Day 2 :
Keynote Forum
Jaime Tisnado
Virginia Commonwealth University, USA
Keynote: Carotid blow out syndrome: Interventional radiologic management
Time : 09:30-10:15
Biography:
Jaime Tisnado graduated from Leoncio Prado Military Academy. He received his BM degree from San Marcos National University, College of Sciences. He received his MD degree summa cum laude from the same San Marcos National University Medical School. He was an Intern at GBMC, a division of John's Hopkins University Hospital in Baltimore, MD, 1965, and then an Intern and Resident in Surgery at The State University of New York, Upstate Medical Center in Syracuse NY, 1966-67. He was a Resident in Radiology for 4 years at Thomas Jefferson University Medical Center in Philadelphia, 1967-71. Then he took 2 years fellowships in Vascular and Interventional Radiology and Neuroradiology both at the same institution, Thomas Jefferson University in Philadelphia, PA, 1971-73. He then became an Assistant Professor of Radiology and Director of Interventional Radiology at Albany Medical College, Albany, NY, 1974-77. Thereafter he moved to Virginia Commonwealth University, in Richmond, VA, where he became Associate Professor of Radiology and Director of Interventional Radiology and eventually became Professor of Radiology and Professor of Surgery, at the same university from 1985 till 2010. Thereafter, he was named one of the few Professor Emeritus of Radiology and Surgery, all at the same Virginia Commonwealth University in 2010 till now. He has published more than 100 articles in peer reviewed journals, about 400 scientific posters and electronic exhibits all over the country and the world, and about 200 abstracts, 4 books, many chapters in books, and about 200 papers presented at meetings, at the local, national, and worldwide level. He has been selected many times to Who is Who in America, the Best Radiologists in America, the Best Physicians in USA, etc. Moreover, he is the only person in the country and in the world who has, at the same time and forever, more than 5 fellowships in the most prestigious professional organizations of USA.
Abstract:
Carotid blow out syndrome (CBOS) is a catastrophic neurovascular emergency associated with a high morbidity and mortality (M&M). The etiology of CBOS is: head and neck malignancies with tumor invasion, postoperative complications, inflammation, trauma, vasculitides, collagen diseases, and post radiation therapy for malignancies, among others. The conventional surgical management has been and is carotid artery and/or branch ligation or bypass, and is rather difficult and associated with significant M&M and could be ineffective in controlling the situation. At this time, the ideal management of this serious problem is the interventional radiology (IR) and interventional neuroradiology (INR) endovascular: insertion of stents of different kinds (covered or uncovered, self-expanding or balloon-expandable) and/or embolization of the carotid or vertebral arteries or branches, with temporary or permanent agents and/or devices. A permanent or temporary success is expected with stent insertion and/or embolization, or both procedures combined. We have managed many patients, not considered ideal candidates for surgery, at least during the acute phase, with stents from different manufacturers, mostly covered. In addition, we have embolized some patients as well and some other patients have had both methods. The procedures have been done in the IR suite by the IR, INR and surgeons as well, working in a team, in a collaborative rather than in an adversarial manner. No major complications related to the procedures have been found. The patients have had a long-term or a temporary improvement in their condition. The emergent management of CBOS by stenting and/or embolization or both is a safe, effective and relatively easy procedure to temporarily manage these seriously ill patients. A longer follow-p and many more patients studied are necessary to establish the definitive role of stenting and/or embolization in CBOS. In conclusion, the conventional surgical management of CBOS may be difficult and/or ineffective, therefore, the endovascular management is considered the first choice of therapy, at least for now, especially in clinically desperate situations.
Keynote Forum
Kang-Yell Choi
Yonsei University, South Korea
Keynote: Degradation of both β-catenin and RAS via targeting the Wnt/β-catenin pathway is an ideal approach for colorectal cancer treatment
Time : 10:15-11:00
Biography:
Kang-Yell Choi finished his doctorate in Biochemistry at the Purdue University in 1993, and performed research related with cell signaling with the yeast pheromone signaling pathway as a model system at Harvard Medical School as a postdoctoral fellow. There, he characterized Saccharomyces Ste5 functioning at the MAP kinase pathway as a 1st protein introduced concept for the "Scaffold Protein" in the community. In 1995, he returned back to Korea as a professor of Yonsei University. Since then, he has been working on mammalian cell signaling related with several different pathophysiologies such as growth control of cells and human cancer. He is serving as the chief of the National Research Laboratory of the Molecular Complex Control for recent 5 years, and currently positioned as the Director of the Translational Research Center for Protein Function Control supported by Ministry of Science, ICT and Future Panning of Korea.
