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Molecular Imaging in Oncology
There are a variety of imaging methods that can display information about a patient‟s biochemistry, and no single modality is superior to all
others . Collectively, these methods are referred to as molecular imaging. Molecular imaging agents and methods have been developed for a variety of systems using different forms of energy. These include nuclear medicine methods, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), MRI, ultrasound methods, CT scans and optical technologies. Although the term „optical‟ implies the use of visible light, it is often more broadly
applied to include near-infrared (NIR) methods as well; the term „photonics‟ is sometimes used to describe both visible and non-visible
radiation. These technologies have different advantages and drawbacks. For example, CT and MRI are able to portray anatomical detail exceptionally well, whereas nuclear medicine and optical methods have very high sensitivity for detecting specific molecules but cannot portray
anatomical detail with high spatial resolution.
1. Thomasson DM, Gharib A, Li K. A primer on molecular biology for
96. imagers. Acad Rad 2004; 11 (Suppl): 85–
1. Molecular Targeted Imaging in Oncology with Radioscintigraphy
Imaging-based biomarkers have many potential uses in all phases of the drug development process, from target discovery and validation to pivotal clinical trials for drug registration . First, as disease biomarkers, imaging end points can be employed to define, stratify and enrich study
groups. One such approach is to apply imaging-based methods to identify appropriate patient populations in which to test targeted agents. An example would be the use of [18F]estradiol (FES) positron emission tomography (PET) scans to identify patients for aromatase inhibitor trials . Although it is routine to assess estrogen receptor status on the diagnostic biopsy of breast tumours, the result of this lab test will apply only to that piece of tissue tested and only to the time point in the course of the tumour at which the biopsy was obtained. Since tumours are heterogeneous, and change over time, the estrogen status of that biopsy may not be an accurate predictor of whether that patient‟s total tumour
burden will respond to hormonal therapy or aromatase inhibitors. It shows images where the FES-PET scan demonstrates that the majority of
bone metastases in this patient express the estrogen receptor, and the post-therapy FDG-PET scan confirms that the patient had a good therapeutic response to hormonal therapy.
9. Kelloff GJ, Sigman CC. New science-based endpoints to accelerate oncology drug development. Eur J Cancer 2005; 41: 491–501.
10. Mankoff DA, Peterson LM, Petra PH et al. Factors affecting the level and heterogeneity of uptake of (18F) fluoroestradiol (FES) in patients with estrogen receptor positive (ER+) breast cancer. J Nucl Med 2002;
Finally, as biomarkers of tumour response, imaging endpoints can also serve as early surrogates of therapy success . For example, clinical trials in breast cancer and other settings [e.g. non-small cell lung cancer (NSCLC) and oesophageal cancer] have demonstrated that
2-[18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET), a functional imaging modality, can provide an early indication of therapeutic response that is well-correlated with clinical outcome. FDG-PET thus has the potential to improve patient management, particularly by signalling the need for early therapeutic changes in non-responders and partial responders, thereby obviating the side effects and costs of ineffective treatment. As an early surrogate for
clinical benefit, the modality also has the potential to facilitate oncologic drug development by shortening phase II trials and detecting clinical benefit earlier in phase III investigations.
14. Kelloff GJ, Hoffman JH, Johnson B et al. Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development. Clin Can Res 2005; 11: 2785–2808.
2. Clinical Advances in PET and Tracer Development
3. Clinical PET/CT in Oncology
1. Diffusion MR Imaging in Tumors
2.Noninvasive Determination of Tissue Oxygen Concentration by
Overhauser Enhanced Magnetic Resonance Imaging
3. Pharmacokinetic Modeling of Dynamic Contrast Enhanced MRI in Cancer
Some clinical imaging methods have potential to facilitate early clinical pharmacokinetic/pharmacodynamic assessments, particularly in patients where traditionally there are no direct measures of
pharmacokinetics/pharmacodynamics throughout the tissues of the body and at the target. These approaches could be used in early studies comparing lead candidates designed to interact with the same target. One example is the use of dynamic-contrast-enhanced magnetic resonance imaging (DCE MRI) as a measurement of the exposure-dependent effects of drugs targeting the tumour vasculature (e.g. anti-angiogenesis) occurring prior to tumour shrinkage [11, 12]..
11. Leach MO, Brindle KM, Evelhoch JL et al. The assessment of antiangiogenic and
antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 2005; 92: 1599–1610.
12. Morgan B, Thomas AL, Drevs J et al. Dynamic contrast-enhanced
magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases. J Clin Oncol 2003; 21:
4. BOLD Imaging of Tumors
5. Dynamic MRI Techniques
6. Magnetic Resonance Spectroscopy in Cancer
A third area where imaging-based biomarkers have promise for speeding drug evaluation is by replacing or supplementing time- and labour-intensive dissection and histological analyses in both preclinical and clinical testing. These noninvasive approaches may enable longitudinal preclinical studies with greater relevance to future clinical study designs. Examples include several optical technologies, sometimes referred to collectively as „optical biopsy‟. Another example is the use of
magnetic resonance spectroscopy (MRS) to monitor total choline levels as a marker in functional imaging for adjuvant therapy for breast or prostate cancer, providing information about therapeutic effects within days after treatment .
