Antonia Dimitrakopoulou-Strauss M.D. is Professor of Nuclear Medicine at the German Cancer Research Center. She was the guest speaker at a lecture organized by the MGH Gordon Center. Below is the presentation summary.
Molecular imaging techniques allow a better staging as well as an individualization and optimization of therapy in oncological patients. The availability of new hybrid scanners, like PET-CT and PET-MRI have revolutionized both diagnosis and therapy management and are therefore a unique tool for personalized cancer treatment. Identification of non-responders early in the course of treatment, the choice of the appropriate therapeutic protocol as well as optimal treatment duration are some aspects which can be improved by the use of molecular imaging techniques and can help to avoid side effects and save costs for the health system. Furthermore, therapies with new targeted drugs, like tyrosine kinase inhibitors or immune checkpoint inhibitors require also a tight monitoring for assessment of a therapeutic result and a fast change to another protocol in case of progress. Standardization of response criteria is another important aspect and a prerequisite for a more routine application of molecular imaging for therapy guidance. Furthermore, the development of new tumor-specific tracers will enable a more accurate assessment of a therapeutic result. Numerous peptides targeting receptoractive tumors are in development with a high potential in a large spectrum of tumors for theranostic approaches, like in neuroendocrine tumors and in prostate cancer.
Dr. Anne van de Ven is a Research Assistant Professor at Northeastern University. She was the guest speaker at a lecture organized by the MGH Gordon Center. Below is the presentation summary.
Intravital microscopy allows the visualization of nanoparticle transport across a sequence of multi-scale physical barriers. Data collected using this approach can be used to simulate, predict, and improve nanoparticle designs for drug and contrast agent delivery to solid tumors. Dr. van de Ven presented an integrated framework that combines patient-derived xenografts, exogenous contrast agents, and experimental nanoparticles to study how patient-specific transport parameters can impact nanotherapeutics delivery.
According to Dr. van de Ven, preliminary data suggests that only a subset of patients will be highly amenable to nanotherapy. Using ferumoxytol as a surrogate, she is currently developing MRI techniques to quantify nanoparticle delivery and relate it to therapeutic efficacy in vivo for the personalized selection of therapy.
Dr. Tae Ho Lee is Assistant Professor of Medicine at Harvard Medical School. He was the guest speaker at a lecture organized by the MGH Gordon Center. Below is his presentation summary.
Phosphorylation of proteins is one of the most important post-translational modifications (PTMs) and a key signaling mechanism in diverse physiological and pathological processes. Its deregulation contributes to age-related diseases, notably cancer and Alzheimer’s disease (AD).
AD is characterized by a progressive loss of memory and other cognitive functions. It affects over 44 million people in worldwide and its incidence is expected to triple over the next 30.years. There is therefore an urgent need to understand the mechanisms underlying the degeneration of neuronal cells. The two defining neuropathological features of AD are extracellular senile plaques and intracellular neurofibrillary tangles (NFTs). The senile plaques are made of amyloid-β (Aβ), cleaved products of the amyloid precursor protein (APP), whereas the neurofibrillary tangles mainly consist of the microtubule-associated protein tau. Many hypotheses have been proposed to explain the etiology and pathogenesis of AD and related disorders; two dominant theories focus on increased production of Aβ and dysfunction of tau. However, currently the pathogenic mechanisms are still not fully understood and there is no effective therapy. Therefore, the ability to define regulatory mechanisms controlling APP processing and tau function will be critical for elucidating the pathogenesis and for designing strategies for preventing and/or treating neurodegenerative diseases.
Death-associated protein kinase 1 (DAPK1) is a death domain-containing calcium/ calmodulinregulated serine/threonine kinase and plays an important role in regulating neuronal function. We demonstrated here that DAPK1 expression is dramatically up-regulated in the 75% hippocampi of AD patients compared with age-matched normal subjects. Moreover, we showed that DAPK1 regulates tau toxicity in modulating microtubule assembly and neuronal differentiation, and DAPK1 overexpression increases tau phosphorylation at multiple AD-related sites in cells and animal models. We also found that DAPK1 increases Aβ secretion in a kinase activity-dependent manner. In addition, the levels of insoluble Aβ and amyloidogenic APP processing are significantly reduced in APP-overexpression/DAPK1-knockout mice brain. Finally, we identified novel DAPK1 substrates that are involved in neuronal cell death and AD including N-myc downstream-regulated gene 2 (NDRG2). Together, these results suggest that DAPK1 may be a critical regulator of tau phosphorylation, APP processing, and neuronal cell death and DAPK1 deregulation may contribute to AD progression. Therefore, DAPK1 may serve a potential therapeutic target for AD.
