recent years, immunotherapy, especially anti immune-suppressive agents such as anti CTLA4 and anti PD1/ PDL-1 antibodies have shown remarkable increases in survival whereas they have relatively limited impact on the classical tumor size parameters. In addition to these improvements, not only increases in survival but increase in percentages of cures re more and more observed with recent anti-cancer drugs. Finally, combination of anticancer drugs such anti-immunosuppressive agents and other anti-cancer drugs may more and more prove to be very beneficial in the future. Consequently, the paradigms of drug development (efficacy criteria for phase II, for instance) as well as the regulatory and registration requirements will further evolve. Such probable evolutions will be discussed.
Isabel Portero Sanchez
Complutense University School of Medicine, Spain
Title: The development of cell therapy products for chronic inflammatory diseases: A new approach to an old problem
Biography:
Isabel Portero Sanchez received her MD at University of Salamanca, PhD at University of La Coruña and completed a Medical Specialization in Internal Medicine & Infectious diseases at “Marques de Valdecilla†University Hospital, Santander, Spain. She has dedicated her career to developing new medicinal products. She has 15 years of experience in the scientific and medical design of experiments and clinical trials for new drugs and biomarkers. She has worked as Medical Director at several Biotech companies and is also Professor at the Department of Medicine (Universidad Complutense, Madrid). She leads a Scientific Group in Advanced Therapies.
Abstract:
Several cell therapy approaches are being studied for chronic inflammatory diseases that occur in spite of optimal anti-inflammatory and immunosuppressive therapies. Most of them are based on the immunomodulator properties of autologous or allogeneic cells from mesenchymal origin (MSCs). There is a substantial body of evidence that supports this approach, some demonstrating the concept in vivo (proofof concept preclinical/clinical studies) and also mechanisms of action. As a consequence, MSCs are being described as immunomodulator cells. Nevertheless, it is well known that, in fact, MSCs exert a variety of actions depending on the local environment where they are cultured and the environment at the tissues they reach. This has been consistently described in a variety of studies; therefore, it is not only the nature of the cell what defines the function but the conditions in culture and the final environment at target tissues. For example, MSCs can promote inflammation instead of ameliorating it, which could be described as doubleedge sword functionality in the immune system. If environment is important and cells finalize their culture phase in an undifferentiated naïve or unconditioned status, it might be conceivable to precondition cells for SOT in order to direct them towards the immunomodulator phenotype which in addition would increase the likelihood of more specific homing, more potency and less dosage of cells. Currently, several strategies for priming or preconditioning of MSCs towards immunomodulation are being explored. In this paper, the most important strategies are reviewed.
Roni Moya
CESPU University, Portugal
Title: Immune modulation with xenogeneic peptides in integrative oncology
Biography:
Roni Lara Moya has done master science in Molecular and Cellular Immunology and Biology from University of Coimbra, Portugal and also in Clinical Advanced Nutrition – University of Barcelona, Spain. She has completed PhD in Biomedicine and Immunology – Gulbenkian Institute of Science and Coimbra University. Currently she is Director of the Graduation Program in Orthomolecular Therapy - CESPU University, Portugal.
Abstract:
Cell therapy with extracts of xenogeneic peptides consists of administering intramuscularly, intravenous, subcutaneous or orally, frozen tissue extracts from sheep, cow or pig in order to modulate the immune system and activate the biological signs of organic regeneration. It is a State-of-the-art treatment in the area of regenerative medicine and immunology demonstrated for the first time in 1912 by Nobel Prize winner Alexis Carrel in the rejuvenation of in vitro aged cells. In 1931, it was applied in humans with great success by Dr Paul Niehens. One of the main areas where the xenogeneic cellular therapy peptides can be applied is Oncology. Purified animal extracts work on innate or acquired immunity by the stimulation of fundamental organs as the thymus, spleen and bone marrow by regulating the transcription, apoptosis, oxidative stress, the activation of B lymphocytes, CD4, CD8, and Natural Killer (NK); as well as the production of its main cytokines (IFN, TNF, IL4, Order, etc). The main purpose of this conference is to addressing the clinical aspects and the most relevant scientific studies of integrative treatment with xenogeneic peptides as a potent immune-modulator in cancer cases.
Marcos d’Ãvila Nunes
University of Sao Paulo, Brazil
Title: Protontherapy vs carbon ion therapy: Advantages, disadvantages and similarities
Biography:
Marcos d'Ãvila Nunes is an Associate Professor at University of Sao Paulo (USP), SP, and Brazil. And he graduated from the Faculty of Medicine of Ribeirao Preto / USP. He did Postgraduate studies in Advanced Theoretical Physics at the School of Engineering of São Carlos / USP. He developed Post Doctorate stage for five years at the Massachusetts Institute of Technology, Boston University Medical Center, National Institutes of Health, University of South Carolina and Wayne State University and he is responsible for seven courses of postgraduate studies at USP. Specialties: Physics of High Energy (LHC), Hadron Therapy, Electron Paramagnetic Resonance Applied to Biological Systems, Biophysics, and Informatics.
Abstract:
More than 100,000 patients have been treated with particle beams around the world, of which about 13% were treated with C-ion RT. In 1946, Wilson R proposed the use of proton for cancer therapy, and the first patient was treated at the Lawrence Berkeley National Laboratory in the USA (1954). In 1994, clinical trial on C-ion RT was launched at the National Institute of Radiological Sciences in Japan. Protons have a better dose distribution but a lower RBE (1.0-1.1) than carbon ions (1.5-3.4). However, RBE depends on radiation quality, LET, fraction size, and the biological aspects of the target. Higher RBE is good for tumor control, but it is bad for normal tissue toxicity. The biological benefits of C-ion RT have been demonstrated in inoperable cases with various types of sarcoma, adenocarcinoma, adenoid cystic carcinoma and malignant melanoma arising from various sites that are well known as photon-resistant tumors (and/or located close to critical structures). At HIT, Heidelberg, there is the Cleopatra and Pinocchio trial, both with a primary endpoint of toxicity. All studies on both proton and carbon ion therapy are small and therefore difficult to compare, also, assessment of the efficacy of proton therapy vs C-ion RT is not feasible, mainly due to the dose fractionation differences. The use of C-ion RT is recommended, when the advantages of using carbon ions outweigh the therapeutic advantages that can already be obtained by fractionated photon RT.
Louna Karam
Lebanese University, Lebanon
Title: The anti-tumor activities of the synthetic retinoid ST1926 against human herpes virus 8- associated primary effusion lymphoma
Biography:
L Karam, a holder of a Medical laboratory Sciences Bachelor in 2011 from Balamand University, has completed her Masters in Genomic and Health in 2013 at the Lebanese University. She worked as a volunteer researcher at the Lebanese University and American University of Beirut the year 2013 till end of 2014. Currently, she has started her second year as PhD candidate. She is undergoing a joint thesis between the Lebanese University, Lebanon and the University of Erlangen (Germany).
Abstract:
Primary effusion lymphoma (PEL) is a rare AIDS-associated B-cell neoplasm, caused by Human Herpes 8 virus (HHV8) infection. PEL has unique clinical manifestations, as it arises as malignant effusions in body cavities such as the pericardial, peritoneal cavities. PEL cells don't present conventional genetic cancer mutations; essentially its oncogenesis is attributed to HHV-8 latent genes, LANA-1, LANA-2, v-cyclin and v-FLIP, known to hold tumorigenic abilities. PEL is life threatening to immunocompromised and elderly people since it is known to relapse after standard chemotherapy treatments. Thus there is a need of new effective, targeted drugs. Among promising recent drugs, ST1926, a novel orally available, synthetic retinoid is promising antitumor agent having no-cross resistance with other chemotherapeutics. It was shown to exhibit a targeted apoptotic and genotoxic effect on a large panel of human solid and leukemic malignancies both in vitro and in vivo. The aim of this study is to elucidate the anti-tumor activities and underlying molecular mechanism, of ST1926 on PEL in vivo/ex-vivo/in vitro preclinical models. Pharmacologically achievable concentrations of ST1926 display potent anti-proliferative effect on PEL cell lines and their corresponding ascites. Also, ST1926 was shown to cause accumulation in preG1-population in cell cycle, as well as it induced apoptosis, DNA damage, PARP cleavage and P53 upregulation in PEL cells and ascites. In addition, ST1926 downregulated all tested viral latent transcripts in ex vivo ascites cells. The promising anti-cancer and anti-viral effects of ST1926 drugs could provide a novel basis for clinical application in PEL. Further, in vivo survival study on PEL-like NOD/SCID mice will be explored.
- Types of Chemotherapy
Location: Room 1
Session Introduction
Nina Radosevic-Robin
Jean Perrin Comprehensive Cancer Center, France
Title: Emerging concepts in breast cancer neoadjuvant chemotherapy
Biography:
Nina Radosevic-Robin obtained her MD degree and board certification in Pathology in Belgrade, ex-Yugoslavia. She trained in cell biology, biochemistry and pharmacology at INSERM, France and NIH-NCI, USA. Since 2012 she has been in charge of tissue tumor biomarker analyses within ERTICa Research Group of the University of Auvergne in Clermont-Ferrand, France. She has published more than 30 articles in peer-reviewed journals and teaches Molecular Pathology and Protein Science at the University of Auvergne.