13. Meisamy S, Bolan PJ, Baker EH et al. Predicting response to neoadjuvant chemotherapy of locally advanced breast cancer with in vivo
431. 1H MRS: A pilot study at 4 Tesla. Radiology 2004; 233: 424–
7. MR Lymphangiography
Functional Computed Tomography
Functional CT redefines CT as a technique that can depict vascular physiology of tumors in addition to detailed anatomy with the potential to provide in vivo markers of tumor angiogenesis. The accumulated data on technical validation and clinical application at this time have reached a critical mass sufficient for the equipment manufacturers to offer perfusion CT software packages commercially. Functional CT is readily incorporated into the patient ‟s routine CT examination, and clinical
experience has identified roles for the technique in cancer diagnosis, staging, risk stratification, and therapeutic monitoring. Using integrated PET/CT systems to combine perfusion CT with FDG-PET creates opportunities for advanced characterization of tumor biology.
Advances in Ultrasound
Ultrasound is still the first and key imaging modality for the routine assessment of patients with cancers. The last few years have seen notable developments on the introduction of new techniques that will expand the roles played by ultrasound. The latter includes the use of ultrasound as a means of inducting heat-mediated tissue coagulation and as a way to target the tumor circulation etc.
2. US Drug and Gene Delivery
Exposure to US causes a transient increase in cell membrane permeability, an effect known as sonoporation (35). Using this technique, tissues can be targeted to stimulate cellular uptake of a drug (e.g., a chemotherapeutic agent) or a gene. Sonoporation requires high acoustic powers (higher than that used in diagnosis and equivalent to those used in physiotherapy) but the power needed is markedly reduced when micro-bubbles are also present. A drug or gene can be incorporated in or on the surface of the microbubbles and tracked in the circulation with an imaging beam; when they are exposed to high power US, the microbubbles rupture, releasing the agent near the target tissue (36). In the case of oncological drugs, this has the advantage of decreasing the dose of the drug needed, so reducing systemic side effects. Encouraging initial in vitro studies have demonstrated sonoporation without inducing cell death (37).
(35).Miller M. Gene transfection and drug delivery. Ultrasound Med Biol 2000;26(suppl 1):59 –62.
(36).Unger E. Targeting and delivery of drugs with contrast agents.In: Thomsen H, Muller R, Mattrey R, eds.Trends in Contrast Media. Medical
412. Radiology.Berlin:Springer,1999:405 –
(37).Brayman A, Coppage M, Vaidya S, Miller M. Transient poration and cell surface receptor removal from human lymphocytes in vitro by 1 MHz ultrasound. Ultrasound Med Biol 1999;25:999 –1008.
1. Advances in Optical Imaging of Cancer
Optical methods represent an exciting new branch of imaging technology for cancer. Optical imaging is divided into intrinsic and extrinsic contrast mechanisms. Intrinsic optical imaging includes infrared (thermal), near infrared (oxygen saturation of hemoglobin), and light scattering. The latter can be used to detect early dysplastic and neoplastic tissue during endoscopy. Intrinsic optical imaging does not require the injection of a contrast agent but relies on the optical properties of tumors to differentiate them from normal tissue. Extrinsic optical imaging is provided by specially designed optical contrast agents. A class of these agents, termed “activatible”, are engineered fluorochromes that are non
fluorescing in their native state but.fluoresce only in the presence of a specific molecular target. These agents, often designed for the
near-infrared spectrum, may provide highly specific information about the characteristics of human tumors in the future.
Molecular Therapy Assessment
One particularly interesting application of enzyme-activated imaging agents has been to use them as tools for objective target assessment of the new therapeutic agents. In one study, the efficacy of an MMP-2 inhibitor (dosing, timing, etc.) was revealed with an MMP-2 targeted imaging probe (47). Small molecule-induced target inhibition could be externally imaged as early as eight hours after therapeutic drug administration. It is clear that the other classes of imaging agents will be developed to image the growing array of different drug targets.
Emission and reflectance imaging is becoming a useful clinical technique when probing supeficial tissue during intraoperative imaging or probing deep tissue structures using an endoscopic approach. These optical techniques are unique and noninvasive, and can quantify functional vascularization and oxygen saturation of tumors. Furthermore, there is an intensified effort to produce fluorescent probes, especially for the near-IR region, that target physiological and genetic responses. These probes, combined with appropriate imaging planar or tomographic technologies could allow unprecedented insights into the biology of living tumors and the cellular circuitry underlying these observations. Optical methods further use non-ionizing radiation and are generally compatible with most