“Biomarker Development” Workshop – April 10, 2014 Exeter Room, Marquis Hall, 97 Campus Drive, University of Saskatchewan Speaker #1 – 8:30 a.m. – 9:15 a.m. Dr. John C. Gore Hertha Ramsey Cress University Professor Director, Vanderbilt University Institute of Imaging Science Vanderbilt University Institute of Imaging Science AA1105 MCN 1161 21st Ave South Vanderbilt University Nashville, TN 37232‐2310 (615) 322‐8357 Email: john.gore@vanderbilt.edu Website: http://www.vuiis.vanderbilt.edu/personnel.php?group=1&email=john.gore The Emerging Role of Quantitative Imaging Biomarkers ‐ The development and applications of quantitative imaging biomarkers dominate much of current biomedical imaging science. Imaging biomarkers have grown in their diversity and impact, and are of particular importance in the evaluation of novel drugs and treatments. Imaging biomarkers may be arbitrarily classified as reporting on composition, metabolism, physiology, biophysics, structure or cellular and molecular properties. In cancer, molecular imaging using PET and optical methods report directly on cellular events and characteristics, and are complemented by MRI, CT and US methods that measure downstream effects such as changes in tumor volume, cell density, tissue vascular properties and blood flow. These are being applied in evaluating new drugs and in clinical trials, and are proving useful in cancer management, especially to evaluate treatment response. Integrating multiple data sets from different modalities such as PET and MRI can provide a more comprehensive view of tumor metabolic and physiological state. In neuroscience, quantitative brain morphometry is used to characterize and distinguish subject groups and identify structural variants in individuals which correlate with behavior and function. PET studies of neurotransmitters and their transporters are well established and provide direct evidence of whether drugs hit specific targets, along with their in vivo binding properties. Functional MRI based on BOLD (blood oxygen level dependent) signals provides unique insights into neural circuits and inter‐regional functional connectivities, which may be quantified to assess changes with treatment, development, degeneration or as an index of severity of disease. Pharmaceutical MRI uses similar measurements to evaluate the actions of drugs and specific signaling pathways in the brain. In diabetes and metabolic disorders, measures of tissue composition, physiology and metabolism provide quantitative indices of disease risk and progression. Overall, there are diverse biomarkers under development in many different areas of application in each modality, and these activities define much of the research in imaging science. Biography ‐ John C. Gore, Ph.D., holds the Hertha Ramsey Cress Chair in Medicine and is a University Professor of Radiology and Radiological Sciences, Biomedical Engineering, Physics and Astronomy, and Molecular Physiology and Biophysics, at Vanderbilt University. Dr. Gore obtained his Ph.D. in Physics at the University of London in the UK and also holds a degree in Law. He is a member of the National Academy of Engineering and an elected Fellow of the American Association for the Advancement of Science, the American Institute of Medical and Biological Engineering, the International Society for Magnetic Resonance in Medicine (ISMRM), the American Physical Society and the Institute of Physics (UK). In 2004 Dr. Gore was awarded the Gold Medal of the ISMRM for his contributions to the field of magnetic resonance imaging. He is also a Distinguished Investigator of the Academy of Radiology Research. He has served twice as an elected trustee of the ISMRM, is editor‐in‐chief of the journal Magnetic Resonance Imaging and is a member of the National Advisory Council on Biomedical Imaging and Bioengineering for NIBIB. He founded the pioneering MRI research program at Hammersmith Hospital in the UK in the late 1970’s prior to establishing and directing the MRI research program at Yale University from 1982‐2002. Since 1982 he has served as the founding director of the Vanderbilt University Institute of Imaging Science, a comprehensive, trans‐
institutional center that is engaged in multi‐modal research for biomedical applications. He has published over 600 original papers and contributions within the medical imaging field. His research interests include the development and application of imaging methods for understanding tissue physiology and structure, molecular imaging and functional brain imaging. 1 “Biomarker Development” Workshop – April 10, 2014 Exeter Room, Marquis Hall, 97 Campus Drive, University of Saskatchewan Speaker #2 – 9:15 a.m. – 10:00 a.m. Piotr Maniawski Director, Clinical Science Philips Healthcare, Advanced Molecular Imaging 595 Miner Rd, Cleveland, OH 44143 (440) 483‐7616 Email: piotr.maniawski@philips.com Website: http://www.philips.com Towards quantitative PET imaging: are we there yet? ‐ Molecular imaging technology is undergoing significant changes ‐ new advancements in detector technology, image reconstruction and development of new image derived biomarkers promise true realization of quantitative molecular imaging. These technologies also allow better integration of hybrid imaging systems. The presentation will focus on the discussion of potential impact of quantitative hybrid imaging on clinical research and practice