Multi-modality molecular imaging of tumors Journal Article
| Authors: | Serganova, I.; Blasberg, R. G. |
| Article Title: | Multi-modality molecular imaging of tumors |
| Abstract: | Molecular-genetic studies of disease and our understanding of the multiple and converging pathways that are involved in disease development (eg, oncogenesis and tumor progression) have expanded rapidly over the past decade. The era of molecular medicine has begun and the benefits to individual patients are widely expected to be realized in the near future. For example, the formerly unresponsive and rapidly fatal gastrointestinal stromal tumors (GIST) and chronic myelogenous leukemia (CML) have shown remarkable responses to imatinib mesylate (Gleevec) treatment, a drug that targets several receptor tyrosine kinases (cKit and Bcr-Abl, respectively) that are mutated or constitutively overexpressed. Biomarker or surrogate imaging that reflects endogenous molecular/genetic processes is particularly attractive for expansion and translation into clinical studies in the near term. This is because existing radiopharmaceuticals and imaging paradigms may be useful for monitoring downstream changes of specific molecular/genetic pathways in diseases such as cancer (eg, FDG-PET). Biomarker imaging is very likely to be less specific and more limited with respect to the number of molecular-genetic processes that can be imaged. Nevertheless, it benefits from the use of radiopharmaceuticals that have already been developed and are currently being used in human subjects. Thus, the translation and application of biomarker imaging paradigms into patient studies will be far easier than either the direct imaging or reporter transgene imaging paradigms. The "direct" molecular imaging motif builds on established chemistry and radiochemistry relationships. Bioconjugate chemistry linking specific binding motifs and bioactive molecules to paramagnetic particles for MR imaging or to radionuclides for PET and gamma camera imaging is rapidly expanding. This has occurred largely through the development of new relationships and focused interactions between molecular/cellular biologists, chemists, radiochemists, imagers, and clinicians. The next generation of direct molecular imaging probes will come from better interactions between pharmaceutical companies, academia, and hospital centers. Such interactions are now being pursued with the objectives of developing and evaluating new compounds for imaging, compounds that target specific molecules (eg, DNA, mRNA, proteins), or activated enzyme systems in specific signal transduction pathways. However, a constraint limiting direct imaging strategies is the necessity to develop a specific probe for each molecular target, and then to validate the sensitivity, specificity, and safety of each probe for specific applications before their introduction into the clinic. Reporter gene imaging studies will be more limited in patients compared with animals, due to the necessity of transducing the target tissue or cells with specific reporter constructs, or the production of transgenic animals bearing the reporter constructs. Ideal vectors for targeting specific organs or tissue (tumors) do not exist at this time, although this is a very active area of human gene therapy research. Each new vector requires extensive and time-consuming safety testing before regulatory approval for human administration. Nevertheless, the reporter gene imaging, particularly the genetic labeling of cells with reporter constructs, has several advantages. For example, it is possible to develop and validate "indirect" imaging strategies more rapidly and at considerably lower cost than "direct" imaging strategies. This is because only a small number of well-characterized and validated reporter gene-reporter probe pairs need to be established. For example, there are now four well-defined human genes (hNIS, hNET, hD2R, and hSSTR2) with complementary, clinically approved, radiopharmaceuticals for PET or gamma camera imaging in patients. These four complementary pairs (gene + probe) are excellent candidates for future reporter gene imaging in patients. Importantly, these human genes are less likely to be immunogenic compared with the reporter g nes currently used in animals (eg, viral thymidine kinases, luciferases, fluorescent proteins). It should also be noted that a single reporter gene-reporter probe pair can be used in different reporter constructs to image many different biological and molecular-genetic processes. Once a complementary reporter-pair (gene + probe) has been approved for human studies, the major regulatory focus will shift to the particular backbone and regulatory sequence of the reporter construct and to the vector used to target reporter transduction to specific cells or tissue, both ex vivo and in vivo. The major factor limiting translation of reporter gene imaging studies to patients is the "transduction requirement": target tissue or adoptively administered cells must be transduced (usually with viral vectors to achieve high transduction efficiency) with reporter constructs for reporter gene imaging studies. At least two different reporter constructs will be required in most future applications of reporter gene imaging. One will be a "constitutive" reporter that will be used to identify the site, extent, and duration of vector delivery and tissue transduction or for identifying the distribution/trafficking, homing/targeting, and persistence of adoptively administered cells (the "normalizing" or denominator term). The second one will be an "inducible" reporter that is sensitive to endogenous transcription factors, signaling pathways, or protein-protein interactions that monitor the biological activity and function of the transduced cells (the "sensor" or numerator term). The initial application of such double-reporter systems in patients will most likely be performed as part of a gene therapy protocol [14] or an adoptive therapy protocol where the patient's own cells are harvested (eg, lymphocytes, T cells, or blood-derived progenitor cells), transduced with the reporter systems, and expanded ex vivo, and then adoptively readministered to the patient. For example, adoptive T-cell therapy could provide a venue for imaging T-cell trafficking, targeting, activation, proliferation, and persistence [33,43]. These issues could be addressed in a quantitative manner by repetitive PET imaging of the double-reporter system in the same subject over time. We remain optimistic; the tools and resources largely exist and we should be able to perform limited gene-imaging studies in patients in the near future. The advantages and benefits of noninvasive imaging to monitor transgene expression in gene therapy protocols are obvious. The ability to visualize transcriptional and posttranscriptional regulation of endogenous target gene expression, as well as specific intracellular protein-protein interactions in patients will provide the opportunity for new experimental venues in patients. They include the potential to image the malignant phenotype of an individual patient's tumor at a molecular level and to monitor changes in the phenotype over time. The potential to image a drug's effect on a specific signal transduction pathway in an individual patient's tumor provides the opportunity for monitoring treatment response at the molecular level. At the moment this requires the use of "diagnostic" reporter gene transduction vectors that target specific organs or tissue (tumors), and this will initially limit the translation and application of reporter gene technology to patients. However, direct and surrogate molecular imaging may begin to fill this gap over the next decade. © 2006 Elsevier Inc. All rights reserved. |
| Keywords: | platelet derived growth factor; treatment response; unclassified drug; review; cancer growth; nonhuman; positron emission tomography; cancer diagnosis; neoplasms; biological marker; animals; gastrointestinal stromal tumor; imatinib; gene expression; epidermal growth factor receptor 2; fluorescence; tumor markers, biological; green fluorescent protein; luciferase; molecular imaging; diagnostic imaging; protein tyrosine kinase; cancer therapy; carmustine; carcinogenesis; experimental animal; imaging system; isotope labeling; bioassay; fluorodeoxyglucose f 18; positron-emission tomography; radiopharmaceutical agent; reporter gene; heat shock protein 90; fialuridine; gene probe; genes, reporter; tracer; molecular biology; image processing, computer-assisted; nuclear magnetic resonance; bioluminescence; autoradiography; genetic linkage; luciferin; virus enzyme; herpes simplex virus type 1 thymidine kinase; 9 (4 [18f]fluoro 3 hydroxymethylbutyl)guanine |
| Journal Title: | Hematology/Oncology Clinics of North America |
| Volume: | 20 |
| Issue: | 6 |
| ISSN: | 0889-8588 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2006-12-01 |
| Start Page: | 1215 |
| End Page: | 1248 |
| Language: | English |
| DOI: | 10.1016/j.hoc.2006.09.006 |
| PUBMED: | 17113460 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 4 June 2012" - "CODEN: HCNAE" - "Source: Scopus" |
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