Historically, scientific disciplines had rigorous barriers delineating skills, methods, and applications. In the new Millennium barriers are dissolving, as multi disciplinary teams initiate multi modality investigations based on multi parametric assessments. In particular, Radiology is moving from an anatomical discipline to encompass physiological, metabolic, genetic and proteomic facets. A new era of Prognostic Radiology will enhance our understanding of tumor development and response to therapy with the promise of improving clinical outcome. Our team has been developing methods to interrogate diverse characteristics of tumors, in particular: i) There is increasing evidence for the importance of tumor oxygenation in development, progression, and response to therapy. Consequently, many techniques have been developed to assess tumor oxygenation. In terms of radiotherapy one of the most critical parameters influencing efficacy is pO2. We have developed a strategy to measure absolute pO2 in tumors using FREDOM (Fluorocarbon Relaxometry using Echo planar imaging for Dynamic Oxygen Mapping). Exploiting the reporter molecule HFB (hexafluorobenzene), we have monitored dynamic changes in local pO2 within a tumor non-invasively at multiple locations simultaneously. Such measurements reveal response to interventions designed to modulate pO2 and we have demonstrated correlations with response to irradiation. Assessment of response to vascular targeting agents provides insight into optimal timing of combined therapy. We have recently identified an analogous proton MRI reporter molecule to assess pO2 in tissues (hexamethyldisiloxane) and this may accelerate application to patients. Such measurements should allow therapy planning to be personalized to the characteristics of an individual tumor and facilitate implementation of effective intensity modulated radiotherapy (IMRT) or inclusion of adjuvant regimens such as hypoxia selective cytotoxins. ii) While most radiotherapy is currently delivered by external beam, radio immunotherapy (RIT) offers even greater specificity and we believe that radioisotopes of arsenic can play a valuable role. Colleagues recently identified a novel target on tumor vasculature, exposed phosphatidyl serine, and developed a highly effective antibody, vatuximab. We have demonstrated that vatuximab may be labeled effectively with 74As facilitating PET imaging for tumor detection. Moreover, identical chemistry allows analogous labeling with 77As, which is an effective ?O- emitter for therapy. Thus arsenic labels offer the potential for tumor detection, dosimetry, and therapy. iii) Gene therapy holds great promise for the treatment of diverse diseases. However, widespread implementation is hindered by difficulties in assessing the success of transfection in terms of spatial extent, gene expression, and longevity of expression. Reporter techniques may help to assay gene expression. 4-fluoro-2-nitrophenyl-?O-D-galactopyranoside (PFONPG) is a novel prototype NMR sensitive molecule, which is highly responsive to the action of ?O-galactosidase. Enzyme action causes very rapid liberation of the aglycone, accompanied by color formation and a 19F NMR chemical shift. Through minor chemical modifications we have examined isomeric substrates, which offer differential enzyme sensitivity and toxicity. By introducing a CF3 group, the NMR signal has been enhanced 3-fold. Substituting a fluoropyridoxol aglycone reduced toxicity and solubility has been modulated by appending secondary sugar moieties. Exploiting S-gal promises even greater sensitivity using 1H MRI. Many now realize that molecular imaging is the key to exploiting and integrating scientific developments. Tissue analysis needs to be non-invasive, three-dimensional and provide dynamic insight into pharmacokinetics and pharmacodynamics. Ideally, imaging would exploit endogenous molecules. However, many critical components of molecular biology, pharmacology, and biomedicine occur at concentrations far below the detection thresholds of traditional imaging modalities, or are associated with signals masked by more intense signals. Thus, there is a need for reporter molecules. Novel agents may build on interdisciplinary experience, indeed, cross-fertilization between the sciences and engineering and medicine may provide the most rapid developments. Cellular and molecular imaging promise to enhance the understanding of tumor development and response to therapy. Non invasive monitoring of pre-clinical tumors expands the diversity of models and efficiency of research. For the clinic, as Radiology moves from an anatomical discipline to encompass physiological, metabolic, genetic and proteomic facets, therapy may be tailored to the characteristics of an individual patient with the promise of improving clinical outcome. We are integrating nuclear magnetic resonance imaging (MRI) , radionuclide imaging (PET and SPECT), bioluminescent and fluorescent imaging techniques to assess tumor development and response to therapy in pre-clinical models, particularly of prostate, breast and lung cancer. As appropriate, discoveries move to the clinic and we are using BOLD MRI as part of a clinical trial to predict the outcome of chemotherapy on locally advanced breast cancer in patients.
RESEARCH INTERESTS
Application of imaging methods to tumor development and response to therapy; development of NMR reporter molecules as probes of physiology and gene transfection; detoxification of xenobiotica; MR miscroscopy and tissue microstructure.
NMR- MRI
Bioluminescent imaging
Oxygen
gene therapy
RECENT PUBLICATIONS
Yu, JX and Mason RP, "Synthesis and Characterization of Novel lacZ Gene Reporter Molecules: Detection of -Galactosidase Activity Using 19F NMR of Polyglycosylated Fluorinated Vitamin B6" J. Med. Chem., accepted, February 2006
Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP. and Parada LF, "Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma," Cancer Cell, 8:119-130, 2005
Zhao D, Jiang L, Hahn EW, Mason RP, "Continuous low-dose (Metronomic) chemotherapy on rat prostate tumors evaluated using MRI in vivo and comparison with histology" Neoplasia, 7:678-87, 2005
Dikmen ZG, Gellert G, Doğan P, Mason R, Antich P, Richer E, Wright WE, Shay JW, "A New Diagnostic System in Cancer Research: Bioluminescent Imaging (BLI)" Turk. J. Med. Sci, 35:65-70, 2005
Liu H, Gu Y, Kim JG, Mason RP, "Near Infrared Spectroscopy and Imaging of Tumor Vascular Oxygenation" Methods Enzymol., 386:349-378, 2004
9. Paroo Z, Bollinger RA, Braasch DA, Richer E, Corey DR, Antich PP, Mason RP, "Validating bioluminescence imaging as a high-throughput, quantitative modality for assessing tumor burden" Molecular Imaging, 3:117-124, 2004
Zhao D, Jiang L, Hahn EW, Mason RP, "Tumor physiological response to combretastatin A4 phosphate assessed by MRI" Int. J. Radiat. Oncol. Biol. Phys., 62:872?880, 2005
Yu J, Kodibagkar VD, Cui W, Mason RP, "19F: A versatile reporter for non-invasive physiology and pharmacology using magnetic resonance" Curr. Med. Chem, 12:819-848, 2005
Cui W, Otten P, Li Y, Koeneman KS, Yu J and Mason RP, "A novel NMR approach to assessing gene transfection: 4-fluoro-2-nitrophenyl-B-D-galactopyranoside as a prototype reporter molecule for B-galactosidase" Magn. Reson. Med., 2004; 51:616-620, 2004
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