Day 1 :
Keynote Forum
Amy H Tang
Eastern Virginia Medical School, USA
Keynote: Developing therapy-responsive prognostic biomarkers, and conquering undruggable oncogenic k-ras-driven pancreatic cancer by attacking its major k-ras vulnerability and the k-ras signaling gatekeeper – the siah proteolysis machinery
Time : 10:00-10:45
Biography:
Amy H Tang received a BS in Biophysics from Fudan University, and a PhD in Biochemistry and Molecular Biology from Pennsylvania State University. She completed her Post-doctoral training supported by two Post-doctoral fellowships, (1) NIH Post-doctoral fellowship and (2) Leukemia and Lymphomia Society (LSA) Senior Post-doctoral Fellowship at UC Berkeley. She is a Professor of Cancer Biology at Eastern Virginia Medical School. She is a lead Pancreatic Cancer Researcher and a Recipient of the highly prestigeous national cancer award – 2010 AACR-PanCAN Innovative Award. She and her research team have developed an innovative strategy and therapy-responsive prognostic biomarkers to control and eradiacte oncogenic K-RAS-driven pancreatic cancer in preclinical and clinical settings. She has published numerous papers in peer-reviewed journals, and secured NIH/DOD/AACR-pancreatic cancer action network innovative grant/lustgarden foundation for pancreatic cancer research. She has served as reviewers at multiple NIH study sections for more than 10 years, and has served as the Editorial Advisory Board Member and reviewer of numerous scientfic journals.
Abstract:
Hyperactive K-RAS signaling is a major menace that drives aggressive cancer cell dissemination, tumor progression and systemic metastasis in human pancreatic cancer. Counteracting K-RAS hyperactivation in attempt to reverse malignant transformation and inhibit latent tumor spread is an important goal in pancreatic cancer biology. Instead of targeting an upstream signaling module such as EGFR/K-RAS/B-RAF/MEK/MAPK/ERK/AKT/mTOR, we targeted the most downstream signaling module in the K-RAS signaling pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of seven-in-absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical gatekeeper required for proper K-RAS signal transduction. We found that inhibiting SIAH function is highly effective to abolish well-established and late-stage pancreatic tumor growth and metastasis in our pre-clinical studies. These findings demonstrate that SIAH is indeed an attractive, logical and potent anti-K-RAS therapeutic target for us to develop new and effective anticancer strategy against human pancreatic cancer. Through our work, SIAH has emerged as a new and effective drug target against oncogenic K-RAS hyperactivation in pancreatic cancer. As one of the most evolutionarily conserved signaling components, SIAH is ideally and logically positioned to become a next-generation anti-K-RAS drug target in human pancreatic cancer. By attacking this most downstream gatekeeper critical for the proper oncogenic K-RAS signaling transmission, we will be in a position to halt the genesis, progression and metastasis of the deadliest forms of human pancreatic cancer in the future. We aim to translate anti-SIAH therapy to benefit our pancreatic cancer patients in the clinic.
