Day 1 :
Keynote Forum
Chandra Joya
University of Texas MD Anderson Cancer Center, TX
Keynote: Epigenetically targeted strategies for brain tumor therapy
Time : 09:20-09:45
Biography:
Joya Chandra, Ph.D., is an Associate Professor at the University of Texas MD Anderson Cancer Center. Research in her lab is directed towards understanding the basis for sensitivity and resistance to cancer therapeutics and optimizing their use. She has published on this topic for the past 15 years. Several of her recent publications have described the mechanism of action of epigenetically targeted agents such as histone deacetylase inhibitors, either as single agents or in combination with other therapies. She has authored over 50 original research papers, invited reviews and book chapters.
Abstract:
Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor, with a five year survival rate of less than 10%. Large scale profiling studies in glioblastoma have afforded insight into the genes that are aberrantly expressed in patients, however, translating this knowledge into improved clincial outcomes remains challenging. Epigenetic enzymes control gene expression and have become popular targets for cancer therapy. In particular, inhibitors of histone deacetylases (HDACi) have been developed for clinical use but have limited activity as single agents. We designed a novel epigenetically targeted strategy based on our finding that high levels of expression of LSD1 (lysine specific demethylase 1) or KDM1A is seen in glioblastoma cells compared to normal human astrocyes, and in pateint derived GBM stem cells compared to normal neural stem cells. LSD1 cooperates with HDAC1/2 and is implicated in several cancers, and we found that histone methylation was modulated by HDACi. Inhibition of LSD1, by knockdown using short hairpin RNA, or with pharmacological inhibitors, induced apoptosis in GBM lines but not normal counterparts, indicating selectivity of this approach for malignant cells. Using FDA approved drugs that target HDACs and LSD1, vorinostat and tranylcypromine, we tested in vivo efficacy of this combination in orthotopic mouse models of GBM and found enhanced survival. RNA-Seq conducted in cell lines suggested that TP53 and TP73 may be viable biomarkers to predict response to these agents, and was validated in vivo. Taken together, our results delineate a novel therapeutic strategy for the treatment of glioblastoma.rnrn
Keynote Forum
BhatKrishna
University of Texas, M.D. Anderson Cancer Center
Keynote: cancer stem cells were identified as distinct subtypes with their individual progenies
Time : 09:45-10:15
Biography:
Dr.Bhat,Krishna P is an Associate Professor at the University of Texas MD Anderson Cancer Center. Research in her lab is directed towards understanding the basis for sensitivity and resistance to cancer therapeutics and optimizing their use.He has published on this topic for the past 15 years. Several of his recent publications have described the mechanism of action of epigenetically targeted agents such as histone deacetylase inhibitors, either as single agents or in combination with other therapies.He has authored over 50 original research papers, invited reviews and book chapters.
Abstract:
In glioblastoma (GBM), Proneural (PN) and Mesenchymal (MES) cancer stem cells (CSCs) were identified as distinct subtypes with their individual progenies (non-CSCs). Here we report that following irradiation, intercellular extrinsic signals from senescent non-CSCs provoke PN CSCs’ compensatory growth, thereby resulting in persistent transcriptomic and phenotypic transformation toward more malignant MES CSCs (PN-MES transition: PMT). PMT of CSCs is accompanied with the activated wound healing pathway, which is significantly associated with poorer prognosis of GBM patients. During PMT of CSCs, a CSC marker CD133 is lost, while CDX expression evolves. These CDX-positive, but not CDX-negative GBM cells are highly tumorigenic and multipotent in vivo, suggesting CDX as a novel MES CSC marker. Inhibition of CDX attenuates clonogenicity and radioresistance. Lastly, CDX and CD133 expressions are independently instructive for poorer prognosis of MES and PN GBM, respectively. Together, irradiation to GBM tumors induces damaged non-CSC-driven PMT of CSCs developing a malignant phenotype, and CDX is a clinically relevant functional marker for MES GBM stemness.
