Day 1 :
National Cancer Institute, USA
Keynote: Identification of novel epigenetic targets in lung cancer using an induced pluripotent stem cell model
Time : 10:00-10:35
David S Schrump is a Surgical Chief who oversees clinical and translational research pertaining to thoracic and gastrointestinal malignancies, including the development of innovative molecular approaches to the diagnosis and treatment of these neoplasms.
He has pioneered the development of epigenomic therapies for thoracic cancers. Using unique in vitro models and correlative experiments with surgical specimens, he has characterized epigenetic responses to tobacco carcinogens, and identified novel therapeutic targets in lung and esophageal cancers and pleural mesotheliomas. His clinical protocols have demonstrated that chromatin remodeling agents simultaneously induce growth arrest and augment immunogenicity of thoracic malignancies; these efforts have provided rationale for combining epigenetic regimens with immunotherapies for these neoplasms.
Background: Lung cancers remain leading causes of cancer-related deaths in males and females worldwide. Despite extensive research efforts, the genetic and epigenetic mechanisms which mediate initiation and progression of these neoplasms have not been fully elucidated. In the present study, we utilized an induced pluripotent stem cell (iPSC) model to investigate epigenetic mechanisms potentially contributing to stemness/pluripotency in lung cancers, and identify novel targets for treatment of these malignancies.
Methods: iPSC were generated from normal human small airway epithelial cells (SAEC) by lentiviral transduction of Yamanaka factors. Immunofluorescence, immunoblot, qRT-PCR, spectral karyotyping, RNA-seq, ChIP-seq, and DNA methylation array techniques were used to characterize the Lu-iPSC. Murine xenograft experiments were used to confirm pluripotency of LuiPSC, and examine in-vivo effects of target gene knock-down.
Results: Lung iPSC (Lu-iPSC) exhibited hallmarks of pluripotency including morphology, surface antigen and stem cell gene expression, in-vitro proliferation, and teratoma formation. Additionally, Lu-iPSC exhibited no chromosomal aberrations, complete silencing of reprogramming transgenes, genomic hypermethylation, up-regulation of genes encoding components of PRC2, hypermethylation of stem cell polycomb targets, and modulation of more than 15,000 other genes relative to parental SAEC. Additional Sex Combs Like-3 (ASXL3), encoding a PRC2 associated protein not previously described in reprogrammed cells, was markedly up-regulated in Lu-iPSC as well as human small cell lung cancer (SCLC) lines and specimens. Knock-down of ASXL3 inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and significantly diminished in-vitro clonogenicity and growth of SCLC cells in-vivo.
Conclusions: These studies highlight the potential utility of our Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis. Our findings support further evaluation of the mechanisms and clinical implicationsof ASXL3 up-regulation in SCLC, and the evaluation of novel pharmacologic regimens targeting ASXL3 for treatment of these highly lethal neoplasms.
deCODE genetics, Iceland
Keynote: The epigenetics of common diseases
Time : 10:35-11:10
Kári Stefánsson, M.D., Dr. Med. has served as President, Chief Executive Officer and a Director since he founded deCODE genetics in August 1996. Dr. Stefánsson was appointed the Chairman of the Board of Directors of deCODE genetics in December 1999. From 1993 until April 1997, Dr. Stefánsson was a professor of Neurology, Neuropathology and Neuroscience at Harvard University.
From 1983 to 1993, he held faculty positions in Neurology, Neuropathology and Neurosciences at the University of Chicago. Dr. Stefánsson received his M.D. and Dr. Med. from the University of Iceland and is board-certified in neurology and neuropathology in the United States.
He has published numerous articles on the genetics of common/complex diseases and has been among the leaders of the world in the discovery of variants in the sequence of the human genome that associate with the risk of common/complex traits.
Dr. Stefánsson was chosen by Time magazine as one of the 100 most influential men of the year for 2007 and by Newsweek as one of the 10 most important biologists of the 21 century. He was the recipient of the Jakobus Award 2007, The World Glaucoma Association Award for present scientific impact 2007, The European Society of Human Genetics Award 2009, and The Andre Jahre Award 2009.
Royal College of Surgeons of Edinburgh, UK
Alyssa Alabassi is a British entrepreneur and UK trained and qualified practicing surgeon with extensive knowledge of the various layers of the health system in UK. She worked in an Advanced Computation Laboratory at Cancer Research UK devising IT solution for connected and integrated care pathways.
She chaired international business meetings on Big Data, Population Based Solutions, Predictive Analysis and Connected Objects.
Her research interest is in Breast Cancer and Familial Breast Disease and has successfully setup prevention clinics for patients at high risk of developing breast cancer.
As healthcare providers, we are trained to treat the symptoms and causes of disease. This may involve prescribing medications or surgically intervening to aid that process. We study the anatomy and physiology of both brain and body, together with the disease process and the drugs we need to prescribe in our endeavor to do that.
Our approach is traditionally reactive rather than proactive. Oftentimes, we are too late in our attempts to impede or halt an illness. Prevention is something we advocate but not heavily invest in. This is primarily because we are traditionally trained in the principles of evidence-based factual medicine and prevention had largely been perceived as anecdotal. There is however a shift in this attitude, which is mainly patient-driven.
In this age of technology and the wide availability of information, there is an increasing awareness that firefighting is no longer sufficient, particularly from the “at-risk” population who’s only available resource was disease-screening aimed at early-detection rather than arresting/ reversing the disease process. Patients are no longer satisfied with waiting to become ill for intervention to take place. The principles of epigenetics teach us that disease causation is multi factorial; therefore, preventative measures should take into account risks that are specific to an individual.
The design of a personalized risk assessment tool to institute successful preventive measures is becoming paramount. To be effective, the acquisition of data encompassing not only familial history and personal medical history but early-life stressors, acquired personal habits, life-style choices and diet should become part of the everyday medical practice since their modulation is key to prevention.
The processing of this data, not just for research and education but to produce technological predictive tools tailored to the individual is what our patients are calling for.