- Special Session
Session Introduction
Sorah Yoon
Beckman Research Institute of City of Hope, USA
Title: Targeted therapeutics in pancreatic cancer for precision medicine
Time : 11:15-12:00
Biography:
Sorah Yoon has completed her PhD from Seoul National University, South Korea and Post-doctoral studies from Beckman Research Institute of City of Hope, USA. She is Staff Scientist of Department of Molecular and Cellular Biology at Beckman Research Institute of City of Hope. She has published more than 19 papers in reputed journals, one book chapter, and 15 patents including USA patents. She was awarded numerous travel awards including Meritorious Abstract Travel award in ASGCT, 2015 and travel award in OTS, 2016. She was also invited as a speaker to drug delivery conferences in China and Malaysia.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies and the 4th leading cause of cancer-related deaths in North America. The survival rate remains less than 5% at 5 years taking into account all stages of the disease. In contrast to other cancer types, the mortality rate of PDAC is increasing, with PDAC being predicted to become the second leading cause of cancer-related mortality by 2020. Despite great efforts to improve the treatment and outcome of patients with PDAC, limited progress has been made. Still, current therapeutic options are very disappointing. Genetic mutaions of tumor supperssor genes have been well characterized in pancreatic cancer. However, the pathophysical progression of PDAC doese not always correlate with these genetic changes, suggesting the possibility that unidentified genetic alterations or epigenetic factors might be involved in the progression of pancreatic maligancy. The loss of heteozygosity of lysine demethylase (KDM6B) encoding histone demethylase makes pancreatic cancer epigenetically silenced in the downstream target of CCAAT/enhancer binding protein alpha (C/EBPα), strong anti-proliferator by affecting p21, a cyclin-dependent kinase (CDK) inhibitor. The decreased expression of KDM6B and C/EBPα is well-correlated through the malignant progression of PDAC. For the precision medicine in pancreatic cancer, to activate the silened gene of C/EBPα for the therapeutics, small activating RNA(saNRA) to C/EBPα is developed. For targeted delivery of C/EBPα, RNA aptamers have been isolated via cell-SELEX, that showed the pancratic cancer cell specificity. The isolated RNA aptamers have been conjugated with C/EBPα-saRNA as targeting modalities. The targeted delivery of the C/EBPα-saRNA conjugates showed the increased expressionof C/EBPα in vitro with translational and transcriptional level. In vivo assay, the targeted delivery of C/EBPα-saRNA conjugates significantly inhibited the tumor growth without toxicity. Using pancreatic cancer specific aptamers, to reduce the non-specific absorption of cytotxic drugs in normal cells, aptamer-drug conjugates (ApDCs) were constructed with active metabolites of prodrugs, gemcitabine and 5FU, and chemotoxins, MMAE and DM1. The ApDCs with gemcitabine and 5FU showed the significant anti-prolieraction effects by inducing double-strand breask in nuclear without affecting non-targeting cells. Also, The ApDCs with MMAE and DM1 showed the stong anti-prolieraction effects by arresting the cycle without the cytotoxicity in non-targeting cells. Taken together, our studies prove the therapeutic strategies for precision medicine in pancrearic cancer by following firstly, targeting somatic mutaions for therapeutics and secondly, aptamer mediated targeted delivery of theapeutics with minimizing the side effects in normal cells.
- Pancreatic Cancer Treatment | Pancreatic Diseases & Disorders
Session Introduction
Gregory David
New York University School of Medicine, USA
Title: Targeting senescence associated inflammation to prevent pancreatic cancer progression
Time : 12:00-12:30
Biography:
David G, PhD, is an Associate Professor of Biochemistry and Molecular Pharmacology at NYU School of Medicine. He received Graduation degree in Molecular Biology from the Pasteur Institute in Paris, studying the bases for acute promyelocytic leukemia. He then did his Post-doctoral work at the Dana Farber Cancer Institute, studying the interplay between chromatin modifiers and cancer using mouse models. His laboratory currently investigates the impact of epigenetic processes in early stages of prostate and pancreatic cancer progression. Recently, his work has focused on the contribution of chromatin modifiers on cell fate decisions, including cellular senescence, as modulators of tumorigenesis, and by inference the identification of epigenetic pathways that can serve as therapeutic targets to prevent cancer progression.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is virtually invariably a fatal disease, and is characterized by invasive and metastatic progression, as well as a striking resistance to conventional therapeutic approaches. In addition, recent reports have demonstrated that inflammation is a key component of precancerous lesion initiation and progression. However, the downstream events linking oncogenic activation KRAS to inflammation are not yet fully understood. Here, we report that the chromatin associated Sin3B co-repressor, previously shown to be required for oncogene induced senescence, promotes KRAS driven pancreatic lesions formation and progression in the mouse. At the molecular level, Sin3B is necessary for KRAS induced or chemically-induced inflammation of the pancreas. Importantly, we have now extrapolated these results to pancreatic human cells and have correlated Sin3B expression levels and inflammation in pre-neoplastic and neoplastic human pancreatic samples. Together, these results point to an unexpected tumor promoting function of senescence associated secreted cytokines. Furthermore, our preliminary results indicate that senescence-associated inflammation depends on the activation of the Interleukin (IL)-1alpha pathway. Thus, we have tested the impact of targeting this pathway in a mouse model of pancreatic cancer and will present the outcome of this study. Together, these studies indicate that senescence and its associate may represent potent therapeutic targets for the prevention of pancreatic cancer and other inflammation-driven cancers.