- Glioblastoma
Session Introduction
Dima suki
University of Texas , USA
Title: Long-Term Survival in Patients with Glioblastoma Multiforme: Frequency and Prognostic Factors
Biography:
Dr. Dima Suki completed her PhD from The University of Texas Houston Health Science Center.rnShe is Professor at The University of Texas MD Anderson Cancer Center in the Department ofrnNeurosurgery, as well as Director of Protocol Development and Data Management, and Co-Directorrnof Clinical Research. She also is adjunct Professor at Baylor College of Medicine, Department ofrnNeurosurgery. Dr. Suki serves on numerous committees, including the Institutional Review Board,rnwhere she is currently Associate Chair. Dr. Suki has over 100 peer-reviewed publications inrnscientific journals and has authored 7 book chapters and books. She serves on editorial advisoryrnboards for several scientific journals.
Abstract:
Glioblastoma multiforme (GBM) is a highly aggressive and rapidly fatal primary brainrntumor. Median patient survival is 12-14 months. Few treated patients survive beyond 5 years.rnVariation in characteristics such as age, performance status, and extent of resection (EOR) canrnextend survival for a few months. However, factors associated with long-term survivals of ≥5 yearsrnare largely unknown, and identifying them may provide insight into GBM and its management. Wernidentified consecutive patients surviving >5 years after initial GBM resection. Their prospectivelyrncollected demographics, clinical, imaging, and treatment data were retrospectively reviewed andrnanalyzed (under an IRB-approved protocol) from 6/1/1993 to 5/31/2010 (to allow for 5-yearsrnsurvival). EOR was measured volumetrically using pre- and post-op MRI’s. Among 701 newlyrndiagnosed GBM patients, 72 patients (10%) survived ≥5 years; the cohort’s overall median survivalrnwas 13.6 months. Four factors correlated significantly with longer survival on both univariate andrnmultivariate analyses: age, KPS, necrosis on the MRI, and EOR. These factors allowedrnclassification of patients into 4 groups whose >5 years survival varied widely. For patients withrn100% resections, >5-years survival is 50% for Group A, 21% for Group B, 13% for Group C, andrn2% for Group D. The corresponding numbers for patients with <100% resection are: 8% (Group A),rn13% (Group B), 1% (Group C), and 1% (Group D). This is the largest series of long-term GBMrnsurvivors (>5 years), emphasizing the importance of patient selection and of maximizing the EOR.
Fares Nigim,
Harvard Medical School, USA
Title: Reactive Oxygen Species Induction in Oncolytic Virus Therapy of Glioblastoma
Biography:
Fares Nigim, MD currenty works under Brain Tumor Research Center at Massachusetts General Hospital and belongs to Harvard Medical School in Boston, Massachusetts with research interest upon neurooncology and neurology as an neurologist rn
Abstract:
Reactive Oxygen Species Induction in Oncolytic Virus Therapy of Glioblastomarnrn Reactive oxygen species (ROS) are signaling molecules that play versatile roles in regulating various cellular pathways in both physiological and pathological conditions such as cancer and virus infection. The effects of ROS on viral replication are context-dependent and the role of ROS in oncolytic virus therapy of cancer is poorly understood. In this study, we investigated ROS induction and its potential impacts on oncolytic herpes simplex virus (oHSV) therapy of the malignant brain tumor glioblastoma. We employed a clinically relevant glioblastoma model that is based on patient-derived glioblastoma stem cells (GSCs) that recapitulate the genotype and phenotype of primary tumors. Two oHSVs were used; G47Δ that lacks ï§34.5 and ï¡47 and has a LacZ insertion inactivating ICP6, and MG18L that contains deletion of the Us3 gene and a LacZ insertion inactivating ICP6. Measurement of intracellular ROS by H2-DCFDA and Mito SOX assays showed that both oHSVs (G47Δ and MG18L) robustly induced intracellular ROS in GSCs at 24 and 48 hours post infection, which was specifically seen in infected cells. Antioxidants, reduced glutathione (GSH) and N-acetylcystein (NAC), potently suppressed oHSVs-induced intracellular ROS. Antioxidants-mediated suppression of intracellular ROS did not affect viral replication or viral spread. However, cell viability assays (MTS and Cell Titer Glo) and dead cell staining (trypan blue or propidium iodide) demonstrated that both antioxidants protected GSCs from early cell death caused by the viruses. Thus we show that oHSV is a potent inducer of ROS upon infection of GSCs. Our results also suggest that virus-induced ROS contribute to early cell death following oHSV therapy of glioblastoma.rnKey words: Reactive oxygen species (ROS), Glioblastoma stem cells (GSCs), Oncolytic herpes simplex virus (oHSV).rn
Fatemeh Nejatbakhshesfahani
Technical University of Munich, München, Germany
Title: Fingerprinting Heterogeneity of Glioma Using PET/MRI Information
Biography:
Fatemeh Nejatbakhshesfahani has completed his M. Sc. at the age of 25 from TUM University department of Biomedical Computing in Munich, Germany from 2013 to 2015 and she started Dr. rer in Human Biology studies from LMU University Radiology Clinic in 2016.
