Day 1 :
Keynote Forum
Ioannis Papasotiriou
R.G.C.C.S.A., Greece
Keynote: Innovations in drug development through transcriptomic analysis of liquid biopsies and exosome utility
Biography:
Ioannis Papasotiriou born in Munich, Germany. He graduated from Medical School of Thessaloniki University in 1997. He made his first specialty in Human Genetic (University of Zurich), and his second specialty in Hematology Oncology (MLU/UKH/Halle/Saale). He obtained two Mater degrees, one in molecular biology in medicine from the Westminster University and one in Oncology from the University of Nottingham. He completed his promotion (MD) in MLU University in the area of TKIs in human cancer cells lines. Between 2001 and 2004 he established Arzt Genetik Zentrum in Thessaloniki where he was a director. Since May 2004 he is the medical director of R.G.C.C.S.A. where the major field of expertise is molecular oncology with main interest in the entity of Cancer Stem Cell (CTCs) like.
Abstract:
Liquid biopsy becomes one of a key tool sampling in cancer, which may be proved to be prognostic and even diagnostic analytical method. Additionally, to that, circulating tumor cells may become relevant entity to indicate new druggable targets. In our study, we analyze plenty of circulating tumor cells transcriptome. The analysis of transcriptome for repeatable expression patterns in combination of data mining, reveal new druggable targets that lead to ligand based drug design of new molecules with pharmacophore properties. Specifically, the analysis revealed a repeatable pattern in hormone depended breast carcinoma cases, where ERK1 and ERK2 transcripts were highly overexpressed. Then a ligand based drug design has been initiated and few candidate molecules have been generated from RGCC1 to RGCC12. Then the candidate RGCC7 showed the best efficacy against this specific type of cancer, both in cancer cell lines and primary cells cultures as well. Furthermore, the candidate RGCC7 has been encapsulated in exosomes derived from cancer cell cultures of the same origin. Then the efficacy of the candidate molecule increased up to 80 percent approximately compared to the non-encapsulated form. This process reveled that firstly selecting the proper sample for analysis is important in finding of druggable targets. And secondly, the improvement of drug delivery can equally be improved by using biological systems that we are already familiar with.
Keynote Forum
Ioannis Papasotiriou
R.G.C.C.S.A., Greece
Keynote: Innovations in drug development through transcriptomic analysis of liquid biopsies and exosome utility
Time : 09:00-09:30
Biography:
Ioannis Papasotiriou born in Munich, Germany. He graduated from Medical School of Thessaloniki University in 1997. He made his first specialty in Human Genetic (University of Zurich), and his second specialty in Hematology Oncology (MLU/UKH/Halle/Saale). He obtained two Mater degrees, one in molecular biology in medicine from the Westminster University and one in Oncology from the University of Nottingham. He completed his promotion (MD) in MLU University in the area of TKIs in human cancer cells lines. Between 2001 and 2004 he established Arzt Genetik Zentrum in Thessaloniki where he was a director. Since May 2004 he is the medical director of R.G.C.C.S.A. where the major field of expertise is molecular oncology with main interest in the entity of Cancer Stem Cell (CTCs) like.
Abstract:
Liquid biopsy becomes one of a key tool sampling in cancer, which may be proved to be prognostic and even diagnostic analytical method. Additionally, to that, circulating tumor cells may become relevant entity to indicate new druggable targets. In our study, we analyze plenty of circulating tumor cells transcriptome. The analysis of transcriptome for repeatable expression patterns in combination of data mining, reveal new druggable targets that lead to ligand based drug design of new molecules with pharmacophore properties. Specifically, the analysis revealed a repeatable pattern in hormone depended breast carcinoma cases, where ERK1 and ERK2 transcripts were highly overexpressed. Then a ligand based drug design has been initiated and few candidate molecules have been generated from RGCC1 to RGCC12. Then the candidate RGCC7 showed the best efficacy against this specific type of cancer, both in cancer cell lines and primary cells cultures as well. Furthermore, the candidate RGCC7 has been encapsulated in exosomes derived from cancer cell cultures of the same origin. Then the efficacy of the candidate molecule increased up to 80 percent approximately compared to the non-encapsulated form. This process reveled that firstly selecting the proper sample for analysis is important in finding of druggable targets. And secondly, the improvement of drug delivery can equally be improved by using biological systems that we are already familiar with.