Dong Tang
Clinical Medical College of Yangzhou University, China
Title: High expression of galectin-1 in pancreatic stellate cells increases the progression of pancreatic cancer
Time : 12:30-13:00
Biography:
Dong Tang has completed his PhD from Nanjing Medical University and Post-doctoral studies from Nanjing University of Medicine. He is a Supervisor and Assistant Chief Physician of Clinical Medical College of Yangzhou University (Subei People's Hospital of Jiangsu Provinc). He got a chance of being Visiting Scholar in the National Cancer Center in Japan from December 2012 to January 2013. He has published more than 20 papers in reputed intanational journals.
Abstract:
Pancreatic cancer is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated pancreatic stellate cells (PSCs) and PDAC cells plays an important role in the development of PDAC. By producing high levels of cytokines, chemotactic factors, growth factors and excessive extracellular matrix (ECM), PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of PDAC. Our founding suggested that Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells, and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage short survival. High expression in PSCs contributes to immune privilege in the pancreatic cancer microenvironment by enhancing apoptosis and anergy of T cells and skewing the Th1/Th2 cytokine balance. Further more, TGF-β1 from pancreatic cancer cells upregulated Galectin-1 expression in PSCs, and in turn to promotes the proliferative activity, MMP2 and MMP9 expression, and invasion of pancreatic cancer cells, as well as the tumor establishment, growth, and liver metastasis. High expression of Galectin-1 in pancreatic stellate cells may provides a therapeutic target for the treatment of pancreatic cancer.
Sally Hodges
University of Kentucky Markey Cancer Center, USA
Title: Pancreatic cancer, the most lethal cancer today
Time : 14:00-14:30
Biography:
Sally Hodges is currently working in a University of Kentucky Markey Cancer Center, USA
Abstract:
Pancreatic cancer is the most aggressive, most lethal cancer in medicine today. The American Cancer Society has estimated that there will be 53,670 new diagnoses of pancreatic cancer and 43,090 deaths in 2017. Those numbers will propel pancreatic cancer to the number three cancer killer, which spot has been held by breast cancer for many years. The overall 5-year survival is less than 10%, but in patients who have received curative resection, the 5-year survival extends to 20%. Pancreas Cancer Action Network has estimated that as a result of the aging population, it will be the number 2 cancer killer by 2025, second only to lung cancer. It has long been accepted that pancreatic cancer is a disease of the elderly. However, there is a subset of much younger individuals who are being diagnosed well before the age of 60. It appears that approximately 10-15% of all individuals diagnosed with pancreatic cancer are below the 60-year-old assumed minimum. The objective of this study is to determine whether there are common genetic mutations, common risk factors, or common past medical factors. The common risk factors in older patients are age and coronary artery disease, but younger patients would not have these diseases. It is important to determine what the younger onset individuals have in common. This will be a secondary analysis of genomic data in the largest cohort of pancreatic cancer patients ever assembled to ferret out the similarities and differences between early onset and normal onset of pancreatic cancer.