Abstract:
This projects is proposing a novel machine learning algorithm based on Generative Method to characterize intra-tumor heterogeneity of glioma. The algorithm was applied on dynamic [18F] FET-PET, [18F] Fmiso PET, rOEF, MRI T1, T2, T1W, T2W, FLAIR, DCE MRI and so on. This probabilistic model allows for different tumor boundaries in each channel, reflecting difference in tumor appearance across modalities. Classification result shows partly distributed feature maps in order to be able to select relevant features amongst wide patient data. The identified parts with different malignancy were discussed and validated according to first, the manual segmentations by clinical experts to investigate the performance on the tumor borders and second, graph maps to investigate the performance on the intra tumor regions. The main aim of the project is focused on the extraction of the additive information from PET and combining it with the MRI images information for each patient and relating them to the grade of malignancy.
Amir Nikouei
Shohada Tajrish Neurosurgical Center of Excellence, Iran
Title: conventional brain glioma resection versus neuronavigation system
Biography:
Dr.Amir Nikouei is from Shohada Tajrish Neurosurgical Center of Excellence, Functional Neurosurgery Research Center of Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran with research interest of neurology and neurosciences
Abstract:
Objective:rnExtent of tumor resection poses a special challenge for neurosurgeons. Image guided surgery (IGS) has become an established technology in surgical management of cerebral tumors, which provides detailed 3D localization of the lesion around important cerebrovasculature and tracts. Since there are few studies regarding using this technology as a part of standard care for patients with cerebral gliomas, we set out to determine whether IGS could improve extent of tumor resection in patients with cerebral gliomas involving eloquent cortical areas along with more desirable prognosis.rnMaterials and Methods:rnFrom January 2013 till October 2015, 26 patients with cerebral gliomas involving eloquent cortical areas were randomized equally into trial group (IGS) and control group (conventional surgery). Patients in trial group underwent functional multislice 3 Tesla Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI) 48 hours before surgery. DTI datasets were merged with anatomical structures, and the relationship between the tumor and adjacent tracts were reconstructed for 3D visualization. Completeness of tumor resection, including volumetric analysis, was examined by early post-operative MRI.rnResults:rnThe statistic analysis confirmed well balance of main variations in both groups. Average mean pre-operative tumor volume in trial and control group was 70.37±7.96 cm3 and 68.82±7.85 cm3 respectively. No significant difference was observed between pre-operative tumor volumes in both groups (P value>0.05). Early post-operative MRI revealed 4.11±2.92 cm3 and 8.78±4.79 cm3 as mean residual tumor volume in trial and control group respectively (P value<0.05). Eleven patients (84.61%) in trial group experienced radical resection (>95%); however, radical resection was just achieved in 3 patients (23.07%) (P value<0.05). While there was no significant difference between mean Karnofsky performance scale (KPS) in both groups of patients before operation, 88.09±20.43 and 66.38±19.32 were recorded as mean KPS for trial and control group respectively (P value<0.05). In addition, excellent outcome ratio (KPS=90-100) was achieved in 76.92% of trial group, while this value was 30.76% in control group (P value<0.05).rnConclusions:rnIGS using neuronavigation system combined with DTI, allows 3D evaluation of the cerebral tumor and their adjacent structures, along with tract mapping for neurosurgeons. Furthermore, this technology can aid to plan the optimal trajectory and higher extent of tumor resection with minimal post-operative neurological deficits.rn
A. De Tommasi
University “A. Moro†of Bari, Italy
Title: PROGNOSTIC FACTORS IN GLIOBLASTOMA MULTIFORME: OUR EXPERIENCE.