in oncology, neurology and cardiovascular applications. It will paint a picture of true integration of clinical information provided by both hybrid modalities leading to disease characterization in addition to detection. Specifically, a new digital PET technology developed by Philips will be discussed in the context of its potential impact on clinical practice and research. Five main topics to be covered are: 1. The vision of the evolution of the role of PET imaging in neurology 2. Description and performance characterization of Philips digital PET technology 3. Impact of the performance improvements on image resolution, sensitivity and quantitative accuracy 4. Specific impact on variety of clinical applications 5. Integration of PET imaging with other imaging modalities – hybrid imaging approach Biography ‐ Piotr Maniawski has 28 years of professional expertise in technical, clinical and business aspects of nuclear medicine. Piotr is a graduate of the Jagiellonian University, Krakow, Poland. He held positions of a medical physicist and radiation safety officer at the Silesian Center of Cardiology, Zabrze, Poland. In 1989, he joined the nuclear medicine research team at Yale University conducting research in applications and reconstruction software development in the area of nuclear cardiology. In 1992, he joined Philips Healthcare as a software engineer and throughout his career at Philips he held several positions in research and development as well as in marketing. His current responsibilities include management of luminary customers, medical advisory board and focus groups to determine strategies for Philips molecular imaging. Piotr is also responsible for the clinical research with Philips collaboration partners. 1988‐1992 Associate in Research – Nuclear Cardiology, Yale University, School of Medicine, New Haven, CT 1992‐1995 Senior & Principal Software Engineer, Picker International, Cleveland, OH 1995‐1999 International Product Sales Manager, Picker International, Cleveland, OH In his professional career:  Knowledge of nuclear medicine instrumentation, image processing and clinical applications  Development of the clinical strategy for Nuclear Medicine business that drives product roadmap requirements Management of luminary accounts, medical advisory board and focus groups to determine strategic requirements (clinical and product)  Management of the clinical research sites to evaluate the clinical performance and demonstrate the value of Philips products 2 “Biomarker Development” Workshop – April 10, 2014 Exeter Room, Marquis Hall, 97 Campus Drive, University of Saskatchewan Speaker #3 – 10:45 a.m. – 11:30 a.m. Dr. Ekaterina (Kate) Dadachova Professor of Radiology and Microbiology and Immunology Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research Albert Einstein College of Medicine of Yeshiva University 1695A Eastchester Rd, Bronx NY 10461 USA (718) 405‐8485 E‐mail: ekaterina.dadachova@einstein.yu.edu Website: http://www.einstein.yu.edu/faculty/7654/ekaterina‐dadachova/ Transformation of Radioimmunotherapy: From Cancer to Infection and Back ‐ My laboratory is developing novel targeted radionuclide therapies for cancer and infectious diseases as well as melanin pigment‐based radioprotectors for cancer patients and nuclear applications. We have pioneered the use of radioimmunotherapy which has been exclusively used in oncology before that for therapy of infectious diseases including HIV. An important area of our research is virally‐induced cancers such as human papilloma virus (HPV) related cancers which we treat by targeting viral antigen expressed by cancer cells. We have already translated some of our basic findings into the clinical trials. Biography – Dr. E. Dadachova received her Bachelor of Chemistry and PhD in Physical Chemistry degrees from Moscow State University in Russia. She is currently a Professor of Radiology, Microbiology and Immunology and a Sylvia and Robert Olnick Faculty Scholar in Cancer Research at the Albert Einstein College of Medicine in New York City. Her research interests are radioimmunotherapy of cancer and infections including invasive fungal infections and HIV with the latter being pioneered by her laboratory. Her research is funded by NIH, Bill and Melinda Gates Foundation and private foundations. She has 120 published peer‐reviewed articles, several book chapters, and has 4 U.S and 4 foreign patents. She received several awards such as Philips Young Investigator Award by Radiological Society of North America, Young Professionals Award from the Society of Nuclear Medicine, Mary Kay Ash Research Award, and last year was recognized by the Dean of the Albert Einstein College of Medicine as one of the top 10 researchers at Einstein. 