Abstract:
Interaction between the Wnt/beta-catenin and the Ras-ERK pathways, two major transforming pathways, have been posited. However, molecular mechanisms and cooperative roles of these two pathways are poorly understood. Both APC and KRAS mutations synergistically promote cellular transformation and tumor growth, attributed to activation of the RAS-ERK pathway via activation of the Wnt/ β-catenin signaling. One key event in this crosstalk is the stabilization of RAS, especially mutant KRAS, by APC loss. Stabilization of both β-catenin and RAS plays a critical role in the synergistic transformation, and both β-catenin and RAS levels are highly increased in CRC patient tissues. Epidermal growth factor receptor (EGFR), a direct transcriptional target of the Wnt/β-catenin signaling pathway, is also overexpressed in human CRC, and plays a role in the synergistic tumorigenesis. Therefore, inhibition of both the Wnt/β-catenin and EGFR-RAS-ERK pathways, especially by reducing levels of the proteins elevated in CRC, could be an ideal approach for the treatment of human CRC. This concept for an ideal therapeutic approach has been proved by small molecules destabilizing both β-catenin and RAS by activation of GSK3β via targeting the Wnt/β-catenin pathway. GSK3β activated by the small molecules induce phosphorylation and subsequent polyubiquitin-dependent proteasomal degradations of both β-catenin and Ras and subsequent transcriptional suppression of EGFR overcome current limitation of the insensitiveness of the EGFR targeting therapies such as cetuximab attributed by a K-Ras mutation of patients. Moreover, these small molecules effectively suppress activaiton of cancer stem cell activated through aberrancies of the Wnt/ β-catenin and Ras-ERK pathways.
Keynote Forum
Christopher S Lange
SUNY Downstate Medical Center, Brooklyn, NY, USA
Keynote: Applying Koch’s postulates to test the cancer stem cell basis of cancer
Time : 11:20-12:00
Biography:
Christopher S Lange Associate Chair, Department of Radiation Oncology, SUNY Downstate Medical Center, Brooklyn (2010-Present), Professor of Molecular and Cell Biology, School of Graduate Studies, SUNY Downstate Medical Center (1992-Present), Professor, Director, Radiobiological Division, Department of Radiation Oncology, SUNY Downstate Medical Center (1980-Present), Associate Director, Residency Program, SUNY Downstate Medical Center (2009), Assistant Professor of Radiology, Radiation Biology and Biophysics,, University of Rochester School of Medicine and Dentistry, New York (1969-1980), NHS Senior Research Officer, Christie Hospital and Holt Radium Institute, Manchester, England (1968-1969), NHS Research Officer, Christie Hospital and Holt Radium Institute, Manchester, England (1962-1968), MRC Research Assistant, Radiobiology Laboratory, Churchill Hospital, Headington, England (1961-1962).
Abstract:
We tested the cancer stem cell (CSC) hypothesis using the patented Hybrid Spheroid (HS) Assay (HSA) and by applying Koch’s postulates to test its validity. The HSA is an in vitro assay that enables one to take a viable sample of an individual patient’s tumor, make a single cell suspension, mix it in known proportions with human fibroblasts (AG1522) and dispense a known number of cells of the mixture into each well of ultra low attachment (ULA) 96-well plates to agglomerate into 1 HS/well, each containing an average of <1 CSC. The HS provides an analog of the CSC niche, enabling the CSC to proliferate (with some daughters differentiating into amplifying transit cells (ATCs)) and undergo 10–15 symmetric divisions before exhausting the nutrients. This satisfies the McCulloch and Till (spleen colony assay) requirements for a stem cell. Applying Koch’s postulates, we answer the following questions: Does the patient’s tumor contain cells with CSC properties?; Can we isolate and propagate these cells?; Can these cells induce the tumor in vivo?; Do these cells contain and express specific gene products that give them CSC properties?; If we disrupt these genes, do the cells lose their CSC properties?; If we eliminate the CSCs do we eliminate the cancer? The HSA was applied to tumor samples taken from individual endometrial adenocarcinoma patients and correctly predicted, based on CSC radioresistance, in patients who fail their standard-of-care treatments. It was therefore concluded that the CSC hypothesis is validated in the HSA.
