2022 MIPS Molecular Imaging Seminar Series

Molecular imaging (MI) originated from the need to better understand the fundamental molecular pathways inside organisms in a noninvasive manner. Over the past two decades, two factors have acted in concert to fuel the ascent of molecular imaging in both the laboratory and the clinic: First, an increased understanding of the molecular mechanisms of disease and second, the continued development of in vivo imaging technologies, ranging from improved detectors to novel labeling methodologies. The advent of molecular imaging has, in turn, prompted a paradigm shift in medical imaging as a whole, from its foundations in purely anatomical imaging towards techniques aimed at probing tissue phenotype and function. We have for many years exploited aberrant targets associated with cancer in order to better diagnose, stage, monitor and treat this disease.

The use of Positron Emission Tomography (PET) for cancer imaging is a well-established and widely used molecular imaging modality both in clinical and research settings. Over the last 30 years, our ability to non-invasively diagnose, localize, and treat many forms of cancer has advanced tremendously. Due to their exquisite selectivity and specificity for cancer biomarkers, radiolabeled antibodies have played an important and growing role in this trend. Within the last half-decade, antibodies have emerged as enticing tools for the PET imaging of cancer and endoradiotherapy and will be the focus of this presentation.

Professor Jason S. Lewis is the Emily Tow Jackson Chair at Memorial Sloan Kettering Cancer Center in New York. He is the Chief Attending of the Radiochemistry & Imaging Sciences Service and serves as the Vice Chair of Research in the Department of Radiology. He holds a joint appointment in the Molecular Pharmacology Program, and he is the Director of the Radiochemistry & Molecular Imaging Probe Core in the Sloan-Kettering Institute. He also holds appointments at the Gerstner Sloan-Kettering Graduate School, New York, NY and the Weill Cornell Medical College, New York, NY. He is an Adjunct Professor in the Department of Biomedical Imaging and Image Guided Therapy, The Medical University of Vienna, Austria.
 
Professor Lewis has served as the 2015 President of the World Molecular Imaging Society and is the President-Elect of the Society for Radiopharmaceutical Sciences. In 2014 he received a Distinguished Investigator Award from the Academy of Radiology Research and he was named a WMIS Fellow in 2015. In 2017 he was elected a Member of the International Society for Strategic Studies in Radiology and was awarded the SNMMI Michael J. Welch Award. In 2019 he was named a Fellow of the Society of Nuclear Medicine & Molecular Imaging and was awarded the SNMMI Paul C. Aebersold Award. In 2019 Professor Lewis was awarded an NCI Outstanding Investigator Award (R35). In 2020 he was awarded the ACS Bioconjugate Chemistry Lectureship Award and was named a Fellow of the Royal Society of Chemistry and the American Association for the Advancement of Science. In 2021 he was awarded the gold Medal from the World Molecular Imaging Society
 
Lewis’ research program is a molecular imaging-based program focused on radiopharmaceutical development as well as the study of multimodality (PET, CT & MRI) small- and biomolecule-based agents and their clinical translation. He has published >300 papers and reviews in the field of radiochemistry and molecular imaging.

F18 Fluoroestradiol, also known as Cerianna (GE Healthcare), is an FDA approved PET radiopharmaceutical for imaging estrogen receptor positive breast cancer. This presentation will provide an overview of ER targeted imaging and a review of the preclinical and clinical data supporting its FDA approval. We will discuss the clinical applications for cancer treatment decision making and research applications for novel drug development.

Yingbing Wang, MD is an attending radiologist at Massachusetts General Hospital. Dr. Wang is dual boarded in diagnostic radiology and nuclear medicine. Her clinical and research focus is on oncology PET imaging. She has been the principal investigator on three prospective trials of novel PET radiotracers for imaging glioblastoma, funded by the Proton Federal Share Grant, for breast cancer, funded by Seragon/Genentech, and Multiple Myeloma funded by Dekkun Corporation. Dr. Wang is also the principal clinical investigator on an imaging trial of machine learning methods to enhance PET image quality, funded by GE Healthcare. She is the director of radionuclide therapies and program director of the Nuclear Radiology Fellowship at MGH.