Abstract:
Neoadjuvant chemotherapy (NACT) is proposed for the aggressive forms of breast cancer (BC), in order to reduce tumor burden and allow breast-preserving surgical treatment. After years of uniform administering the taxane/anthacycline-based regimens to all the BC patients indicated for a NACT, two major changes in BC NACT have taken place during last 10 years and have been rapidly developing: a) use of molecular methods in estimation of BC aggressiveness and b) use of agents which specifically target oncogenic driver-molecules. Those new approaches were made possible by important advances in cancer biopathology. Molecular classification of BC into luminal A, luminal B, HER2+ and triple-negative (TN) subgroup, associated to clinical parameters, provides a basis for the choice of NACT. That way luminal and TN BC are treated by “nonspecific†cytotoxics while the clinical course of HER2+ BC has been markedly improved by agents specifically targeting HER2. In order to avoid overtreatment of luminal BC, there is an increasing use of multigenic tests to predict tumor recurrence risk. On the other side, the resistance to anti-HER2 agents, observed in approximately half of the HER2+ BC, is being reduced by new targeted approaches: inhibition of several HER-family receptors or of the receptors and their downstream signal transducers. In TNBC, targeting EGFR and/or DNA damage response pathway are emerging neoadjuvant approaches. Further development of BC NACT depends on advances in prediction of response to a given treatment. In this light we will present some recent results our group has obtained in the biomarker research.
Darko Katalinic
University of Zagreb, Croatia
Title: Molecularly targeted therapy for metastatic melanoma
Biography:
Darko Katalinic, MD, PhD, DSc, internist and medical oncologist, studied medicine and molecular biology at the University of Rijeka and University of Zagreb, Croatia. He holds a PhD and DSc degree from Zagreb University in Molecular and Cell Biology. A consummate clinician scientist, he has authored more than 100 papers in prestigious journals. His clinical and research interests include medical oncology, hematology, molecular oncology, adjuvant immuno/chemotherapy and targeted therapy as well as discoveries on predictive and prognostic cancer markers in lung cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, prostate cancer, neuroendocrine tumours, melanoma, and sarcoma.
Abstract:
Metastatic melanoma is one of the most aggressive forms of cancer. Fortunately, the future for this form of tumour appears to be bright with the development of new, exciting compounds, both in the arena of targeted therapy and bio/immunotherapy. Moreover, new progress in molecular and cancer biology has expanded our understanding of the molecular and cellular mechanisms of cancer development. Recognition of molecular mutations that drive oncogenesis in melanoma cells has led to the development of promising drugs that selectively target and inhibit tumour mutations and, in turn, provide improved response rates with decreased side-effects and general toxicity. These agents are now the focus of well-designed, randomized trials, the results of which are awaited with huge interest. Understanding cell proliferation and growth, oncogenesis, survival and migration pathways has provided both new targets and insights in melanoma treatment. As such, this remarkable level of complexity makes successful treatment of melanoma metastases all the more challenging.
Shashank Tummala
JSS College of Pharmacy, India
Title: Emergence of various alternatives for cancer chemotherapy in treating colorectal cancer
Biography:
Shashank Tummala is a research scholar in the Department of Pharmaceutics, JSS College of Pharmacy from Ootacamund, India. His area of interest is in the field of Cancer, chemotherapy and gastrointestinal diseases
Abstract:
Out of the various therapies available for the treatment of colorectal cancer, chemotherapy was considered as the vastly used one owing to its faster availability of the drug mainly in the form of intravenous route by injections. But the main limitation associated with the chemotherapy is its harmful cytotoxic effects to the healthy cells thereby minimizing the therapeutic effectiveness of various marketed drugs like oxaliplatin, 5-fluorouracil etc. Also cancer cells develop resistance to the above drugs after treatment for some time which may be termed as multidrug resistance. So various alternatives of delivery systems such as nanoparticulate technology (like solid lipid nanoparticles, liposomes, enteric coated, pH-responsive, polymeric nanoparticles), Immuno conjugates (antibody conjugates, protein conjugates etc) gained prominence for effective treatment of colorectal cancer by imparting site specificity of the active pharmaceutical ingredient there by reducing the toxicity of healthy cells and increasing the therapeutic efficacy of the drug. The nanoparticulate approach also helps in easy penetrability of the drug into the tumors owing to its decrease in particle size making it as an alternative for chemotherapy. As the particle size gets below 400 nm, it prevents elimination by reticulo endothelial system making it available mostly. Also the use of various lipids in the preparation of nanoparticles helps the drug to penetrate inside the tumor due to their hydrophobic outer layer as opposed to the chemotherapy where the drug is distributed evenly from systemic circulation to all rapidly dividing cells. Also so many drugs suffer from multi drug resistance (example Cisplatin) which may be due to the efflux of the drug by p-gp glycoproteins present at the tumor cell surface. The alternatives to chemotherapy help the drug in bypassing the multi drug resistance by formulating them as immuno nanoparticles where they are conjugated with antibody thus helping in its intracellular penetration by receptor mediated endocytosis. These all limitations and novel approaches to overcome those limitations of chemotherapy demands for a detailed view on these alternatives.
Charushila Y Kadam
B. J. Govt. Medical College, India
Title: Clinical utility of serum apoptosis markers for predicting adjuvant chemotherapy treatment efficacy in breast cancer
Biography:
Charushila Y Kadam has submitted her PhD in Medical Biochemistry to Maharashtra University of Health Sciences, Nashik, India. She is currently involved in research on cancer at National Chemical Laboratory, Pune, India. She is a teaching faculty of Department of Biochemistry of Prakash Institute of Medical Sciences and Research, Islampur, India. She has published a book and various research papers in international reputed journals and has been serving as an Editorial Board Member of Cancer studies. She has presented various research papers at different international conferences.
Abstract:
The apoptotic markers such as sFasL, granzyme B, cytochrome c and NO/cyt c ratio has shown a very good sensitivity and specificity at defined intervals for determining adjuvant chemotherapy treatment efficacy in breast cancer. Thus, the measurement of serum levels of these parameters provides a new insight into their clinical utility for adjuvant chemotherapy treatment monitoring in breast cancer.
- Chemotherapeutic Treatment and Strategies
Location: Room 1
Session Introduction
Fenglei Wu
Nanjing Medical University, China
Title: Effect of hENT1 polymorphism G-706C on clinical outcomes of gemcitabine-containing chemotherapy for Chinese non-small cell lung cancer patients
Biography:
Fenglei Wu has completed his PhD at the age of 33 years from Nanjing Medicine University. He is the Director of some projects of NSFC. He has published more than 5 papers in reputed journals and has been serving as an Editorial Board Member of repute.
Abstract:
Both genotype and allele frequency of hENT1G-706C polymorphism differed significantly between responders and poor-responders. To be more specific, the response rate in the patients carrying GG genotype was substantially higher than that in the patients with GC or CC genotype. Using logistic regression analysis, we found that GC or CC genotype presented higher risk of being poor-responders compared with the GG genotype (OR=2.34, 95% CI: 1.14–4.80; P=0.02). The overall survival in patients with GG genotype were significantly higher than those with GC or CC genotype (19.0 vs.15.1 months, P<0.001). The hazard ratio for (GC+CC) genotype was 1.89 (95 % CI: 1.23–2.90, compared with GG carriers, P=0.004).
Jun Young Heo
Chungnam National University, South Korea
Title: Synergistic Bcr/Abl degradation effect is triggered by MB12066 with NQO2 inhibitors in chronic myelogenous leukemia
Biography:
Jun Young Heo has completed his PhD from Chung Nam National University, School of Medicine and Postdoctoral studies from Korean Institute of Science and Technology. He is the Director of Medicinal Biochemistry and member of the European Hematology Association. He has published more than 20 papers in reputed journals including Stem cells, Plos One and Autophagy.
Abstract:
Mutations of Bcr-Abl protein reduce the sensitivity of imatinib treatment for chronic myelogenous leukemia (CML). The resistance against imatinib treatment to CML patients needs to develop another target drug of Bcr-Abl through unknown mechanism. In present study, we investigated the effect of MB12066, small molecule related to quinone derivatives, on k562 cells (CML cell line) and the expression level of Bcr-Abl protein down regulated by MB12066. When k562cells were treated with MB12066, dose-and time-dependent Bcr-Abl degradation was detected, followed by decreasing of procaspase-3 and cleavage of PARP, which represent apoptotic stimuli. Quinone oxidoreductases [NAD(P)H:quinone oxidoreductase 1(NQO1) and NRH:quinone oxidoreductase2 (NQO2)] are the major enzymes involved in the bioreduction of quinone-containing drugs. We found that MB12066 was a substrate of both NQO1 and NQO2 by examining recycling assay. For the functional study of NQO1 and NQO2 in Bcr-Abl degradation, we used inhibitors for each enzymes, dicumarol and quercetin, respectively. Interestingly, Bcr-Abl degradation was inhibited by dicumarol, but it was accelerated by quercetin. Collectively, these results demonstrate that MB12066 destruct the Bcr-Abl through the NQO1 and NQO2 activity and it may show the possibility that combination therapy with NQO2 inhibitor may be beneficial for treating CML patients.