- Clinical Oncology | Chemotherapy | Cancer Screening
Location: Olimpica 1
Chair
Jaime Tisnado
Virginia Commonwealth University, USA
Co-Chair
Kang-Yell Choi
Yonsei University, South Korea
Session Introduction
Shraga Shany
Ben-Gurion University of the Negev, Beer Sheva, Israel
Title: The effect of ionizing radiation on prostate cancer cells is effectively potentiated by pretreatment with the active metabolite of vitamin D and sodium valproate
Time : 12:00-12:30
Biography:
Shraga Shany is a Faculty Member at the Department of Clinical Biochemistry and Pharmacology at the Faculty of Health Sciences in Ben-Gurion University of the Negev, Beer Sheva, Israel. His main research interest is in the field of vitamin D. His studies and publications include the topics of vitamin D status and metabolism in uremia, in rickets, in fracture healing and in the elderly, as well as the auto/paracrine mode of action of 1, 25-dihydroxyvitamin D in inflammatory cells. Recently, his studies are concentrated on the anti-carcinogenic activities of the active metabolite vitamin D, and its analogs, alone, and in combination with other drugs and radiotherapy. He has more than 140 peer reviewed publications with more than 3000 citations. He is teaching Clinical and Basic Biochemistry in the School of Medicine at Ben-Gurion University.
Abstract:
Ionizing radiotherapy (IR) is known to be an effective treatment of prostate cancer, as well as for other types of cancer. However, this treatment causes many severe side effects. On the other hand, recent studies demonstrate the anti-carcinogenic activity of the active metabolite of vitamin D, namely 1, 25 dihydroxyvitamin D3 (1, 25(OH)2D3). The aim of this study was to try to develop cancer–sensitizing pretreatments that may potentiate the therapeutic effect of IR. Such achievement will allow the use of lower radiation doses and limit its side effects. Toward this aim, we have incubated in vitro prostate cancer cells treatment with 1, 25(OH)2D3 alone, or with combination with other anti-carcinogenic drugs, such as sodium valporate (VPA) before IR. The results show that while IR alone (4Gy) of DU145 line of prostate cancer cells decreased cell proliferation by 30.6%, IR after pretreatment with 100nM 1, 25(OH)2D3 and 1 mM VPA, efficiently suppressed cell proliferation by 87.9% (p<0.0001). At the same time the combined pretreatment increased the DNA double-strand breaks by 58.1%, as compared to 11.8% in radiated cells without the pretreatment (p<0.002). The combined pretreatment enhanced IR induced cell cycle s-phase arrest and cell apoptotic death. The results support our highly efficient in increasing the effect of the anti-carcinogenic activity of IR. Usage of such pretreatment would increase the therapeutic effect of IR and may allow the use of lower doses of IR with less severe side effects.
Howon Seo
Korea Advanced Institute of Science and Technology, South Korea
Title: In vivo quantitation of circulating tumor cells with high-speed confocal microscopy in mouse tumor model
Time : 12:30-13:00
Biography:
Howon Seo is pursuing an Integrated Master’s and Doctoral Degree program at Korea Advanced Institute of Science and Technology in South Korea. He completed his Bachelor’s Degree in Biochemistry and has worked in intravital imaging of circulating tumor cells with high-speed confocal microscopy. He is interested in the study of cancer metastasis and metastatic cancer therapy.