Novel radiopharmaceuticals for PET are being evaluated for the diagnosis of prostate cancer. Gastrin-releasing peptide receptor (GRPR) -targeting radiopharmaceuticals are not as widely accepted as the prostate-specific membrane antigen (PSMA)-targeting ones. However, GRPR still are a valuable class of radiopharmaceuticals even when compared with PSMA in the evaluation of prostate cancer. The presentation will provide data to support this statement.

Dr. Iagaru is a Professor of Radiology - Nuclear Medicine and the Chief of the Division of Nuclear Medicine and Molecular Imaging at Stanford University Medical Center. He completed medical school at Carol Davila University of Medicine, Bucharest, Romania, and an internship at Drexel University College of Medicine, Graduate Hospital, in the Department of Medicine in Philadelphia. He began his residency at the University of Southern California (USC) Keck School of Medicine, Los Angeles, in the Division of Nuclear Medicine, where he was the chief resident. Dr. Iagaru finished his residency and completed a PET/CT fellowship at Stanford University's School of Medicine in the Division of Nuclear Medicine. His research interests include PET/MRI and PET/CT for early cancer detection; clinical translation of novel PET radiopharmaceuticals; peptidebased diagnostic imaging and therapy; targeted radionuclide therapy.

Over the past 14 years since joining the faculty at Stanford, Dr. Iagaru has received several awards including the Society of Nuclear Medicine (SNM) 2009 Image of the Year Award; AuntMinnie 2016 Best Radiology Image, American College of Nuclear Medicine (ACNM) Mid-Winter Conference 2010 Best Essay Award; 2009, 2014 and 2015 Western Regional SNM Scientist Award; 2011 SNM Nuclear Oncology Council Young Investigator Award; and the 2020 Sanjiv Sam Gambhir Distinguished Scientist Award, Western Regional SNM. Dr. Iagaru published more than 200 papers in peer-reviewed journals, as well as 7 book chapters and 1 book.

Dr. Boada is Professor of Radiology and Associate Chair for Basic Science Translational Research at Stanford University Medical School. Dr. Boada joined Stanford university in 2021 after being Professor of Radiology, Psychiatry and Neurosurgery at New York University Medical School and the Director of the Center for Advanced Imaging Innovation and Research. Prior to joining NYU in 2012, Dr. Boada directed the MR Research Center (MRRC) at the University of Pittsburgh for ten years. His research efforts have been focused on the development of novel MRI techniques for addressing open neuroimaging questions in a translational setting. As part of these efforts he led the development and validation of novel techniques for assessing tissue viability during evolving stroke as well as the development of sodium MRI applications for brain tumor diagnosis and therapeutic monitoring. He has also been a regular contributor to the development of Ultra-High Field MRI applications for human studies and has demonstrated the unique capabilities of this technology for mechanistic studies of Bipolar Disease. During his tenure at NYU, he developed novel techniques for robust and continuous cardiac and respiratory motion correction of simultaneously acquired MR/PET data, as we all, for anatomically MRI-guided reconstruction using AI. Dr. Boada has been a reviewer of NIH grants for numerous NIH and NSF study sections including concurrent charter memberships on the Diagnostic Radiology (MEDI) as well as the NINDS Training and Career Development (NST) Study Sections and most recently in the Clinical and molecular Imaging Probes (CMIP) study section. He is a member of the International Society for Magnetic Resonance in Medicine where he has served on the Governance and Annual Program Committees. He was also inducted into the College of Fellows at the American Institute for Medical and Biological Engineering in 2009, named a fellow of the International Society for Magnetic Resonance in Medicine in 2012 and a Distinguished Investigator of the Academy of Radiology Research in 2015.