- Pancreas | IPMN pancreas | Pancreas Transplantation | Advanced Pancreatitis Treatment
Session Introduction
Pradeep Kumar Vaitla
University of Mississippi Medical Center, USA
Title: Pancreas Transplantation
Time : 14:30-15:00
Biography:
Pradeep Kumar Vaitla has completed his Medical School from Osmania Medical College, India and Internal Medicine Residency from Texas Tech Univeristy followed by Nephrology Fellowship at Ochsner Clinic in New Orleans and later Transplant Nephrology Fellowship at Emory University, Atlanta. He has served as Living Donor Kidney Program Director and is currently serving as Medical Director for Kidney- Pancreas Trasnplantation at University of Mississippi Medical Center, Jackson, MS. He is an active member of the American Society of Nephrology, the American Society of Hypertension and the American Society of Transplantation. He is the author or coauthor of 13 abstracts in peer-reviewed professional publications.
Abstract:
Objective of the talk is to discuss the evaluation of potential pancreas transplant reciepients, transplant lisitng criteria from UNOS (United Network of Organ Sharing), early and late complications of pancreas transplantation, immunosuppression and bascis of allograft rejection, treatment of pancreas rejection and combined kidney-pancreas transplantation. Presented information will be collected from UNOS guidelines, highly respected and peer reviewed journals like American Journal of Transplantation (AJT), Clinical Journal of the American Society of Nephrology (CJASN), Transplantation, American journal of kidney diseases (AJKD) and established medical facts.
Pamela L Paris
University of California San Francisco, USA
Title: Circulating biomarkers for early detection of pancreatic cancer
Time : 15:00-15:30
Biography:
Pamela L Paris, PhD, received her undergraduate degree from John Carroll University, where she obtained a degree in Chemistry magna cum laude. She was awarded two fellowships, the Sherman Clarke Fellow and Merck Fellow, while conducting her advanced education in Biophysical Chemistry at the University of Rochester. Upon completion of her PhD, she did a Post-doctoral fellowship at the Cleveland Clinic in Prostate Cancer Genetics. She joined the Department of Urology in 2001 as an Associate Researcher, received support from the Prostate Cancer Career Development Program from 2001 to 2003, and was promoted to Associate Professor in the Department of Urology in 2009. She received a joint appoint in the Division of Hematology-Oncology in 2010 and was advanced to Professor in 2012.
Abstract:
Intraductal papillary mucinous neoplasm (IPMN) is a precursor cystic lesion to pancreatic cancer. With the goal of classifying IPMN cases by risk of progression to pancreatic cancer, we undertook an exploratory next generation sequencing (NGS) based profiling study of miRNAs (miRNome) in the cyst fluids from low grade-benign and high grade-invasive pancreatic cystic lesions. Thirteen miRNAs (miR-138, miR- 195, miR-204, miR-216a, miR-217, miR-218, miR-802, miR-155, miR-214, miR-26a, miR-30b, miR-31, and miR-125) were enriched and two miRNAs (miR-451a and miR-4284) were depleted in the cyst fluids derived from invasive carcinomas. Quantitative real-time polymerase chain reaction analysis confirmed that the relative abundance of tumor suppressor miR-216a and miR-217 varied significantly in these cyst fluid samples. Ingenuity Pathway Analysis (IPA) indicated that the genes targeted by the differentially enriched cyst fluid miRNAs are involved in five canonical signaling pathways, including molecular mechanisms of cancer and signaling pathways implicated in colorectal, ovarian and prostate cancers. Our findings make a compelling case for undertaking in-depth analyses of cyst fluid miRNomes for developing informative early detection biomarkers of pancreatic cancer developing from pancreatic cystic lesions.
Jose R. Torrealba
University of Texas Southwestern Medical Center, USA
Title: Acute cellular and antibody-mediated rejection of the pancreas allograft: Pathology, risk factors and outcomes
Time : 15:30-16:00
Biography:
Jose R Torrealba has completed his MD in 1994 from the Central University of Venezuela. He then did a Post-doctoral fellowship in Molecular Biology at the University of Wisconsin, in Madison, Wisconsin and obtained his degree in Anatomic and Clinical Pathology from the Univeristy of Wisconsin. He specialized in Immunopathology of Transplantation at the University of Toronto, Canada in 2005. He held a job as Assistant Professor of Pathology at the University of Wisconsin until 2010 and currently is the Dr. George and Anne Race Distinguished Professor of Pathology at the Department of Pathology, UTSW Medical Center in Dallas, Texas.