Abstract:
The circulating tumor cells (CTCs) have been considered as a seed for cancer metastasis and the level of CTCs in metastatic cancer patients has been considered as a valuable indicator for predicting the grade of cancer metastasis, efficacy evaluation of anti-cancer therapy, and potential early diagnosis of cancer recurrence. Currently, ex vivo isolation of CTCs based from a peripheral blood sample has been a major strategy for the quantitation of CTCs. However, accurate quantitation of rare CTCs, as few as 1~2 cells per ml of blood sample in patients with metastatic cancer, is technically challenging and suffers extremely low sensitivity. These limitations can be overcome by using intravital flow cytometry which provides direct detection and quantitation of circulating cells in blood flow. For direct observation of fast-flowing cancer cells in the bloodstream, a custom-built high-speed video-rate laser-scanning confocal microscope system was implemented. After the intravenous injection of cancer cells and long circulating reference cells such as red blood cells (RBCs), a dynamically changing number of circulating cancer cells and RBCs was continuously monitored by real-time imaging. By extracting the calibration factor from hemocytometric imaging analyses with intravenously injected RBCs, we could estimate the level of intravenous injected CTCs in the whole blood of a mouse. To evaluate the degrees of cancer metastases with in vivo CTC-quantitation approach, an orthotopic tumor mouse model was used. The dynamic change of metastatic CTC-level was observed during a few hours and the longtitudinal change of metastatic CTC was monitored in a single mouse, in vivo.
Ning Deng
Jinan University, China
Title: A new disulfide-stabilized diabody against bFGF and the inhibition of cancer
Time : 14:00-14:30
Biography:
Ning Deng has his expertise in antibody drug and tumor polypeptide vaccine around tumor angiogenesis inhibition. He has established antibody design and construction system, included the phage antibody library, affinity maturation and improvement based on antibody structural simulation, evaluation system for tumor peptide vaccine. He also researched on the mechanism of tumor angiogenesis in ovarian cancer and stem cell evaluation.
Abstract:
Angiogenesis plays a critical role in tumor growth. Fibroblast growth factor-2 (FGF-2) is one of the most important angiogenic factors. The over-expression of bFGF plays a crucial role to promote tumor growth, progression and metastasis. Neutralizing antibodies against FGF-2 may suppress the growth of tumor cells by blocking the FGF-2 signaling pathway. In our lab, we scanned human anti-bFGF antibody from the phage antibody library. The results showed that the human anti-bFGF antibody could significantly inhibit the tumor angiogenesis and inhibit the tumor growth and migration. Based on this antibody, a newly small molecular antibody of disulfide-stabilized diabody (ds-Diabody) against bFGF was constructed by site-directed mutation and overlap extension PCR (SOE-PCR) at the position of VH44 and VL100 in the scFv. The ds-Diabody was expressed in Pichia pastoris system. We found that the ds-Diabody against bFGF could maintain good antigen binding activity and stability in vitro and in vivo. The ds-Diabody against bFGF could efficiently suppress the proliferation, migration and invasion of human lung cancer (A549 cells) and breast cancer (MCF-7 cells), inhibit bFGF-induced activation of downstream signaling regulators, phospho-Akt and phospho- MAPK. In the nude mouse xenograft model, the ds-Diabody against bFGF could significantly inhibit tumor growth, tumor angiogenesis and lymphangiogenesis. The ds-Diabody against bFGF showed stability in vivo and could more effectively suppress the tumor growth through blockade of bFGF signaling pathway and inhibition of tumor angiogenesis, which may make it a potential therapeutic candidate antibody drug for human lung cancer therapy.
Sercan Ergun
Ordu University, Turkey
Title: Through which pathway does trastuzumab and miR-122-5p combinatorial administration lead breast cancer cells to apoptosis: intrinsic or extrinsic pathway?
Time : 14:30-15:00
Biography:
Statement of the Problem: In most of breast cancer cells, HER2 receptors are known to be cleaved by an ectodomain sheddase, ADAM10, to liberate HER2 extracellular domain (ECD). This provides ligand-independent growth to breast cancer cells and trastuzumab, anti-HER2 agent, cannot inactivate HER2 by binding ECD portion of it. In our previous studies, we found that miR-122-5p, miRNA targeting ADAM10, and trastuzumab combinatorial administration to HER2-positive breast cancer cell line, SKBR3, increases the efficiency of trastuzumab by leading SKBR3 cells to apoptosis more through blocking the sheddase activity of ADAM10 on HER2. The aim of this study is to display that miR-122-5p, together with trastuzumab, leads SKBR3 cells apoptosis by which pathway: intrinsic or extrinsic.