- Molecular Biomarkers/Immuno-Oncology Biomarkers/Drug formulation/Clinical and Translational BiomarkersBiomarkers in patient selection/Cardiovascular BiomarkersImaging Biomarkers/Biomarker Discovery & ValidationImmunological Biomarkers
Location: Amsterdam, Netherlands
Session Introduction
Xiao wang
Lund University | Sweden
Title: Association between circulating microRNAs and recurrent venous thromboembolism
Biography:
Xiao Wang is a researcher in Center for Primary Health Care Research (CPF), Lund University. Her research interests are different biomarkers (miRNA, Mitochondrial DNA and telomere length) associated with the pathogenesis of chronic diseases, such as venous thromboembolism (VTE), diabetes and mental disorders. Xiao Wang has found for example, miR-424-5p are associated with deep-vein thrombosis (DVT) and markers of hypercoagulability. In a recent study, the potential association between miRNAs and recurrent VTE was investigated. Her findings have been published in the journals of Thromb Haemost, Clin Epigenetics and Int J Neuropsychopharmacol et.al.
Abstract:
Patients with unprovoked first venous thromboembolism (VTE) are at a high risk of recurrence. Although circulating microRNAs (miRNAs) have been recently found to be associated with deep vein thrombosis and markers of hypercoagulability, this study is the first to examine whether circulating miRNAs are associated with the risk of VTE recurrence. A nested case-control study design was used, where plasma samples were obtained from 78 patients with unprovoked VTE from the Malmö thrombophilia study (MATS). A total of 39 VTE patients with recurrent VTE (cases) were matched with 39 VTE patients without recurrent VTE from the MATS study population by age and gender (controls). Plasma levels of 179 different miRNAs were evaluated in the 78 sample (after stop of anticoagulant treatment) using qPCR. A total of 110 miRNAs were detected throughout all samples. Among those, 15 miRNAs were found to be associated with recurrent VTE after adjusting for multiple comparisons. The highest odds ratio was found for miR-15b-5p (OR=7.8 per standard deviation increment) using conditional logistic regression. The following miRNAs, miR-15b-5p, miR-197-3p, miR-27b-3p and miR-30c-5p, exhibited a trend over time, with larger difference in miRNAs levels between cases and controls for earlier recurrence. Of these 15 miRNAs, eight miRNAs were correlated with TGFβ1/2 expression in the blood. None of them correlated with primary VTE. The findings indicate that circulating miRNAs are novel biomarkers for especially early VTE recurrence. Some of these miRNAs are involved in the regulation of platelets, coagulation, and TGFβ-pathway, which suggest that these pathways might be of importance in recurrent VTE.
Marjut Niinivirta
Uppsala University Hospital | Sweden
Title: Tumoral expression of pyruvate kinase L/R as a predictive marker for treatment of metastatic renal cancer patients with sunitinib and sorafenib
Biography:
Marjut Niinivirta is an Oncologist working at the Uppsala University Hospital in Sweden and pursuing PhD at Uppsala University, researching on predictive markers in renal cell cancer.
Abstract:
Patients with metastatic renal cell cancer (mRCC) are commonly treated with the tyrosine kinase inhibitors (TKI) sunitinib and sorafenib. No predictive marker is available to select patients who will gain from these treatments. Tumoral pyruvate kinase L/R (PKLR) is a membrane protein with highly specific expression in the renal tubule. We have previously shown that the tumoral expression of cubilin is associated with progression free survival (PFS) in mRCC patients treated with sunitinib and sorafenib and in the present study; we investigated if PKLR can predict response in these patients. The expression of PKLR was analyzed in tumor tissue from a cohort of patients with mRCC (n=139) using immunohistochemistry. One hundred and thirty-six (136) of these patients were treated with sunitinib or sorafenib in the first or second-line setting. Thirty were censored because of early toxicity leading to the termination of treatment. The remaining patients (n=106) were selected for the current study. Fifty-five (52%) of the tumors expressed membranous PKLR. Patients with PKLR tumor expression experienced a significantly longer PFS compared to patients with no expression (eight vs. five months, p=0.019). In addition, the combined expression of PKLR and cubilin resulted in a higher predictive value than PKLR alone. We show that tumoral PKLR membrane expression is a positive predictive biomarker for sunitinib and sorafenib treatment in patients suffering from mRCC. Our results also indicate that the combined expression with cubilin more accurately than PKLR alone can select patients with no benefit from treatment.
Beata Burzynska
Polish Academy of Sciences | Poland
Title: Transcriptomic biomarkers based approach for predicting the risk of heart failure development in post-infarction patients with the use of the ddPCR method
Biography:
Beata Burzynska has completed her PhD from Warsaw University of Life Sciences, Poland. She is a PI at the Department of Genetics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences. She conducted Post-doctoral Training at the Louisiana State University Health Sciences Center. She has published more than 40 papers in SCI journals and has been serving as a Board Member of the Committee on Biotechnology, Polish Academy of Sciences.