There is increasing evidence to support a role for metabolism in tumor development, with deregulation of cellular energetics an established hallmark of cancer. Changes in tumor metabolism is an early biomarker of successful response to both chemotherapy and radiotherapy. There are several clinical imaging methods that can be used to probe cancer metabolism and this talk will focus on the role of MR in phenotyping cancer metabolism and its heterogeneity, particularly to grade tumors and detect early response to therapy. For example, proton MR spectroscopy (¹H-MRS) has been used to detect oncometabolites in a range of tumors secondary to mutations in mitochondrial enzymes. ¹H-MRS can be used to detect fumarate and succinate due to mutations in fumarate hydratase and succinate dehydrogenase respectively, as well as changes over time following treatment.

Hyperpolarized carbon-13 MRI (¹³C-MRI) is an emerging non-invasive imaging method for studying metabolism. This technique allows non-invasive measurements of tissue metabolism in real-time with pyruvate being the most promising clinical hyperpolarized carbon-13 probe, which is rapidly metabolized into lactate in most tumors. This talk will present how changes in hyperpolarized lactate can be used to identify aggressive breast, renal, and prostate cancers, as well as early response to neoadjuvant chemotherapy in breast cancer. By correlating imaging with tissue-based measures of metabolism, the molecular basis for these changes in lactate is increasingly being understood, including the role of the pyruvate transporter (MCT1), lactate exporter (MCT4), and the enzyme lactate dehydrogenase (LDH).

More recently, deuterium metabolic imaging (DMI) has been used to study the metabolism of oral deuterated glucose and the presentation will show how this technique compares to hyperpolarised carbon-13 MRI based metrics of oxidative and reductive metabolism in the brain at clinical field strength. New imaging methods such as these to probe tumor metabolism could play an important role in stratifying tumors and detecting response to therapy, particularly in the context of developing targeted therapies against key tumor metabolic pathways.

Ferdia Gallagher is Professor of Translational Imaging and a Cancer Research UK Senior Cancer Research Fellow at the University of Cambridge, an honorary Consultant Radiologist at Addenbrooke’s Hospital, and a Fellow of Gonville and Caius College, Cambridge. He leads the Clinical Molecular Imaging Group in the Department of Radiology and the preclinical imaging group in the Anne McLaren Unit on the Biomedical Campus. He has expertise in metabolic imaging and multinuclear MRI for stratification of tumours and response to therapy. The group has a particular interest in understanding the molecular basis of metabolism in a range of cancers, and how novel non-invasive imaging methods to probe this metabolism can be translated into patient studies. The ultimate goal is to develop new imaging biomarkers of early detection and treatment response for patient benefit.

Engineered materials that integrate advances in polymer chemistry, nanotechnology, and biological sciences have the potential to create powerful medical therapies. Dr. Khademhosseini is interested in developing ‘personalized’ solutions that utilize micro- and nanoscale technolgoies to enable a range of therapies for organ failure, cardiovascular disease and cancer.In enabling this vision he works closely with clinicians (including interventional radiologists, cardiologists and surgeons). For example, he has developed numerous techniques in controlling the behavior of patient-derived cells to engineer artificial tissues and cell-based therapies. His group also aims to engineer tissue regenerative therapeutics using water-containing polymer networks called hydrogels that can regulate cell behavior. Specifically, he has developed photo-crosslinkable hybrid hydrogels that combine natural biomolecules with nanoparticles to regulate the chemical, biological, mechanical and electrical properties of gels. These functional scaffolds induce the differentiation of stem cells to desired cell types and direct the formation of vascularized heart or bone tissues. Since tissue function is highly dependent on architecture, he has also used microfabrication methods, such as microfluidics, photolithography, bioprinting, and molding, to regulate the architecture of these materials. He has employed these strategies to generate miniaturized tissues. To create tissue complexity, he has also developed directed assembly techniques to compile small tissue modules into larger constructs. It is anticipated that such approaches will lead to the development of next-generation regenerative therapeutics and biomedical devices.