Biography:
A. De Tommasi currently working FROM 2010 – TO NOW BARI GENERAL HOSPITAL AND UNIVERSITY OF BARI HEALTHCARE – NEUROSURGERY CHAIRMAN AND HEAD OF THE NEUROSURGICAL AND NEUROTRAUMATOLOGICAL DEPARTMENT ,CLINICAL, SURGICAL, DIDACTIC AND ADMINISTRATIVE ACTIVITIES AND RESPONSIBILITIES,Faculty Lecturer in cranio-cerebral and vertebro-medullary Traumatology during FROM 1976 -TO 1991,From 1978 to 1993, Professor of Neurosurgery at the Nurses’ College at the Domenico Cotugno Hospital in Bari. From 1979 to 1995, Professor of Neurosurgery at the School for Technicians in Resuscitation and Anaesthesia at the De Bellis Institute in Castellana Grotte, Italy. Since l980, Professor of Neurosurgery and Neurotraumatology at the Faculty of Medicine at the University of Bari. Since l980, Professor of Neurosurgery and Neurotraumatology at the School of Specialization in Neurosurgery at the University of Bari.
Abstract:
INTRODUCTION: Glioblastoma Multiforme (GBM) is the most common and aggressive cerebral neoplasm in adults with an incidence of 5.26 cases per 100000 inhabitants per year. It usually occurs in the sixth and seventh decade of life. The prognosis is severe with an average survival of 12-18 months. Several studies have been conducted to identify the prognostic factors in GBM. The only fact resulting from these studies is the prognostic role of age. The importance of the subject’s functional status at diagnosis and of the lesion’s location is still unclear. MATERIALS AND METHODS: Our study is a retrospective analysis of 50 patients from 2010 to 2013. The average age is 63 years old with a M:F rate of 1.6. As far as the identification of prognostic factors is concerned, the following aspects have been taken into account: age, gender, Kasnofsky Performance Status (KPS) at the admission, lesion’s location, and the extent of surgical resection. At the admission, 18 % of patients had a KPS of 60 or lower, 75% showed a KPS value of 70 or 80, 6% had a KPS of 90, and none had a KPS of 100. After the operation, the situation changed with 62% of patients with a KPS of 90-100, 30% with a KPS of 70-80 and only 8% of subjects showing a KPS of 60 or lower. RESULTS: The univariate analysis results have been verified with a multivariate analysis for which the Cox model and the stepwise selection of variables have been used. The prognostic role of each risk factor has been evaluated with a survival analysis using the Cox model. The univariate analysis showed that an age of 65 or more, and a KPS of 80 or more are usually associated with a better outcome. Lesion’s location in eloquent area and the subtotal extent of surgical resection have a negative influence on survival (with no relevant statistical significance). Gender does not show a relation with the prognosis of subjects with glioblastoma multiforme. CONCLUSION: The first aspect emerging from our study is the importance of the surgery in improving the patient’s symptoms and functional status. The univariate analysis showed that age is the only risk factor with a statistical significant influence on survival. No association emerged between the extent of resection and the subject’s survival despite a p value close to 0.05. In multivariate analysis the p value is 0.08 with a OR of 2.35. Therefore, an explorative analysis of the interaction between the lesion’s location and the extent of resection was conducted so as to give a more appropriate interpretation of this result. This analysis highlighted that a greater extent of resection is associated with a better outcome in both cases where GBM is located in eloquent or non eloquent area. Keywords: glioblastoma multiforme, prognostic factors
- Neurooncology
Session Introduction
Sun Jin kim
University of Texas,USA
Title: Targeting the Microenvironment for Therapy of Primary and Metastatic Brain Tumors
Biography:
Dr. Sun Jin Kim received MD in 1986 and PhD in 1993 from the College of Medicine and the Graduate School of Seoul National University. He completed the residency in the Seoul National University Hospital and postdoctoral fellowship in the University of Texas MD Anderson Cancer Center. He was an invited scientist in the National Cancer Center Research Institute, Tokyo, Japan. He is a professor in the Department of Cancer Biology, UTMDACC and has published more than 80 papers in peer-reviewed journals. He has been involved in clinical translational research programs developing the clinical trials of novel molecules and protocols.