3 “Biomarker Development” Workshop – April 10, 2014 Exeter Room, Marquis Hall, 97 Campus Drive, University of Saskatchewan Speaker #4 – 11:30 a.m. – 12:15 p.m. Dr. Dayan B. Goodenowe President/CEO Phenomenome Discoveries Inc. 204‐407 Downey Road Saskatoon SK Canada S7N 4L8 (306) 244.8233 Ext. 232 Email: d.goodenowe@phenomenome.com Website: http://www.phenomenome.com The discovery, development, and clinical implementation of quantitative serum biomarkers for disease and disease risk ‐ Contracting a disease requires two factors: host susceptibility and an environmental triggering event (internal or external). The less susceptible the host is to a disease, the greater the triggering event needs to be for the disease to "catch". Assuming that chronic age‐associated diseases such as cancer and neurodegeneration do not selectively target elderly subjects, one must conclude that the aging process increases our susceptibility to certain diseases such that weaker triggering events are capable of initiating the disease cascade, resulting in increased prevalence with age. Using a non‐targeted metabolomics discovery technology platform, the natural history of a disease can be investigated in subjects with a particular disease and compared to subjects without the disease. Metabolomics measures the collective environmental and genetic state of a subject and therefore has the potential to identify both disease and susceptibility biomarkers. Using colorectal cancer and Alzheimer's disease as examples, the discovery of specific biomarkers that are involved in these disease processes will be described and how these biomarkers can be translated into quantitative diagnostic assays suitable for population based screening for pre‐disease risk. Secondarily, a model of disease prevention through targeted disease risk modification will be presented for discussion. Biography – Dr. Goodenowe obtained his undergraduate degree at the University of Saskatchewan in Agricultural Chemistry before going on to complete a Ph.D. in Medicine at the University of Alberta, where he studied the neurochemical effects of psychiatric drugs. Professionally, he has held research scientist positions in both pharmaceutical and agricultural chemical industries, and as an independent consultant specializing in biological mass spectrometry methods. Dr. Goodenowe is the President and CEO of Phenomenome Discoveries Inc. (PDI) which he cofounded in 2000. Phenomenome Discoveries Inc. (PDI) is a human health research company that uses its patented metabolomic biomarker discovery platform and patented informatic research tools to discover novel metabolite biomarkers. PDI has small molecule serum biomarker discovery programs in cancer and neurodegenerative disease, and has validated and filed patents on diagnostic biomarkers in multiple human health disorders. PDI has diagnostic and therapeutic programs for neurodegenerative diseases including Alzheimer’s disease and multiple sclerosis, as well as for cancer including colorectal cancer, ovarian cancer, and pancreatic cancer. Dr. Goodenowe’s primary research interest is disease prevention via the identification and treatment of causal risk factors. 4 “Biomarker Development” Workshop – April 10, 2014 Exeter Room, Marquis Hall, 97 Campus Drive, University of Saskatchewan Speaker #5 – 1:45 p.m. – 2:30 p.m. Dr. Robert S. Kerbel Professor, Department of Medical Biophysics University of Toronto Senior Scientist, Sunnybrook Research Institute S‐217, 2075 Bayview Avenue Toronto, ON M4N 3M5 (416) 480‐5711 E‐mail: robert.kerbel@sri.utoronto.ca Website: http://medbio.utoronto.ca/faculty/kerbel.html On the Urgent Need for Development of Validated Predictive Biomarkers for Antiangiogenic Drugs in Oncology ‐ Dr. Kerbel’s primary research interest concerns a particular class or type of drug used to treat cancer, namely, antiangiogenic drugs, which are designed to target the newly forming blood vessels present in tumors which provide the necessary oxygen and nutrients for progressive expansion of tumor mass and spread of cancer. Six such drugs have been approved for the treatment of approximately ten different types of cancer, over the last decade. All target exclusively or primarily the proangiogenic pathway mediated by VEGF (vascular endothelial cell growth factor). Despite these successes, the impact of these drugs, which are extremely expensive (e.g. one of them, Avastin, the VEGF antibody, costs around $5,000/month), are usually associated with very modest clinical benefits in prolonging survival; they can also have many side effects. One factor to explain the limited effects of such drugs is that all of the randomized phase III trials undertaken that led to the approval of these drugs were undertaken on unselected patients. As such, this has almost certainly resulted in a ‘dilution’ of the positive signal achieved by some patients benefiting from receiving this type of therapy, in contrast to those that did not. Consequently there has been an intensive effort underway to try and develop predictive biomarkers for antiangiogenic drugs where expression of a particular biomarker is associated with an increased probability of a patient meaningfully responding to an antiangiogenic drug or therapy. Thus far no such predictive biomarker has been validated, but a number are being investigated. These include elevated expression of certain forms of VEGF, development of elevated hypertension – a common side effect associated with such drugs, changes in blood flow detected by imaging, and pharmacogenomics or cytokine/growth factor changes induced by therapy. Biography – Dr. Kerbel received his PhD in 1972, after which he undertook postdoctoral training in London. He started his independent research program in 1975 at Queen's University and was appointed Director of a Cancer Biology Program in the Dept. of Pathology in 1981. In 1985 he was recruited as Director of Cancer Biology at Mt. Sinai Hospital, Toronto. He then moved to Sunnybrook Health Sciences Centre to do the same from 1991 until 2001. Currently