Ali Khademhosseini is currently the CEO and Founding Director at the Terasaki Institute for Biomedical Innovation. Previously, he was a Professor of Bioengineering, Chemical Engineering and Radiology at the University of California-Los Angeles (UCLA). He joined UCLA as the Levi Knight Chair in November 2017 from Harvard University where he was Professor at Harvard Medical School (HMS) and faculty at the Harvard-MIT’s Division of Health Sciences and Technology (HST), Brigham and Women’s Hospital (BWH) and as well as associate faculty at the Wyss Institute for Biologically Inspired Engineering. At Harvard University, he directed the Biomaterials Innovation Research Center (BIRC) a leading initiative in making engineered biomedical materials. Dr. Khademhosseini is an Associate Editor for ACS Nano. He served as the Research Highlights editor for Lab on a Chip. He is a fellow of the American Institute of Medical and Biological Engineering (AIMBE), Biomedical Engineering Society (BMES), Royal Society of Chemistry (RSC), Biomaterials Science and Engineering (FBSE), Materials Research Society (MRS), NANOSMAT Society, and American Association for the Advancement of Science (AAAS). He is also the recipient of the Mustafa Prize ($500,000 prize) and is a member of the  nternational Academy of Medical and Biological Engineering, Royal Society of Canada and Canadian Academy of Engineering, and National Academy of Inventors. He is an author on >650 peer-reviewed journal articles, editorials and review papers, >70 book chapters/edited books and >50 patents/patent applications. He has been cited >90,600 times and has an H-index of 152. He has made seminal contributions to modifying hydrogels and developing novel biomaterial solutions for addressing pressing problems in healthcare. He has founded 2 companies, Obsidio Medical and Biorae. He received his Ph.D. in bioengineering from MIT (2005), and MASc (2001) and BASc (1999) degrees from University of Toronto both in chemical engineering.

Quantitative image biomarkers are increasingly being discovered for clinical diagnoses. Receiver operating characteristic (ROC) curve is commonly is commonly used to evaluate their diagnostic performance. The performance of an ROC curve is independent of disease prevalence. When translating a biomarker to clinical applications, a cutoff threshold needs to be chosen in order to make diagnostic/clinical decisions. The choice of the cutoff value impacts the practical performance of the diagnostic test. Various methods for optimal choices of cutoff values can be found in literature. In this talk, we provide formulation for the optimal cutoff value that maximizes the kappa statistics of the diagnostic and true disease status under a known disease prevalence. We also discuss the design and sample size calculation for a validation study. Examples of applications, including the evaluation of the PTSD Checklist for the PTSD diagnosis using DSM-5 (PCL-5) and a MCG diagnostic biomarker for coronary heart disease diagnosis, are presented.

Ying Lu, Ph.D., is Professor of Biomedical Data Science in the Department of Biomedical Data Science, and by courtesy in the Department of Radiology and Department of Epidemiology and Population Health, Stanford University School of Medicine. He co-directs the Stanford Center for Innovative Study Design, BERD Research Methods Core of the SPECTRUM, and the Biostatistics Core of the Stanford Cancer Institute. Before joining Stanford, he spent 15 years as a faculty in the Department of Biostatistics and Epidemiology and the Department of Radiology at the University of California, San Francisco. His research areas are biostatistics methodology and applications in clinical trials, statistical evaluation of medical diagnostic tests, radiology, osteoporosis, meta-analysis, medical decision making. He published more than 300 research papers in peer-reviewed journals, edited two books and numerous book chapters. Dr. Lu received his BS in Mathematics from Fudan University, MS in Applied Mathematics from Shanghai Jiao Tong University, and Ph.D. in Biostatistics, from the University of California, Berkeley.