Isabel Portero Sánchez
Complutense University School of Medicine, Spain
Title: Advanced therapies in cancer research
Biography:
Isabel Portero received her MD at University of Salamanca, PhD at University of La Coruña and completed a medical specialization in Internal Medicine & Infectious diseases at “Marques de Valdecilla†University Hospital, Santander, Spain. She has dedicated her career to developing new medicinal products. She has 15 years of experience in the scientific and medical design of experiments and clinical trials for new drugs and biomarkers. She has worked as Medical Director at several Biotech companies and is also a Professor at the Department of Medicine (Universidad Complutense, Madrid). She leads a scientific group in Advanced Therapies.
Abstract:
Chemotherapy continues to be the cornerstone treatment for cancer, though biotechnological antibodies have revolutionized this field, adding unquestionable value to traditional treatment schemes, and continue offering more advances. The latest player in the field is Advanced Therapies, which are defined by EMA and FDA as those treatments based on, or which include, “Cell Therapy†“Gene Therapy†and “Tissue Engineeringâ€. Advanced Therapies are considered a potential new breakthrough in cancer treatment, mainly through three strategies in which they can offer an important contribution: —Oncolitic virus, that delivers powerful poisons directly to cancer cells —Manipulation of cancer cell microenvironment with Cell therapy products, in order to skip tumor immune evasion and thus helping the immune system attack cancer cells —Treatments aimed at new genes and cancer pathways, plus better tests to predict which patients will benefit from them. In this talk a revision of current achievements in Advanced Therapies for cancer will be presented.
Maamoun Fatfat
American University of Beirut, Lebanon
Title: TPEN induces DNA damage in human colon cancer cells: Role of Chk1 and DNA-PK
Biography:
Maamoun Fatfat is a Post Doctorate from position at American University of Beirut and Weill Cornell Medical College, Qatar. He was also an application specialist of Flow Cytometry at SARAMED S.A.L Beirut–Lebanon. His area of expertise is in the field of Tissue and Cell Biology, Molecular Biology, Organic chemistry. He also presented posters in many National Congresses.
Abstract:
The maintenance of optimal metal levels is an essential aspect of cell homoeostasis. In many types of cancers, the levels of metals such as iron, zinc and copper diverge from the norm. This disturbance of intracellular metal levels has been the basis of several cancer treatments. TPEN (Tetrakis-(2-Pyridylmethyl) ethylenediamine) is one such drug that exploits disturbances of intracellular metal levels to exert its anticancer effects. Previously, we have shown that the zinc chelator TPEN is involved in copper chelation inside the cell which selectively kills colon cancer cells (HCT116). We have additionally shown that this anticancer effect is mediated by TPEN’s involvement in redox cycling, which increases the generation of reactive oxygen species. In this study we aimed to decipher the mechanisms of TPEN antitumor activity through studying its effects on DNA damage. We show that TPEN causes ROS generation and the death of HCT116 cells at concentrations as low as 5 µM. Pre-treatment of cells with the copper chelator Neocuproine and with CuSO4, restored cell viability and reduced ROS generation, suggesting the requirement of cellular copper for TPEN toxicity. In a spectrophotometric analysis, we found that TPEN binds to calf thymus DNA through an intercalative mode and this binding was enhanced as the ratio of TPEN to DNA was increased. Using the comet assay, TPEN was found to induce significant DNA damage as compared to control cells. In addition, TPEN increased the expression of key proteins involved in DNA damage pathways, such as p-ATM, p-chk1, and p-H2AX. RNA silencing revealed the involvement of chk1 and DNA-PK in cell death caused by TPEN, since the silencing of these genes restored cell viability. Further mechanistic studies are underway to assess the role of DNA damage proteins in TPEN anti-colon cancer effects.
Sezer Saglam
Istanbul Bilim University, Turkey
Title: Chronobiological capecitabine (chemotherapy) for low chemotherapy toxicity
Biography:
Sezer Saglam has completed Medical Faculty in 1991. He finished his internal medicine residency at Cerrahpasa Medical Faculty between 1991 and 1996. He completed his medical oncolology subspecialty at Istanbul University Oncology Institute. He has been working on Gastrointestinal Oncology especially rectal, gastric and neuroendocrine tumors. He has been working at Ä°stanbul Bilim University for 4 years. He has published fist randomized trial (Istanbul R-01) in rectal cancer.
Abstract:
In 17 patients (20%), total tumor regression was achieved according to Dworak pathological grading system. Grade III diarrhea occurred in nine patients (10.5%), while only one patient had grade 3 thrombocytopenia. Grade II or III proctitis were seen in nine (10.5 %) subjects and grade I or II cystitis in six (6.9%). Only three patients (3.3%) developed hand and foot syndrome (both grade I–II). There were no grade IV toxicities.
Annie Agnes Suganya S
Rajiv Gandhi Center for Biotechnology, India
Title: Role of chemoresistance and self-renewal ability of cancer cells in recurrence
Biography:
Annie Agnes Suganya S has completed her Masters in biotechnology at the age of 23 from Bharathidasan University and working as a Research Fellow in Rajiv Gandhi Center for Biotechnology, India.
Abstract:
Recurrence is a major reason for mortality in many forms of cancer including oral squamous cell carcinoma (OSCC). It is explained that CSCs, possessing self-renewal ability and resistance to therapy survive the treatment and recreate tumor after the withdrawal of the treatment. The notion that CSCs possess self-renewal property as well as chemoresistance stems from the fact that CSCs isolated based on one of the CSC markers or sphere culture enriching CSCs exhibit increased self-renewal ability and chemoresistance than their counterparts. Majority of cancer researchers treat drug selected cells as CSCs and it has been shown that important signaling pathways regulate both chemoresistance and self-renewal ability. Our first attempt was to analyze whether these two properties are interdependent using oral cancer cell lines and primary OSCC samples. Even though all the cancer stem cells are not chemoresistant, we show that the cells possessing both self-renewal ability and chemoresistance are responsible for cancer recurrence. Further, we provide evidences for the induction of self-renewal ability in chemoresistant cells by microenvironment using co-culture system and 3D-coculture systems. Our study proves that signaling pathways that induce of self-renewal ability in chemoresistant cells play a major role in recurrence after chemotherapy. The present study implies that targeting signaling pathways that impart self-renewal ability in chemoresistant cells may improve the therapeutic outcome.
- Antimicrobial Drugs
Location: Room 1
Session Introduction
Maude Loignon
University of Montreal, Canada
Title: Some HIV protease inhibitors have also other beneficial, non-virological effects with potential therapeutic applications
Biography:
Maude Loignon has completed her MSc in 2007 and her MD in 2012. She is now a 3rd year Resident in Microbiology and Infectious Diseases at the University of Montreal, Canada. She has published 7 papers in peer-reviewed journals.
Abstract:
The introduction of HIV-protease inhibitors (PIs) in antiretroviral therapy drastically diminished the incidence, prevalence and severity of opportunistic infections. These beneficial effects are primarily due to immune reconstitution following the decrease of HIV replication. We reported that some PIs increase the RALDH’s activity and consequently augment the production of retinoic acid (RA) in vitro. We demonstrated that in vivo, PIs (as part of an optimal antiretroviral therapeutic regimen) decrease serum RA concentrations. These discrepancies of in vivo and in vitro data are due to the fact that RA synthesis and its alteration by PIs take place intracellularly. Elevated intracellular RA level increases its own catabolism and inhibits (feedback) its synthesis. Based on these and other published data we have suggested that altered RA metabolism by PIs might affect the expression of retinoid-responsive genes and retinoid-mediated signaling pathways. Several beneficial effects of PIs, such as improvements in the control of certain infections of HIV-associated nephropathy (HIVAN), Kaposi’s sarcoma, other cancers, HIV-dementia, HIV-associated colitis, etc., could be partially explained by their direct effect on RA synthesis. Moreover, therapeutic uses of synthetic retinoids have been proven efficacious in the treatment of Kaposi’s sarcoma and HIVAN and experimentally, RA is synergistic with primaquine against Pneumocystis. PIs also inhibit the aspartyl proteases of several parasites and fungi as documented by numerous publications. And finally, other effects such as inhibition of the proteasome-ubiquitin process and diminished apoptosis are now exploited for the treatment of different cancers and neurodegenerative disorders.
Bin Li
The University of Hong Kong, China
Title: Identification of miR-29c/FBXO31 as a key regulatory mechanism in esophageal cancer chemoresistance
Biography:
Bin Li has completed his PhD at the age of 30 years from University of Hong Kong, and his PhD research focused on the role of Id1 in activating PI3K/AKT signaling pathway and promoting esophageal cancer progression. He is currently a Postdoctoral research scientist, and he has established highly chemoresistant and metastatic esophageal cancer cell models. His current research interests include functional identification and characterization of novel genes/miRNAs associated with chemoresistance and metastasis, the mechanistic study and targeted therapy; identification and characterization of esophageal cancer stem cells. He has over ten peer-reviewed research papers published in reputed journals.