Abstract:
rnThe median survival of patients with the primary or metastatic brain tumor is limited due to resistance to all standard therapies. The mechanism of pan-resistance against the systemic therapy has been attributed to the blood-brain-barrier and/or p-glycoprotein, which prevent the drugs from reaching the brain lesions. We have recently reported that activated astrocytes and endothelial cells establish gap-junction communication channel with the tumor cells and protect tumor cells from chemotherapeutic agents by a mechanism involving the phosphorylation of endothelin receptors on tumor cells leading to up-regulation of multiple genes, among which are survival or anti-apoptotic genes. We translated in vitro observation into the preclinical in vivo models that nude mice bearing orthotopic human glioblastoma or metastatic human breast or lung cancers in brain were treated by the blockade of the endothelin axis, using the dual antagonist, macitentan, combined with taxol or temozolomide. The combination therapy significantly regressed the established primary or metastatic brain tumors and prolonged the disease free survival of mice for months after mice in other treatment groups died. Immunohistochemical analysis demonstrated that treatment with macitentan inhibited phosphorylation of the endothelin receptors A and B on tumor cells and tumor-associated endothelial cells. The addition of chemotherapeutic agents produced massive apoptosis in both tumor cells and dividing tumor-associated endothelial cells.rnInhibition of endothelin receptor phosphorylation on both tumor cells and tumor-associated endothelial cells inhibits survival pathways in these cells, which enhances their sensitivity to chemotherapy. Macitentan plus chemotherapy is well tolerated, produces durable responses, and clinical evaluation is ongoing.rn
- Young Researchers Fourm
Biography:
Julie has finished her Master in Biomedical Sciences (option radiation science) at the Ghent University in 2011 with great distinction. She has a special interest in neurosciences and medical imaging of the brain. At the moment, Julie has been working as a Ph.D. student for 5 years at the department of nuclear medicine of Ghent University Hospital. Her focus is on PET/MRI imaging of high-grade brain tumors. Since 2013 she is a member of the organizing committee of the Belgian Molecular Imaging Community. Two papers were published in 2014 and 2 new papers are currently submitted.
Abstract:
Background: Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains challenging but has a large impact on further treatment and prognosis. In this study, uptake of 18F-fluorodeoxyglucose (18F-FDG), 18F-fluoroethyltyrosine (18F-FET) and 18F-fluoromethylcholine (18F-FCho) positron emission tomography (PET) tracers were investigated in a F98 GB and RN rat model applying kinetic modeling (KM) and graphical analysis (GA), with the aim to clarify our previous results. Methods: Dynamic 18F-FDG (GB n=6 and RN n=5), 18F-FET (GB n=5 and RN n=5) and 18F-FCho PET (GB n=5 and RN n=5) were acquired with continuous arterial blood sampling. Arterial input function (AIF) corrections, KM and GA were performed. Results: The influx rate (Ki) of 18F-FDG uptake described by a 2-compartmental model (CM) or using Patlak GA, showed more trapping (k3) in GB (0.07 min-1) compared to RN (0.04 min-1) (p=0.017). K1 of 18F-FET was significantly higher in GB (0.06 ml/ccm/min) compared to RN (0.02 ml/ccm/min), quantified using a 1-CM and Logan GA (p=0.036). 18F-FCho was rapidly oxidized complicating data interpretation. Using a 1-CM and Logan GA no clear differences were found to discriminate GB from RN. Conclusions: Based on our results we concluded that using KM and GA both 18F-FDG and 18F-FET were able to discriminate GB from RN. Although KM is the only method for absolute quantification, based on our semi-quantitative results and due to the laborious set-up for obtaining an AIF, SUV is proposed for translation into the clinic. 18F-FCho PET did not allow discrimination between GB and RN.