Dr. Kerbel holds a Canada Research Chair in Tumor Biology, Angiogenesis and Antiangiogenic Therapy, and is a professor in the Dept. of Medical Biophysics at the University of Toronto. His main interests have been devising new cancer treatment strategies having improved efficacy and reduced toxicity. This culminated in his studies of combinatorial low‐dose ‘metronomic’ chemotherapy and antiangiogenic drugs. Some of his findings are now being evaluated in multiple phase III clinical trials, particularly in breast and colorectal cancer. Other contributions include development of improved preclinical therapy models involving early stage or advanced metastatic disease, linking the fields of angiogenesis and oncogenes, uncovering mechanisms by which antiangiogenic drugs increase chemotherapy efficacy and alter malignant tumor progression, and elucidating mechanisms of acquired antiangiogenic drug resistance. He has published 389 papers, given over 800 invited lectures. Among the awards he has received include the Canadian Cancer Society Robert Noble Award for Excellence in Cancer Research, the Breast Cancer Research Award from the European Institute of Oncology, a Man of Distinction Honor by the Israel Cancer Research Fund, and the Colin Thomson Memorial Medal from the Association for International Cancer Research. 5 “Biomarker Development” Workshop – April 10, 2014 Exeter Room, Marquis Hall, 97 Campus Drive, University of Saskatchewan Speaker #6 – 2:30 p.m. – 3:15 p.m. Dr. Amy K. LeBlanc Associate Professor of Small Animal Clinical Sciences College of Veterinary Medicine University of Tennessee 2407 River Drive Knoxville, TN 37996 (865) 974‐8387 E‐mail: aleblanc@utk.edu Website: http://www.vet.utk.edu/faculty/leblanc.php Companion Animals in Comparative Oncology Research – Comparative oncology employs the tumor‐bearing pet dog as a relevant and complementary model for cancer drug discovery and development. Pet dogs with cancer are now recruited by veterinary oncologists worldwide in prospective clinical trials to more deeply explore toxicity and efficacy data gathered in traditional preclinical studies involving rodents, non‐human primates and other ‘large’ mammalian species such as purpose‐bred dogs or pigs. This approach is gaining traction as an innovative method for streamlining drug discovery and development. To date, most comparative oncology studies have been designed and executed to evaluate new anti‐cancer drugs utilizing tumor‐bearing dogs with specific naturally‐
occurring cancers as models for humans. These studies have proved extremely valuable for modeling of PK‐PD relationships, refining drug dose and schedule, and validation of an individual drug’s target in vivo. The National (NCI‐COTC; Cancer Institute’s Comparative Oncology Trials Consortium http://ccr.cancer.gov/resources/cop/COTC.asp) is a cooperative effort which provides infrastructure and resources to support this effort among academic veterinary centers in the US. To complement ongoing efforts in this field, we propose expansion of comparative cancer imaging. Diagnostic imaging is critical to diagnosis and management of malignancy in both humans and animals. Molecular imaging techniques allow for detection of disease‐specific signals that provide individualized data to aid in patient selection, response to therapy, and prognostication. In this talk, I will highlight the past and ongoing successes of comparative oncology studies which have informed anti‐
cancer drug development, and explore opportunities for such studies to demonstrate the value of spontaneous canine cancers as a unique tool in imaging agent development. Biography ‐ Dr. Amy LeBlanc is a board‐certified veterinary oncologist, Associate Professor with tenure and Director of Translational Research at the University of Tennessee College of Veterinary Medicine (CVM) and UT Graduate School of Medicine (GSM). Dr. LeBlanc assumed her joint appointment between the CVM and GSM and directorship in June 2009 after serving as an Assistant Professor in the Department of Small Animal Clinical Sciences since May 2004. She currently serves on the Society of Nuclear Medicine and Molecular Imaging’s Preclinical Imaging Task Force and the Advanced Continuing Education committee for the American College of Veterinary Internal Medicine. In July 2014, she will join the NIH/NCI’s Comparative Oncology Program as a staff scientist. Dr. LeBlanc’s group at the University of Tennessee has published the seminal work describing molecular imaging of dogs and cats using PET/CT, focusing on the forward and back‐translation of 18F‐labelled radiopharmaceuticals. Her current funded research efforts are reporter gene imaging (NIS expression) in oncolytic virotherapy of canine cancer in collaboration with Mayo Clinic College of Medicine. Dr. LeBlanc has a strong interest in animal modeling for development of new cancer imaging agents and identification of imaging biomarkers, development and optimization of PET imaging hardware and imaging protocols, and in fostering collaborations with industry and academic partners to support relevant Investigational New Drug (IND) studies in man. She has authored 39 peer‐
reviewed manuscripts and given numerous invited lectures on the inclusion of companion animals in imaging‐
based translational research and the value of comparative oncology in drug and imaging agent development. 6