Abstract:
Esophageal cancer ranks as the 6th most frequent cause of cancer death in the world. Chemoresistance is a major obstacle in cancer therapy, but the mechanism remains unclear. MicroRNAs have received increasing attention as a novel and promising targets in cancer diagnosis, prognosis and treatment. Identification and experimental validation of the chemoresistance-related miRNAs in esophageal cancer are urgently needed. We have established esophageal squamous cell carcinoma (ESCC) cell line models of acquired chemoresistance to 5-FU (FR sublines). MicroRNA profiling and subsequent RT-PCR confirmation showed that miR-29c was one of the most down-regulated miRNA in FR sublines. We found that miR-29c overexpression could revert acquired chemoresistance of FR cells, and that lower miR-29c expression in ESCC was associated with poor survival of patients. FBXO31, a novel F Box protein with prognostic significance in ESCC, was amongst the upregulated mRNAs identified in the FR cells using cDNA microarray and was predicted by computational algorithms to be a target of miR-29c. Our data showed that FBXO31 increased chemoresistance of ESCC cells in vitro and in vivo, and that ectopic expression of miR-29c significantly reduced FBXO31 expression. More importantly, FBXO31 mediated the functions of miR-29c in chemoresistance of ESCC cells. In summary, this study greatly enhances our understanding of the functions of miR-29c and FBXO31 in esophageal cancer; their significance in diagnosis, prognosis and treatment warrants further investigation.
Natalia Martins
Polytechnic Institute of Braganca, Portugal
Title: Folk medicinal plant extracts as a source of biomolecules with antifungal properties against Candida species
Biography:
Natália Martins has 25 years and she is a PhD student from University of Minho since March 2013. She is graduated in Dietetics and Nutrition from Polytechnic Institute of Bragança (including a period of extra-curricular training in Brazil), in Natural Medicine from School of Alternative and Complementary Medicines of Oporto, and also attended other short courses in Traditional Medicine. She has published 7 articles in ISI and Scopus indexed journals, and presented 12 abstracts in national and international conferences/congresses.
Abstract:
Increasing rates of opportunistic fungal infections and microorganisms with drug-resistance have been observed. Candida species are the most common pathogens, considered the fourth leading cause of hematogenous infections. Thus, it is crucial to discover alternatives to the current antifungal agents. Healing properties of medicinal plants are widely recognized, but some properties and the related mechanisms of action remain unknown. Therefore, the anti-Candida potential of hydromethanolic extracts obtained from ten folk medicinal plants (Echinacea purpurea L.; Eucalyptus globulus Labill.; Foeniculum vulgare Mill.; Juglans regia L.; Matricaria recutita L.; Melissa officinalis L.; Pterospartum tridentatum L.; Rosa canina L.; Rubus ulmifolius L. and Tabebuia impetiginosa L.) was evaluated, by using disc diffusion assay and determination of minimal inhibitory concentrations by microdilution method. J. regia was the most effective, inhibiting the growth of the tested nineteen Candida strains (halo diameter varying between 9-14 mm) and causing a growth reduction of 3-5 Log(CFUs) for Candida parapsilosis and C. tropicalis, and 0.5-2.5 for C. albicans and C. glabrata. E. globulus also exhibit a significant potential, being effective against seventeen Candida strains (halo diameter ranging between 9-21 mm) and causing a growth reduction of 2-5 Log(CFUs). P. tridentatum and R. ulmifolius showed similar antifungal effects, being effective against six Candida strains (halo diameter ranging between 9-19 mm). So, as main conclusions, hydromethanolic extracts of E. globulus and J. regia could constitute promissory alternatives to the current antifungal agents, but more detailed studies are needed in order to identify the bioactive compounds and related mechanism of action.
Thomas Prince
National Cancer Institute, USA
Title: HSP90 and tyrosine kinase inhibitors: A synergistic combination for combating cancer?
Biography:
Thomas Prince research has primarily revolved around molecular chaperones and their role in cancer and disease. Raised in the Mid-South, I did graduate training in biochemistry and molecular biology at Oklahoma State University with Robert Matts. Upon graduating then began post-doctoral experience at Pacific Northwest National Laboratory with Steve Wiley studying systems biology and receptor tyrosine kinase processing. After this I travelled to Harvard Medical School to work with Stuart Calderwood on the cellular stress response in cancer. Currently I am working with Len Neckers at the National Cancer Institute focusing on HSP90 biology in cancer.
Abstract:
The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing a new paradigm of cancer analysis. Tyrosine kinases have long been understood to initiate and promote malignant cell growth. Targeting tyrosine kinases to fight cancer has been a major strategy for the pharmaceutical industry for almost 3 decades. Despite the initial success of tyrosine kinase inhibitors, the ability of cancer to evolve resistance and switch between oncogenic signals has made the effective use of tyrosine kinase inhibitors difficult. The molecular chaperone HSP90 physically supports global tyrosine kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas has compiled a trove of data that indicates a number of cancers over-express or possess mutant tyrosine kinases that depend on HSP90 and its cohorts. Targeting HSP90 function could therefore complement tyrosine kinase inhibitors for treating cancer by inhibiting cancer evolution and preventing oncogenic switching. Based on this hypothesis our work has focused on the interplay between tyrosine kinases and the HSP90 molecular chaperone machine with the aim of developing synergistic combinations of molecular therapies to combat cancer.
- Workshop Session
Location: Melia Meeting
Chair
Isabel Portero Sanchez
Complutense University, Spain
Session Introduction
Isabel Portero Sanchez
Complutense University School of Medicine, Spain
Title: Drug discovery through traditional medicines
Biography:
Isabel Portero received her MD at University of Salamanca, PhD at University of La Coruña and completed a medical specialization in Internal Medicine & Infectious diseases at “Marques de Valdecilla†University Hospital, Santander, Spain. She has dedicated her career to developing new medicinal products. She has 15 years of experience in the scientific and medical design of experiments and clinical trials for new drugs and biomarkers. She has worked as Medical Director at several Biotech companies and is also a Professor at the Department of Medicine (Universidad Complutense, Madrid). She leads a scientific group in Advanced Therapies.
Abstract:
The history of the discovery of new medicinal products have been “monopolized†by chemical agents for centuries, which it is to be said, they have offered the vast majority of important contributions to Medicine. For this reason, drug development has always been an issue of chemists and chemical engineers. Still, traditional “small drugs†(chemicals) are the most numerous and useful medical treatments we currently use to deal with many diseases. In the 80´s a new player entered that has revolutionized the treatment of many diseases: Molecular antibodies produced in living organisms factories. There medicines are classified into the term “Biotechnological drugsâ€. There is no doubt of the enormous contribution of biotechnological drugs to cancer or immune diseases clinical management. Lately, in the past 15 years, a new paradigm in drug development has been broken. Now it is not only molecules that can cure, but the cells themselves acting as medicinal products. In addition, the old idea of using genes to cure diseases, replacing wrong copies or inserting those that lack, has experienced a huge growth and development. As a result, we were ready for a new drug development scenario in which cells and genes are medicines, being called “Advanced Therapies†by EMA and FDA. Advanced Therapies drug development has a unique regulation, different from chemical and classical biotech products. Not only is the law differently, but also the processes themselves vary. Allogeneic v’s autologous source, manufacturing in cell factories, preclinical studies in which (for example) ADME does not apply, clinical studies designed differently from traditional Phase I-III trials. All these aspects and challenges foreseen for the upcoming future will be discussed in deep in this workshop.
Biography:
Dirk Büscher received his PhD in Biology in the area of Immunology from the University of Hannover, Germany, and focused his postdoctoral work at the Salk Institute, La Jolla, California, on molecular developmental biology and stem cell research. In 2004, he joined Cellerix SL and moved up to the position of Vice President of R&D representing the company in several scientific advices at EMA. Additionally he served as industry expert on mesenchymal stem cells in internal EMA workshops. In 2007 he obtained an International Executive MBA from the Instituto de Empresa (IE). 2010 He accepted a position as chief executive officer of Gri-Cel SA, a newly created fully owned subsidiary of Grifols SA, dedicated to advanced therapies and innovative therapeutic approaches. He currently serves on the boards of VCN Bioscience, Araclon Biotech, and TiGenix NV.
Abstract:
Gene Therapy approaches to fight cancer has seen promising results within the last few years, utilizing different strategies. A rather old approach is the use of oncolytic viruses (Virotherapy). Virotherapy started at the beginning of the twentieth century after the occasional observation of transient clinical remission during viral infections in cancer patients. In an initial phase almost every newly-discovered virus was injected into tumors. Later, during the 1950s and 60s, only viruses displaying natural tumor tropism were selected. Lack of clear clinical results led to virotherapy being abandoned; however increased knowledge in virology has prompted a more rational use of specially-designed viruses and a revival of this technology. Oncolytic adenoviruses are promising anticancer agents due to their ability to recognize tumor cells, infecting both dividing and non-dividing cells and selectively self-amplify inn tumor cells. After an initial infection and viral replication cancer cells are lysed and virus progeny is released, resulting in an infection of neighboring cancer cells. Theoretically infection and replication can continue until the whole tumor mass is eradicated. However the stromal structure often limits an effective spreading. Virus may also reach distant metastases by entering the blood stream. Another limitation for the spreading and body-wide distribution is the pre-existing/induced immune response against an oncolytic virus. We currently test in phase I clinical trials an oncolytic adenovirus expressing a stromal degrading enzyme, which will hopefully shed more light on its usefulness and /or limitations.