Abstract:
The histopathologic parameters associated with acute cellular rejection (ACR) of the pancreas allograft have been well defined and have undergone modifications over the years to reflect the latest diagnostic and prognostic updates. Antibody-mediated rejection, in the other hand, is a relatively recently identified entity that we are yet learning how to diagnose and manage. This presentation will cover both the latest Banff approved diagnostic criteria for ACR and AMR with emphasis on our own research findings on incidence, risk factors, pathologic diagnosis, treatment and outcomes of pancreas AMR. Briefly, we have found that pancreatic AMR occurred in about 10% of patients by 1-year post-transplant. The most important risk factors associated with AMR included non-primary simultaneous pancreas-kidney (SPK) transplant, primary solitary pancreas (PAN) transplant and race mismatch. After pancreas rejection, patient survival was 100% but 20% of pancreas grafts failed within one year. Graft survival after acute cellular rejection (ACR), AMR and mixed rejection was similar. Of biopsies that stained >5% for the AMR surrogate marker C4d, 80% were associated with increased Class I donor specific antibodies (DSA). AMR occurs at a clinically significant rate after pancreas transplantation, and the diagnosis should be actively sought by staining the allograft biopsy using C4d staining and screening for DSA levels in patients with graft dysfunction, especially after nonprimary SPK and primary PAN transplantation.
- Special Session
Session Introduction
Filipa Ribeiro Crespo Lucas
Hospital de Cascais, Portugal
Title: Critical acute pancreatitis
Time : 16:30-17:15
Biography:
Filipa Ribeiro Crespo Lucas has completed her Medicine Master degree from the University of Lisbon, Portugal. She is now working as a Physician at the Cascais Hospital, Portugal, where she has started her Internal Medicine Internship last January. Her master thesis was about the impact of tobacco and its components on the cervix cancer.
Abstract:
The critical acute pancreatitis (CAP) has recently emerged as the most sever acute pancreatitis. The shock is a complex pathophysiological process that often results in multiple organ dysfunction syndrome (MODS) and death. The MODS, though newly described, was observed in intensive care unit (ICU) patients for several decades. However, the cardiogenic shock-related acute pancreatitis is a rare event. A 53-year-old Caucasian man with a critical shock-related acute pancreatitis (distributive and hypovolemic/cardiogenic) was admitted in our ICU. He had a chronic pancreatitis medical history. He had alcohol drinking and cigarette smoking habits and a chronic HCV (serum anti-HVC antibodies were positive and serum RNA HCV was negative) history and past HBV infection (serum anti-Hbs and Hbc antibodies were positive and Ag Hbs were negative). The patient developed a cardiovascular, a renal (AKIN 3), respiratory MODS and a compartmental syndrome too. The patient recovered over a few days with invasive support by transpulmonary thermodilution, with a cardiogenic shock evolved to distributive shock, norepinephrine support, invasive-ventilation-support and dialysis (CRRT). Emergency operations were undertaken: A total colectomy (sigmoid ischemia) is an ileostomy and a cholecystectomy. Afterwards, after 5-months internment in the hospital, with some nosocomial infections, the clinic evolution was good enough for the patient to leave the hospital with hemodynamic stability. Patients with severe acute pancreatitis require intensive care. Within hours to days, a number of complications (e.g., shock, pulmonary failure, renal failure, gastrointestinal bleeding, or multiorgan system failure) may develop. The goals of medical management are to provide intensive supportive care, to limit infection and to identify and treat complications whenever appropriate.