Central nervous system demyelination represents the pathological hallmark of multiple sclerosis (MS) and is thought to contribute to other neurological conditions including traumatic brain injury, stroke and Alzheimer’s disease. The ability to assess demyelination quickly and quantitatively is crucial for the diagnosis and treatment of these diseases. As current imaging approaches for demyelination rely on magnetic resonance imaging, which is neither quantitative nor specific for demyelination, Dr. Pedro Brugarolas set out to develop a PET tracer for demyelination. He described the development of a novel radioligand for brain imaging based on the FDA-approved drug for MS, 4-aminopyridine (4-AP). After demonstrating that C-14 labeled 4-AP localizes to demyelinated areas in mouse models of MS –presumably through binding to exposed potassium channels in demyelinated axons– he designed a fluorinated derivative of 4-AP compatible with with F-18 labeling and PET. Dr. Brugarolas then developed a novel radiochemical method to label this compound and performed PET/CT imaging in rats harboring demyelinated lesions. According to Dr. Pedro Brugarolas, this is the first example of a PET radioligand for potassium channels in the brain potentially opening a new window for looking at brain diseases.
Dr. Pedro Brugarolas is a radiochemist at the University of Chicago. He was the guest speaker of a lecture organized by the Gordon Center and his presentation was titled "[18F]3F4AP: a new PET tracer for imaging brain demyelination."
According to Dr. Sei Kwang Hahn from Pohang University of Science and Technology in South Korea, smart photonic materials have a variety of biomedical applications for biosensing, molecular imaging, surgery and therapies. In a conference organized by the Gordon Center, he discussed his research efforts to develop melanoidin nanoparticles for in vivo noninvasive photoacoustic mapping of sentinel lymph nodes, photoacoustic tomography of gastro-intestinal tracts, and photothermal ablation cancer therapy. Dr. Hahn and his colleagues created biodegradable polymer waveguides and upconversion nanoparticles for photochemical tissue bonding. They also synthesized cell-integrated poly(ethylene glycol) hydrogels for in vivo optogenetic sensing and therapy. Real-time optical readout of encapsulated heat-shock-protein-coupled fluorescent reporter cells made it possible to measure the nanotoxicity of cadmium-based quantum dots in vivo. Using optogenetic cells to produce glucagon-like peptide-1, Dr. Hahn developed smart contact lenses composed of biosensors, drug delivery systems and power sources for the treatment of diabetes as a model disease.
Anna M. Wu, Ph.D. is Professor and Vice Chair of the Department of Molecular and Medical Pharmacology at UCLA. She was the guest speaker at a lecture organized by the MGH Gordon Center. Below is her presentation summary.
Engineered antibody fragments can provide a versatile platform for non-invasive imaging of cells and tissues based on cell surface phenotype. When labeled with positron-emitting radionuclides (such as I-124, Zr-89, Cu-64, F-18), engineered fragments can be employed for high resolution, sensitive, quantitative imaging by PET (positron emission tomography) and provide highly specific molecular assessments of tumor biology and response to treatment. For example, an I-124 prostate stem cell antigen (PSCA)-specific minibody demonstrates sensitive imaging in mouse models of prostate cancer and provides a PET imaging readout of response to anti-androgens. Antibody-based targeting and imaging of CD markers (CD4/CD8 on T cells; CD20 on B lymphocytes) provides a means for assessing immune cell subsets and monitoring responses to cancer immunotherapy, such as treatment with anti-CD137 or anti-PD-L1 antibodies. ImmunoPET can provide a broad approach for noninvasive, whole-body monitoring of key factors such as target expression in vivo, response to therapy, and immune responses, and stands to play an expanding role in the detection and management of cancer.About the Gordon Lecture Series: The Gordon Center for Medical Imaging at Massachusetts General Hospital and Harvard University develops new biomedical imaging technologies used in diagnosis and therapy. In addition to translational research, the Center organizes lectures and symposiums as part of its effort to inspire the public and the scientific community about the latest research topics in medical imaging.
Cardiac Magnetic Resonance (MR) offers a comprehensive evaluation of cardiac function, morphology and blood flow. Yet clinical adoption of cardiac MR remains relatively limited due to a number of factors such as the exam length and complexity.
But according to Dr. Anja Brau, Director of Global Cardiac MR at GE Healthcare, cardiac MR use is very likely to increase thanks to recent breakthroughs in cloud-based analytics, supercomputing platforms and imaging technology. The next generation of cardiac MRs is expected to decrease scan acquisition time and improve image resolution while exploiting existing MR’s strengths in flow quantification and tissue characterization.
Dr. Anja Brau was the guest speaker at a seminar series organized by the MGH Gordon Center and her lecture was titled “Latest Innovations and New Directions in Cardiac MR.”
About the Gordon Center for Medical Imaging:
The Gordon Center for Medical Imaging at Massachusetts General Hospital and Harvard University develops new biomedical imaging technologies used in diagnosis and therapy. In addition to translational research, the Center organizes lectures and symposiums as part of its effort to inspire the public and the scientific community about the latest research topics in medical imaging.