Rossana GarcÃa
Gradocell, Spain
Title: Production of advanced therapy products: Scale up to industry processes?
Biography:
Rossana GarcÃa studied Biological Sciences at the Complutense University of Madrid (Spain) and is Master in Production and Applied Quality. She has more than 28 years experience in pharmaceutical industry and research, working for 10 years as Research Technician in Antibióticos-Farma SA, where she was responsible for the cell culture laboratory. Later, she specialized in the cultivation of stem cells at the National Center for Biotechnology (National Research Council), where she worked for 3 years in the laboratory of Dr. Antonio Bernad, specialist in this field. After this specialization, she joined Genetrix Group at the Department of Cell Therapy where she worked for 4 years in R&D. Finally, she worked for 6 years as Manufacturing Manager in the Manufacturing Plant of Cell Based Medicinal Products (CBMPs) of Cellerix SA (Genetrix Group company) actually Tigenix. She is Founder, CEO and Technical Consultant of Gradocell Group (Gradocell Consulting and Gradocell Pharma SL) since 2010.
Abstract:
Development of advanced therapies medicinal products represent a major challenge for companies or institutions who choose to manufacture and promote this type of medicines. ATMPs production requires a deep understanding of GMP, as well as a strong technical qualification. Facilities and equipment are unusual compared to the manufacture of conventional drugs, which increases the manufacturing complexity. From the viewpoint of quality control, analysis techniques are not very robust and some of them very complex. However, these medicines have become in the last 10 years in a hopeful alternative for some incurable diseases. This has led to extensive development of medicinal products for Gene and Cell Therapy for many indications, having conducted numerous clinical trials with these therapies. Currently, most of these therapies are experimental, with good safety and promising signs of efficacy. Only four products are approved by regulatory agencies and marketing stage, although it is estimated that in the coming years to increase the number of registrations of new ATMPs.
- Chemotherapy side effects and precaution
Location: Room 1
Session Introduction
Hiroyuki Osada
RIKEN Center for Sustainable Resource Science, Japan
Title: Screening of novel antimalarial agents in RIKEN NPDepo
Biography:
Hiroyuki Osada is a Deputy Director of RIKEN Center for Sustainable Resource Science. He completed his education from The University of Tokyo in Department of Agricultural Chemistry. He is editorial member of different journals. He also published more than 9 research papers.
Abstract:
Malaria is one of the most serious infectious diseases. Since parasite strains resistant to traditional antimalarial drugs such as chloroquine (CLQ) and artemisinin (ART) derivatives appeared, novel antimalarial agents are required to be developed urgently. I will introduce the screening method and the hit compounds showing the antimalarial activity in this presentation. It is known that malaria parasite has high LDH activity. We established a HTS system using the LDH assay to isolate growth inhibitors of the parasite strain 3D7 cultured in vitro. Using this system, we selected 450 compounds from 17,000 compounds of RIKEN NPDepo (Natural Products Depository) chemical library with 5 µg/mL or less IC90 activity of parasite growth. As the second screening, we evaluated the toxicity toward mouse NIH3T3 and rat NRK cells of these compounds. Eighty six compounds showed selective inhibition against parasite with IC50 values lower than one thirtieth of those toward mammalian cells. Finally, as the third screening, we examined growth inhibitory effect of these 86 compounds on the CLQ resistant parasite strains (K1 and Dd2) and found that 36 compounds were as effective on the resistant strains as on 3D7 strain. NPD10928 (IC50 88 nM) was selected as one of the potent inhibitors against malaria parasites. We administrated NPD10928 to a malaria infectious mouse (ip, 20 mg/kg), and found that the growth of parasite was reduced significantly. In addition, I will introduce other antimalarial agents that were found by our screening.
Minoru Yoshida
RIKEN Center for Sustainable Resource Science, Japan
Title: Chemical genomics for target identification of antifungal theonellamides
Biography:
Identification of the cellular targets of bioactive small molecules is a major challenge in the development of these molecules as biological tools and therapeutics. Recently, much attention has been drawn to a chemical genetic approach, which uses physical and/or genetic interaction between the compound and its target. Thanks to a wealth of genomic information, genome-wide screening of genetic interaction has become available. We constructed a whole ORF library (ORFeome) of fission yeast and performed reverse proteomics including global analyses of protein subcellular localization (localizome) and protein gel mobility (mobilitome). In combination with these databases and chemical genetic profiling using the strains expressing the ORFeome, we developed a systematic method for drug target identification. This method enabled us to identify the rather unusual mechanism of action of theonellamides (TNMs), marine antifungal cyclic peptides. TNMs were shown to bind to 3beta-hydroxysterols including ergosterol in the fungal cell membrane, thereby inducing abnormal accumulation of 1,3-ï¢-glucan, proving the effectiveness of chemical genomics. Furthermore, we show that in mammalian cells TNMs recognize specific cholesterol-containing membrane domains, induce phase separation of lipid membranes, and induce cell contraction. The usefulness of TNMs as a tool for lipid biology will be discussed.
Abstract:
Identification of the cellular targets of bioactive small molecules is a major challenge in the development of these molecules as biological tools and therapeutics. Recently, much attention has been drawn to a chemical genetic approach, which uses physical and/or genetic interaction between the compound and its target. Thanks to a wealth of genomic information, genome-wide screening of genetic interaction has become available. We constructed a whole ORF library (ORFeome) of fission yeast and performed reverse proteomics including global analyses of protein subcellular localization (localizome) and protein gel mobility (mobilitome). In combination with these databases and chemical genetic profiling using the strains expressing the ORFeome, we developed a systematic method for drug target identification. This method enabled us to identify the rather unusual mechanism of action of theonellamides (TNMs), marine antifungal cyclic peptides. TNMs were shown to bind to 3beta-hydroxysterols including ergosterol in the fungal cell membrane, thereby inducing abnormal accumulation of 1,3-ï¢-glucan, proving the effectiveness of chemical genomics. Furthermore, we show that in mammalian cells TNMs recognize specific cholesterol-containing membrane domains, induce phase separation of lipid membranes, and induce cell contraction. The usefulness of TNMs as a tool for lipid biology will be discussed.
Emil Toma
University of Montreal, Canada
Title: Clindamycin & primaquine for Pneumocystis jirovecii pneumonia; 27 years after
Biography:
Emil Toma has completed his DSc in Microbiology and specialization in infectious diseases in 1971, at the University of Bucharest, Romania. In 1986, he joined the University of Montreal, Canada where he is a full Clinical Professor in the Department of Microbiology, Immunology and Infectious Diseases. He has published more than 138 papers in peer-reviewed journals, 5 books and wrote several chapters in 8 other books. He also developed a “boosted-reverse transcriptase inhibitor†(patented in USA, Australia and Canada).
Abstract:
Pneumocystis jirovecii pneumonia (PCjP) is still a common AIDS-defining disease and cause of mortality in HIV-infected persons. Moreover, it is increasingly reported in other immunodeficient populations. Conventional treatments, trimethoprim-sulfamethoxazole (Tmp/Smx), pentamidine or atovaquone are effective in 80-96% of cases and/or carry a high risk of drug-related events. Increasing prevalence of sulpha allergy or intolerance is now reported. The combination of clindamycin with primaquine (Cm/Prq) is known for its anti PCjP effects since 1988, in addition to their effects on Plasmodium infections. Our group firstly reported its use in humans as salvage therapy in patients unresponsive or intolerant to conventional agents in 1988. A meta-analysis of salvage therapy for PCjP who failed a first regimen reported that Cm/Prq was the most effective alternative therapy. We also performed two double-blinded controlled studies (1993, 1998) showing that Cm/Prq is as effective and better tolerated (P=0.04) than Tmp/Smx when used as primary therapy. Our results were confirmed by larger studies and 2 other meta-analysis showing that Cm/Prq had the same rates of success, failure or treatment-limiting effects as Tmp/Smx or Tmp/dapsone. Atovaquone was less effective than Tmp/Smx, had higher relapse rates and it is much more expensive. In conclusion, Cm/Prq is a reasonable alternative to Tmp/Smx for both salvage and primary therapy of PCjP in both HIV-infected or other immunodeficient populations and this after 27 years in use.
Natalia Martins
1Polytechnic Institute of Braganca, Portugal
Title: The use of different phenolic compounds rich extracts obtained from cultivated thyme for antioxidant and antibacterial purposes
Biography:
Natalia Martins is a PhD student from University of Minho since March 2013. She graduated in Dietetics and Nutrition from Polytechnic Institute of Bragança (including a period of extra-curricular training in Brazil), in Natural Medicine from School of Alternative and Complementary Medicines of Oporto, and also attended other short courses in Traditional Medicine. She has published 4 articles in ISI and Scopus indexed journals, and presented 10 abstracts in national and international conferences/congresses.