Abstract:
Introduction: Cardiovascular diseases are the most important cause of mortality in developed countries. Despite continuous advances in diagnosis and treatment, heart failure (HF) remains a serious medical, social and economic problem. An acute myocardial infarction (AMI) is an event in coronary artery disease often leading to the development of heart failure. Classic risk factors of HF only partially explain why some patients suffer later from decompensation of the left ventricle, whereas others function quite well.
Aim: The aim of our study was to identify distinct biomarkers that correlate with HF development.
Methodology: We collected blood samples from AMI patients on admission (1st day of AMI). Clinical evaluation was performed after six months of AMI and patients were divided into HF (n=37), non-HF (n=26) and moderate-HF groups (n=119). Microarrays were used to analyze individual gene expression profiles of the patients. Seven differentially expressed transcripts that best discriminate between HF, non-HF and moderate-HF patients were selected. Microarray results were validated by the ddPCR method using blood RNA. Reference values were obtained for all transcripts and all groups of patients and the HF prognosis risk score was calculated.
Results & Conclusion: The obtained results show that the identified gene expression changes at the early phase of AMI allow differentiating patients who developed HF from those who did not and that they may serve as a convenient tool contributing to the prognosis of heart failure.
David G Ostrow
International Cannabis Cancer Treatment Institute | USA
Title: Entourage of biomarkers resulting from the binding of cannabinoids to their receptors: a review and research opportunities
Biography:
David G Ostrow is an MSTP graduate from the University of Chicago and is triple Board Certified in Psychiatry, Addiction and Cannabinoid Medicine. He is the Co-Founder of the American Academy of Cannabinoid Medicine, Research Director of the International Cannabis Cancer Treatment Institute, and Clinical Director of VALEO Programs for LGBTQ Persons of Chicago Lakeshore Hospital.
Abstract:
In trans-membrane signaling, interactions between agonists and their receptors cause a cascade of effects. Since phytocannabinoids contain many active ligands, and the internal endocannabinoid system has multiple receptors linked to a variety of secondary messengers, these complex mixtures can have widely varied effects based on the ratios of cannabinoid molecules, their routes of administration and the specific cells and organs targeted. Thus, the use of biomarkers has the potential to clarify the pathophysiology of the condition or symptom being treated and the mechanism(s) by which cannabinoids restore homeostasis and health. We present an extensive review of findings on six major receptors with high affinity for (Endo) cannabinoid molecules that demonstrate the common pathways and secondary feedback loops that shift MAPK signaling, cause changes in biomarkers, and restore cellular functions and homeostasis: CB1, CB2, PPARg, GPR18 and 55, and TRPV1 are covered. In both animal and in vitro studies, it was found that the cannabinoid receptors (CB1 and CB2) and GPR18 and 55 function antagonistically due to co-expression on the surface of cells. GPR18 is co-located with CB1 and GPR55 with CB2. Later, along with increased levels of lysophosphatidylinositol (LPI), itself being a membrane biomarker for decreased survival in multiple cancers. Agonist binding to both CB receptors inhibits adenylyl cyclase, halting the MAPK pathway, thereby limiting cancer cell migration and metastasis; stimulation of GPR receptors does the opposite. CB2 mediated responses reduce inflammatory markers such as IL-2, TNFa, and neutrophilia: its associated GPR55 has opposite effects. GPR18 agonist improves cardiac function and reduces markers of cardiomyopathy, as well as promoting the destruction of infectious agents. Autism is associated with mutations of the CB1 receptor and GPRs. Effects at PPARg were found to reduce glial cell activation and halt the production of fibrillary tangles and the resulting formation of amyloid beta plaques causing Alzheimer’s. Conventional diabetes medicines act at this receptor as well, possibly explaining the association seen between diabetes, insulin resistance and early onset AD. TRPV activation by cannabinoids was found to promote apoptosis of cancer cells by inactivation of the MAPK pathway and activation of caspases. In the case of capsaicin activation, influx of calcium through opening of Ca+ channels occur in contrast to cannabinoid binding. This produces an endogenous entourage effect through increased levels of anandamide and its co-synthesized analogues OEA and PEA. CB1 activation in the CNS produces a similar entourage of lipid biosynthesis that regulates glutamate and GABA neurotransmission. These encouraging results from in vitro and rodent models are beginning to be translated into controlled human trials of cannabinoid treatment of Alzheimer's, CVD, cancer, chronic pain, and autism that utilize appropriate biomarker measures to supplement the long-term clinical endpoints of chronic disease.