Methodology & Theoretical Orientation: SKBR3 cells were first transfected with the miR-122-5p mimic for 48 hours. Then, 0.5 μM trastuzumab was applied to miR-122-5p-transfected SKBR3 cells and non-transfected SKBR3 cells for 24 hours. Next, the expression levels of CASP3, CASP8 and CASP9 genes, which are key molecules in apoptotic pathway, were examined by real-time PCR.
Findings: Expression levels of CASP3 and CASP8, but not CASP9, increased significantly in miR-122-5p-transfected Trastuzumab-administered SKBR3 cells when compared to non-miR-122-5p transfected Trastuzumab-administered SKBR3 cells. A significant increase in the expression level of CASP8 with CASP3 showed apoptosis to be activated via extrinsic pathway (instead of the mitochondrial intrinsic pathway regulated by CASP9) with the effect of miR-122-5p in trastuzumab-administered SKBR3 cells.
Conclusion & Significance: Consequently, the apoptosis enhancing effect of trastuzumab and miR-122-5p combinatorial administration through extrinsic pathway may be presented as a new treatment option for HER2+ breast cancer.
Abstract:
Sercan Ergun is working as Teaching Assistant in Ordu University and is about to finish his PhD in Department of Medical Biology and Genetics of Ondokuz Mayıs University. He was included as Researcher in a team studying briefly epigenetic changes in disease mechanisms of different types of cancers, including oncogenic/tumor suppressor gene and miRNA expression level changes, cell death mechanism analysis, development of some cancer therapy agents’ efficiencies via miRNAs. Now, he is part of a team studying in silico miRNA and ceRNA analysis, miRNA heterogenetiy, piRNA expression changes in different cancer types, especially urological cancers. He has many published many articles related to these studies. He and his team have conducted many studies on different diseases other than cancer, like Glanzmann's thrombasthenia, hemophagocytic lymphohistiocytosis, immune thrombocytopenic purpura, familial mediterranean fever, βeta (β)-thalassemia, secondary hyperparathyroidism and he has many other articles on them.
Ewa L Gregoraszczuk
Jagiellonian University, Poland
Title: Leptin receptor antagonist as a potent histone deacetylases (HDACs) inhibitor in ovarian cancer cells
Time : 15:00-15:30
Biography:
Ewa L Gregoraszczuk specializes in Reproductive Endocrinology as well as Hormone Dependent Cancer. She graduated from the Jagiellonian University in Krakow, Poland. From 1998, she has been the Professor of Endocrinology, Head of Department of Physiology and Toxicology of Reproduction. She has authored 173 peer-reviewed articles in leading journals such as Biology of Reproduction, Reproduction, Reproductive Toxicology, Toxicology, Cancer Chemotherapy and Pharmacology. She is a Member of the Polish Endocrinology Society, International Society of Endocrinology (ISE), The New York Academy of Sciences, and The European Tissue Culture Society. She has been a Promoter for 60 MD, 16 PhD and 3 Habilitations. Her research topics are focused on the effects of metabolic hormones produced by adipose tissue in light of the increasing incidence of obesity and related problems in reproduction and hormone dependent cancer; reprotox and canceriogenic action of endocrine disruptors, testing antiepileptic drugs as a potent anticancer in combination with chemotherapy; testing leptin receptor blockers as a novel treatment for ovarian cancer.