Abstract:
Currently, oxidative stress related damages and opportunistic infections exert a direct implication on public health. Environmental factors and whole cellular metabolism comprises the first intervenient on the imbalance homeostasis. Additionally, stress and the overuse of chemical substances, namely antimicrobial drugs, improve this problem by two ways: Increasing free radicals generation and suppressing immune system functions. Thus, to improve health and wellbeing other safer and effective alternatives are necessary. Thymus vulgaris L. (thyme) has been widely cultivated not only for nutritional but also medicinal purposes. Essential oils have been the main focus of research studies but its incorrect use might provide toxicity. In the present study, the antioxidant and antibacterial activities of thyme phenolic-compounds rich extracts, obtained by decoction, infusion and hydroalcoholic extraction were analyzed and compared. Furthermore, the extracts were characterized in terms of phenolic compounds by HPLC-DAD/ESI-MS. The extract obtained by decoction evidenced the most pronounced antioxidant (reducing power, free radicals scavenging activity and lipid peroxidation inhibition) and antibacterial (against gram-positive and gram-negative bacteria) potential, related to the its highest abundance of phenolic compounds, followed by the extracts obtained by infusion and hydroalcoholic extraction, respectively. Rosmarinic acid (in all the preparations), luteolin 7-O-glucoside (in the hydroalcoholic extract) and luteolin 7-O-glucuronide (in the infusion and decoction) were the most abundant phenolic acids and flavonoids found. The obtained data supports the idea that the compounds responsible for the antioxidant and antibacterial activities are water-soluble, conferring considerable health benefits to the studied plant that could be included as complement of daily food.
Qin-Shu Shao
University of Minnesota, USA
Title: Tentative application of middle gastrectomy in early gastric cancer in the middle one-third of the stomach
Biography:
Qin-Shu Shao is a Surgery Professor, Chief Physician and Director of Gastrointestinal Surgery of Zhejiang Provincial People's Hospital. He has published more than fifty articles in important national journals, 8 articles in SCI. He is a Standing Committee of Zhejiang Provincial Surgery Branch of Chinese Medical Association, a member of the National gastric Professional Committee of Chinese Anti-Cancer Association, a Professional Committee of hepatobiliary and pancreatic tumors surgery of Zhejiang Province, a Magazine Editorial of “Chinese Journal of Gastrointestinal Surgery" and "Chinese Journal of Digestive Surgery".
Abstract:
This lecture will address a variety of topics related to the use of middle gastrectomy with regional lymph node resection as a new therapeutics in early gastric cancer in the middle one-third of the stomach. And will include discussion of: The therapeutics for gastric cancer in recent years; compare the advantage and disadvantage of these therapeutics; compare the difference of surgery time, lymph node resection, aerating time, hospitalization time post operation, feed after 3 months and Visick graded index between group A (middle gastrectomy with regional lymph node resection), group B (total gastrectomy with D1 lymph node resection) and group C (endoscopic mucosal resection.). We found that middle gastrectomy with regional lymph node resection in early gastric cancer will not increase the risk and time of surgery and it can reduce the risk of lymph node migrating, complication related to surgery and improve the quality of life.
Biography:
Triple-negative breast cancer (TNBC) is a high risk form of this disease, even after surgery, due to the absence of targets for hormone treatment and anti-Her-2 therapy. Chemotherapy is the main therapeutic strategy for such breast cancer patients although the outcome is often unsatisfactory. Thus, the development of combination adjuvant therapies is essential for improved prognosis in TNBC patients. In this study, we investigated the efficacy of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for post-mastectomy TNBC patients. Experimental design: From 2008 to 2012, 90 post-mastectomy TNBC patients were included in this retrospective study: 45 cases received chemotherapy alone or with sequential radiotherapy; a further 45 cases received chemotherapy with/without radiotherapy and sequential CIK infusion. Survival analysis showed significantly higher disease-free survival (DFS) rate and overall survival (OS) rates in the CIK treatment group compared with the control group (p=0.0382, p=0.0046, respectively; log-rank test). Multivariate survival analysis showed that CIK adjuvant treatment was an independent prognostic factor for OS of TNBC patients. In subgroup analyses, CIK adjuvant treatment significantly increased the DFS rate of patients with pathological grade III and significantly increased the OS rate of patients in N1, N2, N3-stage, IIB, III TNM stage and with pathological grade III. These data indicate that adjuvant CIK treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of TNBC patients, particularly those with lymph node metastasis, advanced TNM-stage and poor pathological grade.
Abstract:
Jianchuan Xias is a Director of Cell Therapy and Healthcare Research Center and Deputy Director of Biotherapy Center. He completed his BS in Biology (1980-1984) from Nanchang University, Jiangxi, P R, China, and then he joined Harbin Medical Univercity, Haerbin, P R China and completed his MS in Cancer genetics during 1991 to 1994 and also achieved his PhD in Cancer genetics from the same university in 1997. After completion of his PhD, he went for his Postdoctoral studies which he completed in the year 2000 from the Sun Yat-sen University Cancer Center, Guangzhou, P R China. From the year 2000 to 2003 he worked as a Post doctorate at Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Biography:
Galatea Kallergi completed her BSc from the University of Patras, Greece in 1995. She finished her MSc in Cell Biology in 1997. She obtained her PhD in 2003 in Medical School of Crete, Greece. Her Postdoctoral studies were both in Biochemistry and Tumor Biology lab in University of Crete. She is principle investigator in two different EU funding research projects in Medical School of Crete. She has published 19 papers. She works in the field of cancer biology and liquid biopsy. Her work was focus on the identification of new signal transduction pathways in cancer cells and in CTCs.
Abstract:
Circulating tumor cells are considered as a liquid real time biopsy. Their phenotype is not always in concordance with the primary tumor due to cancer evolution. Therefore their characterization is critical before and after therapy in order to determine the response to therapy. Our results on CTCs have shown that CTCs phenotype can change in response to standard chemotherapy. Particularly blood samples from 55 early Triple negative breast cancer patients (TNBC) was examined before and after adjuvant chemotherapy. The expression of Cytokeratins (CK), Estrogen Receptor (ER), Progesterone Receptor (PR), EGFR and HER2 on CTCs was assessed using double immunofluorescent experiments and ARIOL analysis. Our results revealed that CTCs were detected in 39 out of 55 (70.9%) patients with early TNBC tumors before the initiation and in 34 out of 55 (61.8%) after the completion of adjuvant chemotherapy. The frequency of ER-, PR- and HER2- expressing CTCs was significantly reduced post-chemotherapy (p=0.019, p=0.017, 0.018) while the frequency of EGFR was not altered. The percentage of ER-, PR-, HER2- and EGFR-expressing CTCs in metastatic TNBC patients was 26%, 34%, 57% and 62%, respectively. Triple staining experiments revealed that there was no co-expression of CK/EGFR/ER, CK/EGFR/PR or CK/PR/HER2 in CTCs suggesting that ER, PR and EGFR were expressed in different subclones of CTCs in TNBC patients. In conclusion a significant percentage of CTCs in TNBC patients express HER2 and EGFR before treatment, implying that these receptors could be a potential target for the limitation of metastasis. EGFR-expressing CTCs persist after adjuvant chemotherapy, suggesting that additional treatment with EGFR-targeting agents could be used post-chemotherapy to eliminate chemo-resistant CTCs.
Biography:
Hiroshi Maeda is a world renowned expert in macromolecular therapeutics. He was successful in creating theworld first polymeric drug, SMANCS, approved for treatment of hepatoma in Japan. Consequently, he discovered the concept of EPR effect of macromolecular-drugs, ubiquitous mechanism for solid tumor selective targeting of polymeric drugs. He received MS, University of California, Fulbright Fellow, and PhD, MD, Tohoku University. He published more than 450 papers in reputed journals. He was awarded Lifetime-Achievement-Award at Royal-Pharmaceutical-Society, Princess-Takamatsu-Award in Cancer Research, Tomizo-Yoshida-Award, highest award of Japan-Cancer-Assoc., and was also selected as most cited influential scientist in pharmacology by Thomson Reuters 2014.
Abstract:
Cancer is the largest human burdens in health issue. However, its therapy has not really improved much even after emergence of molecular target-drugs, antibody-drugs, liposomal- or polymeric micellar-drugs, etc. We proposed a new concept of cancer drugs 30 years ago using macromolecular drugs (nanomedicines). In this concept the tumor vasculature is the target, which depends on the uniquely different pathophysiology, contrary to normal, such as micro-architecture, excessive production of vascular mediators like bradykinin and NO, and impaired lymphatic clearance from tumor bed. This concept named enhanced permeability and retention (EPR) effect is the basis of tumor-selective drug delivery. This is observed for biocompatible macromolecular-drugs of >50 KDa. It covers, however, only the first step in tumor-delivery, yet it is most critical. Second step is access to tumor cells. The third step is tumor cell-uptake. In the second step, liberation of low-MW-drugs occurs from nanoparticle facilitating rapid diffusion to tumor cell-membrane. In the third step, one can utilize upregulated glucose-transporterfor internalization. We developed recently polymer-(HPMA)-conjugated pirarubicin (THP) via hydrazon bond, which is more selectively cleaved in acidic tumor environment, and liberated the low MW drug which is rapidly taken up into tumor cells more than 30 x of doxorubicin. Using this conjugate our preliminary clinical results showed to be very promising. In drug-dose below toxic level, it exhibits remarkable therapeutic effect. In many solid tumors, blood vessels are frequently embolized and blood flow is hampered. To circumvent this and enhance the EPR effect, we found use of nitroglycerin and inhibitors of angiotensin converting enzyme is highly beneficial, that facilitate tumor drug-delivery 2-3 fold. The EPR effect is also observed in metastatic tumors and inflamed tissues. All in all there are more to come for nanomedicine in cancer therapy, and enhancement of EPR will be highly recommended for tumor delivery without involving serious adverse effects.
- Control And Epidemiology
Location: Room 1
Session Introduction
Ntirenganya Faustin
University of Rwanda, Rwanada
Title: Equitable access to oncological services, challenge for developing countries: Experience from Rwanda
Biography:
Ntirenganya Faustin is a Consultant breast, onco-plastic, reconstructive surgeon and clinical oncologist, Lecturer of surgery and coordinator of general surgery Masters Program at the College of Medicine and Health sciences, University of Rwanda. He obtained his Doctorate of medicine at National University of Rwanda, where he did his General surgery residency before going for fellowships at University Paris XI, France. He is a member of the College of Surgeons of East, Central and Southern Africa and of Rwanda Surgical Society. He has published many papers in local, regional and international peer-reviewed journals, participated and presented papers to a good number of international conferences. Winner of 2010 ASGBI Surgical Foundation Award, 2013 Mamadi Soudavar Travelling Fellowship Award, he is engaged in global health issue, especially global surgery and strives for universal access to quality health care, including giving access to high quality cancer care services to the poor.
Abstract:
Cancer represents a significant and rising burden of disease and a serious public health issue and outcomes are worse in Low and Middle Income Countries (LMICs). The United Nations conference in 2011 highlighted the importance of addressing health and health infrastructure needs to treat non communicable diseases including cancer in developing world. Rwanda Ministry of Health (MOH) has prioritized addressing this disease burden through approaches including standardization and expansion of access to quality cancer services. It is in that framework that, in partnership with Partners in Health (PIH), Butaro Cancer Centre of excellence has been created in 2012, in rural Rwanda. The vision was to create, strengthen and sustain high quality oncology services with equitable access to all cancer patients. Parallel to that, the MOH has integrated cancer services in all levels of the health system, from the community, passing by health centers, district hospitals to referral hospitals. These services include awareness, early detection and screening, diagnosis and treatment. Key challenges are related to sustainability of services especially chemotherapy, access to radiotherapy as currently it is not available in the country due to a few number of cancer specialists and poverty. In addition, awareness is still low and patients are present often at advanced stages. Providers are not well-prepared to communicate and deal with the complexities of cancer care. Distance and constraints of the medical care system also can impede to the accessibility of care. In conclusion, equitable access to cancers services is still a big challenge for developing countries including Rwanda. A wide range of actions are still needed to effectively prevent, diagnose, treat and control the many, often advanced forms of cancer seen in that part of the world.
Deependra Singh
Finnish Cancer Registry, Finland
Title: Screen detected symptoms of breast cancer and its relation with program performance indicators in Finland
Biography:
Deependra Singh has completed his MPH at the age of 24 years and Doctoral training in epidemiology from University of Tampere. He is currently working as a researcher in Finnish Cancer Registry, Helsinki. He is also a Doctoral student in epidemiology at School of Health Sciences, University of Tampere since 2014. He is currently running a project funded by Finnish Cancer Organization on ‘Screen detected symptoms of breast cancer and its relation with screening program performance in Finland’, as a program leader. The initial results from the project have been published in a high profile international journal.
Abstract:
A key component of breast cancer screening program is the collection of data on symptoms at the time of screening visit. In many cases, however, the data are not subsequently analyzed for relationships between symptoms and screening program performance. It is a unique study that analyzes the role of symptoms and its relation with screening program performance in a longitudinal outlook. The screening dataset consists of the total number of visits (4.5 million screening visits) made by screening age women since the start of the program and followed for more than 20 years (until 2012). Key symptom variables- lump, retraction, secretion were analyzed for their role with program performance indicators- Cancer detection rate, attendance rate, recall rate, etc. in a longitudinal outlook. Various innovative methodological approach are used to better fit the screening data of a repeated (women invited every two years) mammography screening program. Marginal and conditional probability models were developed to calculate the cumulative probability of any or first false positives and cancer detection in those who reported symptoms compared to those with no symptoms. The result shows a promising role that symptoms can contribute to a population-based screening program in addition to mammography screening. The implication of the results can be more favorable in a setting, with no repeated screening program at a population level, where clinical breast examination (CBE) is feasible provided that adequate diagnostic services are available.
- Development of New Antibiotics
Location: Room 1
Session Introduction
Juan Bueno
Anadolu University, Turkey
Title: Anti-biofilm drug discovery new topics in antimicrobial adjuvants for antibiotic improvement
Biography:
Juan Bueno is MD with Master’s degree in Microbiology, with expertise in design and implementation of antimicrobial platforms to evaluate natural products. He has more than 25 papers in this field and two book chapters. He is a Reviewer of Journal of Microbial & Biochemical Technology and Journal of Pharmacy and Pharmacology. Currently he is working as a a visiting scientist at Pharmacy School in Anadolu University in Eskisehir, Turkey.
Abstract:
Biofilm is considered as a microbial structure, composed of cells incrusted in a polymeric matrix which is attached in an inert or living surface. Biofilm matrix is an impermeable barrier that increases the resistance to biocides and drugs, because attached cells embedded in biofilm are 1000-fold more resistant to antimicrobials than planktonic free-floating cells. In this way it is believed that this mechanism of resistance is responsible for around 100,000 nosocomial lethal infections per year in the United States. In fact, the antibiotic treatment has been evaluated using planktonically-grown bacteria and not polymicrobial biofilms and their associations; complicating the administration of an effective therapy and cure. Because the biofilm pattern contributes to increasing microbial resistance, it is an imperative necessity to develop new drugs and biocides with the ability to destroy the cells cells within the biofilm structure. An important approach is the standardization of in vitro screening assays to evaluate activity, drug susceptibility testing as well as antimicrobial combinations with clinical correlation. For implementing this drug discovery platform, it is necessary to control several variables including, microbial species to be employed, biofilm growth conditions, and the best method for quantification of the microorganisms is included in the biofilms, with the end to obtain new compounds for attack chronic infections. The aim of this lecture is to give a rational approach for to implement antibiofilm drug discovery screening platforms, looking for new adjuvants to improve the current antimicrobial therapy.
Luis RodrÃguez-Borlado
Coretherapix SLU, Spain
Title: Challenges in I+D development of an advanced medicine product
Biography:
Luis RodrÃguez-Borlado has a PhD in Biochemistry and Molecular Biology from the University Autónoma of Madrid with the study of molecular bases of immune system development. After developing a scientific career in academic laboratories in Spain and The Netherlands developing high-throughput screenings to identify new therapeutic cancer targets, he joined Coretherapix in 2008 (a company belonging to the Genetrix group). At Coretherapix he has been responsible for designing the cell characterization and pre-clinical studies enabling the filing of the IMPD corresponding to Coretherapix’s first cell candidate product, a task he has led in his role of Scientific Director.
Abstract:
Advanced therapy medicinal products are new medical products based on genes, cells or tissues. These advanced therapies herald revolutionary treatments of a number of diseases or injuries, such as ischemic heart disease, Alzheimer's, cancer or immune-deficiencies. They have huge potential for patients and industry but they also present challenges that need to be properly addressed to be able to translate these therapies to the clinic. Marketing authorization of ATMPs requires, as for all medicinal products, that the applicant demonstrates that the product is consistently manufactured to a predefined quality, and that it is safe and efficacious in patients. Moreover, the use of a live material incorporates new challenges to the process related with bioequivalence between different cellular batches and the development of potency assays. After an AMI, the loss of contractile tissue drives to a degenerative process and finally to a chronic heart failure. There are no efficient therapies besides the organ transplantation and the scarcity of donors, the cost of the treatment and the side effects associated have limited the application of this therapy. Cell therapy has rose as an alternative for the treatment of this pathology but to be clinical effective it needs to be affordable, to produce a robust regenerative response and to be reproducible and equivalent between the different GMP produced batches. Coretherapix has initiated a clinical trial using allogeneic cardiac stem cells for the treatment of the acute myocardial infarction.
Nazim Serdar Turhal
Anadolu Medical Center, Turkey
Title: A proposal for more affordable biologicals in developing countries
Biography:
Nazim Serdar Turhal had his training in Internal Medicine in Griffin Hospital at Yale University Affiliated Program until 1992. He was trained in Hematology, Oncology and Bone Marrow Transplantation at Mount Sinai School of Medicine Hospital until 1997. He then worked at Marmara University in Istanbul until 2014 and as Professor of Medicine since 2006. He recently relocated to Anadolu Medical Center as a Senior Oncology Staff. He has over 130 publications and over 1000 citations. He is board certified in Medical Oncology until 2016 by European School of Medical Oncology and until 2017 by American Board of Internal Medicine.