Abstract:
Post-translational histone modifications can play an important role in the cancer development. Leptin, produced by adipose tissue has been identified as a growth factor in certain hormone related cancers including ovarian cancer. Currently, several groups of scientists are working on synthesizing leptin receptor blockers, and number of leptin receptor antagonist were tested in breast, colon and prostate cancer, suggesting their future use in anticancer therapy. The question arises whether the leptin receptor blockers may also act as inhibitors of HDAC in ovarian cancer. As a model we used the epithelial ovarian cancer (chemoresistant-OVCAR-3 and primary-CaOV-3) and folliculoma (adult –KGN and juvenile- COV434) cell lines. Two antagonists: superactive human leptin antagonist-SHLA and quadruple leptin mutein -LAN 2 (L39A/D40A/F41A/I42A have been applied. Particular cell lines were treated with leptin in a dose of 40 ng/ml (noted in obese women) and antagonist in a dose 1000 ng/mL Effect of blockers on HDACs (1,2,3,4,5,6 7,8,9) gene (real time PCR) and protein expression (western blot) were tested, HDACs expression was higher in OVCAR-3>CaOV-3, and higher in COV434>KGN. Leptin increased HDAC 1, 7 and 9 gene expression only in OVCAR-3, while in granulosa tumour cells increased HDAC 2, 6, 7 in KGN and 9 in COV434. SHLA was the most potent HDACs inhibitor in OVCAR-3 cells and reversed stimulatory effect of leptin on HDAC1, 9 gene, and HDAC4, 5 protein expressions. In granulosa tumor cells, Lan-2 seemed to be most potent inhibitor. Reversed stimulatory effect of leptin on HDAC9 gene expression and HDAC 1, 5 protein expression in COV434 cells in KGN cell line both antagonist reversed stimulatury effect of leptin on HDAC 5, 6, 7. It was concluded that leptin receptor antagonist as HDACs inhibitors should be emerged as an exciting new class of potential anticancer agents. However, histopatological type of cancer should be taken into consideration in the choice of leptin receptor inhibitors.
Ibrahim Khalifeh
American University of Beirut Medical Center, Lebanon
Title: Comparing BRAF mutation status in corresponding primary and metastatic cutaneous melanomas: Implications on optimized targeted therapy
Time : 15:30-16:00
Biography:
Ibrahim Khalifeh After earning his MD from Damascus Medical School in 1999, completed a surgery internship (2000-2001) and pathology residency (2001-2002) at American University of Beirut Medical Center. In 2002, he left for the USA where he did four years of training in Pathology and Laboratory Medicine at Wayne State University in Detroit (2002-2006), Oncologic Pathology and Cytopathology fellowships at MD Anderson Cancer Center (2006-2008) then he joined the University of Alabama where he completed one year of fellowship in Dermatopathology (2008-2009). Dr. Khalifeh is a diplomat of the American Board of Anatomic and Clinical Pathology, Cytopathology and Dermatopathology. He joined the Department of Pathology and Laboratory medicine at AUBMC in 2009 as assistant professor. He has been involved in multiple projects related to cutaneous leishmania, melanoma, dysplastic nevi and BRAF.
Abstract:
Background: Selective oral BRAF inhibitors show promising results in the treatment of metastatic melanomas. Consequently, this mandates checking the concordance of BRAF status in primary (PM) and metastatic (MM) melanomas to optimize individual targeted therapy.
Design: Extended BRAF testing for 9 mutations on 95 lesions from 40 patients (men/women: 27/13; age= 59 13 years) including 40 PM with their corresponding MM (n=42), recurrences (n=9) and second primaries (n=4) was performed. Multiple metastatic sites were present in 9 patients [2 sites (n=6), 3 sites (n=2) and 4 sites (n=1)].
Results: BRAF mutation status was obtained for 85/95 (89.5%) lesions. V600E was the only identified mutation type documented in 35.4% of PM vs. 18.9% of MM. The overall PM-MM BRAF status discordance rate was 32.3% (11/34), and this was significantly more frequent in PM with mutant BRAF (8/12; 67%) versus PM with wild-type BRAF (3/22; 14%, p=0.005) Patients with metastasis to lymph nodes (3/20; 15%) were less likely to be discordant compared to those with metastasis to other sites (8/14; 57.1%, p=0.023). Females (7/13; 53.8%) were more likely to have discordant PM-MM BRAF status than males (4/21; 19%, p=0.06). Patient age was similar in patients with concordant and discordant BRAF status (58 13 vs. 62 14 years; p=0.41). PM anatomic location (p=0.23) and time-to-metastasis (p=0.55) were also unrelated to PM-MM BRAF mutation discordance. Discordant BRAF mutation status was predicted by multivariate binary logistic regression: 1) the presence of a mutant BRAF in PM [OR (95% C.I.) = 23.4 (2.4-229.7)] and 2) male gender [OR = 0.094 (0.01-0.93)]. MM-MM BRAF concordance was available for 6 possible comparisons and displayed a 100% concordance rate.
Conclusion: A high discordant rate implies the need for re-testing of the MM before initiation of BRAF targeted therapy. High MM-MM concordance advocates that testing the most accessible metastatic site is sufficient to obtain accurate BRAF mutation status.