Abstract:
The information on the efficacy of newer agents is spreading rapidly on internet era. It is increasingly difficult in a democratic society to say “no†for a particular treatment for patients no matter how expensive it is. The bureaucracy is showing many obstacles in registration, marketing authorization, licensing steps of these new agents in many developing countries with limited resources. These obstacles may emerge in many forms. These measures are justifiable under budget pressures but instead of complicating the authorization process and testing the patience of both the industry and the patients who are waiting for the approval, I propose forming an advisory board similar to FDA and EMEA for the developing countries and simplifying the approval process under one authority which will be practical for the industry too. The industry will finance this board with application fees and the board then can use its influence on bringing down the price of these molecules in representing countries and justify the lower prices with commitment to substantial contribution to phase I-III trials in these particular countries. A correlative link can be established in between the contribution and the price. Difficulties of this will be: 1) Agreeing upon who will represent a particular country (politicians, physicians, clinicians and pharmacologists); 2) Getting together in harmony; 3) Agreeing upon representation; 4) Administrative power; 5) Convincing the industry. It may be difficult and painstakingly slow process but certainly worth trying!
- Antimicrobial Agents and Medicines
Location: Room 1
Session Introduction
Hiroyuki Osada
RIKEN Center for Sustainable Resource Science, Japan
Title: Screening of novel antimalarial agents in RIKEN NPDepo
Biography:
Dr. Hiroyuki Osada has received his Ph.D. degree from the University of Tokyo, Japan. He joined RIKEN in 1983 and he became a Deputy Director of RIKEN Center for Sustainable Resource Science from 2013. He discovered KGF/FGF7 when he studied with Dr. S.A. Aaronson in NCI, Bethesda, USA as a visiting scientist (1985-86). As a head of the Antibiotics Laboratory, RIKEN, he discovered many novel bioactive compounds (reveromycin, tryprostatin, etc) from microorganisms. He is serving as an editorial board or advisary member to international journals (Cancer Science, Journal of Antibiotics, ACS Chemical Biology, etc). He is the president of the Society for Actinomycetes, Japan and the Japanese Association for Molecular Target Therapy of Cancer. He received many prestigious awards including the Inhoffen Award (2015). He is the author and co-author of over 350 publications and books (Bioprobes, Protein Targeting with Small Molecules, etc).
Abstract:
Malaria is one of the most serious infectious diseases. Since parasite strains resistant to traditional antimalarial drugs such as chloroquine (CLQ) and artemisinin (ART) derivatives appeared, novel antimalarial agents are required to be developed urgently. I will introduce the screening method and the hit compounds showing the antimalarial activity in this presentation. It is known that malaria parasite has high LDH activity. We established a HTS system using the LDH assay to isolate growth inhibitors of the parasite strain 3D7 cultured in vitro. Using this system, we selected 450 compounds from 17,000 compounds of RIKEN NPDepo (Natural Products Depository) chemical library with 5 µg/mL or less IC90 activity of parasite growth. As the second screening, we evaluated the toxicity toward mouse NIH3T3 and rat NRK cells of these compounds. Eighty six compounds showed selective inhibition against parasite with IC50 values lower than one thirtieth of those toward mammalian cells. Finally, as the third screening, we examined growth inhibitory effect of these 86 compounds on the CLQ resistant parasite strains (K1 and Dd2) and found that 36 compounds were as effective on the resistant strains as on 3D7 strain. NPD10928 (IC50 88 nM) was selected as one of the potent inhibitors against malaria parasites. We administrated NPD10928 to a malaria infectious mouse (ip, 20 mg/kg), and found that the growth of parasite was reduced significantly. In addition, I will introduce other antimalarial agents that were found by our screening.
Minoru Yoshida
RIKEN Center for Sustainable Resource Science, Japan
Title: Chemical genomics for target identification of antifungal theonellamides
Biography:
Minoru Yoshida received his PhD (1986) from the University of Tokyo, where he worked as Assistant and Associate Professors and accomplished mode-of-action studies on trichostatin A (TSA) and leptomycin B (LMB). He identified histone deacetylase and Crm1 as the specific targets of TSA and LMB, respectively. He moved to RIKEN as Chief Scientist in 2002, and has been playing a leading role in chemical biology.His work has unearthed new targets for drug discovery, and several inhibitors of these targets have come into practical use as anticancer drugs. He received many awards including Japan Academy Prize.
Abstract:
Identification of the cellular targets of bioactive small molecules is a major challenge in the development of these molecules as biological tools and therapeutics. Recently, much attention has been drawn to a chemical genetic approach, which uses physical and/or genetic interaction between the compound and its target. Thanks to a wealth of genomic information, genome-wide screening of genetic interaction has become available. We constructed a whole ORF library (ORFeome) of fission yeast and performed reverse proteomics including global analyses of protein subcellular localization (localizome) and protein gel mobility (mobilitome). In combination with these databases and chemical genetic profiling using the strains expressing the ORFeome, we developed a systematic method for drug target identification. This method enabled us to identify the rather unusual mechanism of action of theonellamides (TNMs), marine antifungal cyclic peptides. TNMs were shown to bind to 3beta-hydroxysterols including ergosterol in the fungal cell membrane, thereby inducing abnormal accumulation of 1,3-ï¢-glucan, proving the effectiveness of chemical genomics. Furthermore, we show that in mammalian cells TNMs recognize specific cholesterol-containing membrane domains, induce phase separation of lipid membranes, and induce cell contraction. The usefulness of TNMs as a tool for lipid biology will be discussed.
Shamim Ahmad
Aligarh Muslim University, India
Title: Can we consider honey as an alternate antibacterial and curative medicine in the battle against human ailments specially multi –resistant infections?
Biography:
Dr. Shamim Ahmad is a distinguished senior Professor of Microbiology, Officer In-Charge & Teacher In-Charge (Administrative Affairs) currently working at the Microbiology Section , Institute of Ophthalmology, JN Medical College, Faculty of Medicine , Aligarh Muslim University, India since January, 10, 1983.He has also served as a teaching faculty on deputation from Aligarh for more than 5 years at Faculties of Medicine in the Department of Clinical Microbiology, Al-Arab Medical University, Benghazi, Libya and Department of Medical Microbiology, College of Medicine, Faculty of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia. Prof. Ahmad is the recipient of at least 6 prestigious International Fellowships including "DAAD (W. Germany), "JSPS"(Japan) "ROYAL SOC.-London" (UK), "DAAD" (Germany), "TUBA" (Turkey) and "SAIA" (Slovak Republic). He has published a large number of research papers , book and book chapters in various International journals. He has the credit of supervising / Co-supervising about 47 Ph.D./ M.Phil/ M.Sc. and MS (Ophthalmology) students for their theses beside presenting about 100 research papers and chaired many scientific sessions at various National and International conferences in various countries, having won "Best Paper Award". At present, Prof. Ahmad has honor to be Chief Editor / Editorial Member / Reviewer in the Editorial Boards of at least 43 International Journals of world repute.
Abstract:
Prevalence of alarming multi-antibiotic- resistance among clinical bacteria all over the world has led researchers to think about the development of an effective antibacterial agent to combat many human diseases including multi-resistant pathogens specially involving superbugs-MRSA, VRSA and other organisms. The answer may be hidden in Honey, a natural bee product having an excellent “track record†over 4 000 years of usage as a wound dressing and being easily available over the globe. Honey is a remarkable viscous fluid, prepared by bees from flowers of various plants. Surprisingly, medical uses of Honey for curing various ailments have been endorsed by Holy Quran as “Healer for Mankindâ€, and Prophetic Narrations beside Vedas and Bible books. The Russians made its use in 1st World War to prevent wound infection. Honey has been found to be effective against aerobic, anaerobic, Gram-positive and Gram-negative bacteria. In the recent times, it has been “rediscoveredâ€, with numerous reports of animal models including studies in our laboratory on corneal ulcers’ rabbit models and clinical studies, case reports and randomised controlled trials. The results, thus, have encouraged the use of honey in clinical practice as a natural and safe wound healer. Many International workers including our laboratory have explored Honey’s miracles in various medical fields like Microbiology, Ophthalmology, Surgery, Plastic Surgery, Paediatrics, Gynaecology, Dermatology, Gastroenterology, Dentistry and even cosmetics. Further, A long term in vitro and in vivo research on antibacterial tests and curative properties of Manuka Honey on MRSA,MSSA from Eye patients in UK along with recent treatment trials in dry eye syndromes in human beings in our laboratories in India provides potential prospects and scope of Honey to fight many resistant bacterial population not only in eye infections but many human ailments including alarming untreated and unhealed wounds and ulcers as a possible alternate effective antibacterial option in future particularly involving multi-resistant super bugs like Methicillin- Resistant Staphylococcus aureus – MRSA strains.