Assessing responses to cancer therapy using molecular imaging

Biochimica et Biophysica Acta 1766 (2006) 242 – 261 www.elsevier.com/locate/bbacan

Review

Assessing responses to cancer therapy using molecular imaging André A. Neves, Kevin M. Brindle ⁎ Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK Received 21 June 2006; received in revised form 12 October 2006; accepted 16 October 2006 Available online 24 October 2006

Abstract Tumor responses to therapy in the clinic are still evaluated primarily from non-invasive imaging measurements of reductions in tumor size. This approach, however, lacks sensitivity and can only give a delayed indication of a positive response to treatment. Major advances in our understanding of the molecular mechanisms responsible for cancer, combined with new targeted clinical imaging technologies designed to detect the molecular correlates of disease progression and response to treatment, are set to revolutionize our approach to the detection and treatment of the disease. We describe here the imaging technologies available to image tumor cell proliferation and migration, metabolism, receptor and gene expression, apoptosis and tumor angiogenesis and vascular function, and show how measurements of these parameters can be used to give early indications of positive responses to treatment or to detect drug resistance and/or disease recurrence. Special emphasis has been placed on those applications that are already used in the clinic and those that are likely to translate into clinical application in the near future or whose use in preclinical studies is likely to facilitate translation of new treatments into the clinic. © 2006 Elsevier B.V. All rights reserved. Keywords: Diagnostic imaging; Cancer therapy; MRI; PET; Nuclear imaging; Metabolism; Angiogenesis; Gene expression; Apoptosis; Immunotherapy; Receptor imaging; Staging; Recurrence

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . 2. Tumor cell proliferation and metabolism . . . . . . . . 3. Alterations in tumor angiogenesis and vascular function 4. Gene expression . . . . . . . . . . . . . . . . . . . . . 5. Cell tracking and immunotherapy imaging . . . . . . . 6. Receptor imaging . . . . . . . . . . . . . . . . . . . . 7. Cell death . . . . . . . . . . . . . . . . . . . . . . . . 8. Staging, detection of recurrence and drug resistance . . 9. Clinical drug development and evaluation. . . . . . . . 10. Future challenges and directions. . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Medicine is undergoing a profound transformation; just as 20th century biology developed a more molecular approach to ⁎ Corresponding author. Tel.: +44 1223 333674; fax: +44 1223 766148. E-mail address: [email protected] (K.M. Brindle). 0304-419X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2006.10.002

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understanding biological systems, early 21st century medicine is adopting a progressively molecular approach to diagnosing and treating disease. Major breakthroughs over the last few decades in genomic, proteomic and metabolomic profiling have delivered significant advances in our understanding of the underlying molecular basis of disease. As a consequence, approaches to diagnosis and treatment of disease are being based

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increasingly on the underlying causative molecular events. An aim of molecular imaging, the subject of this review, is to provide disease-specific molecular information through targeted non-invasive imaging measurements [1]. Despite major developments in non-invasive clinical imaging, the evaluation of responses to cancer therapy are still based largely on volumetric and morphological criteria, in particular relative tumor sizes before and after treatment. These approaches, which were introduced 25 years ago [2], and revised in 2000 [3], are known as the WHO (World Health Organization) and RECIST (Response Evaluation Criteria in Solid Tumors) criteria, respectively. According to the earlier (WHO) criteria, the size of a tumor should be estimated based on two perpendicular diameters, and positive tumor response to therapy should be defined as a reduction of at least 50% in the product of these two diameters [2]. The WHO criteria were replaced in 2000 by unidimensional measurements (RECIST), which defined therapy-induced response as a 30% decrease in the largest dimension of the tumor [3]. These criteria, however, are very limited in their ability to assess the early effects of therapy, as was shown recently by the results of clinical trials using endothelial growth factor receptor (EGFR) kinase inhibitors, in which RECIST-based X-ray computed tomography (CT) was unable to predict patient survival benefit [4]. In addition to noninvasive imaging, the response of tumors to therapy can also be assessed by histopathological analysis, where response is normally defined as the percentage of remaining viable tumor, relative to the fibrotic tissue, produced by the treatment [5]. However, this analysis is normally only performed after complete resection of the tumor, since analysis of biopsies is usually unreliable due to intrinsic tumor heterogeneity [6]. This approach provides, therefore, only a limited, discontinuous, invasive and delayed method to detect treatment response. A better understanding of the molecular signature of cancer [7] has allowed the development and clinical use of a new generation of drugs that target specific molecular entities in cells, such as receptors, genes, or signaling pathways. However, DNA microarray-based disease profiling, together with the results of recent clinical trials using targeted therapies, have demonstrated clearly the intrinsic heterogeneity of human tumors, both genetically and phenotypically [8]. Patients with similar tumor types frequently have markedly different responses to the same therapy. The development of novel targeted cancer therapies could benefit significantly, therefore, from the introduction of targeted imaging methods, which allow an early assessment of treatment response. These could allow an oncologist to rapidly assess the effectiveness of a new therapy, long before there was any reduction in tumor volume. This would allow the abandonment of ineffective treatments at an early stage and the selection of more effective treatments, with attendant welfare benefits for the patient and cost benefits for the health care system. This new approach to imaging might facilitate, for example, the testing of new cytostatic therapies in patients with early stage disease, where they may be more effective, rather than in patients with late stage disease, which is usually the case now and where these treatments may be much less effective. Furthermore, since these therapies may have little initial effect

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on tumor volume, a positive response to treatment may be missed by conventional imaging measurements of tumor volume. Targeted, or molecular imaging (MI), involves the coupling of conventional imaging technologies with the use of specific molecular probes, designed to detect aspects of underlying biochemistry and cell biology that report in the image on disease progression and responses to treatment [9–14]. The development of effective MI agents for in vivo use in the clinic, however, is a formidable challenge, when compared with the development of agents designed for in vitro characterization of disease. Sensitivity, stability, specificity and the pharmacokinetics of the imaging probe are all key issues that must first be addressed and optimized in preclinical animal models. There are three main clinical imaging modalities that are currently being used for molecular imaging. These include the nuclear imaging methods, such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET), magnetic resonance imaging (MRI) and so-called photonic imaging, which includes optical imaging and imaging in the near infra-red (NIR). X-ray computed tomography (CT) and ultrasound methods have mostly been used to determine tissue morphology, although even here there are examples where they have been used to detect specific tumor responses to treatment, for example detection of apoptosis using ultrasound [15]. PET and SPECT have very high sensitivity (detection of radiolabelled probe molecules in the picomolar range), unlimited depth penetration, excellent signal-to-background ratios and a broad range of clinically applicable probes (see Table 1) [16]. The drawbacks include patient exposure to radiation, which may limit the number of examinations that can be performed, and relatively low spatial resolution (currently 3–7 mm, in clinical practice). PET has the added disadvantage that it requires a conveniently located and expensive cyclotron and radiochemistry facility to produce the very short-half life isotopes and to incorporate these into suitable probe molecules [17]. Some radiotracers, however, such as gallium −68, can be produced in relatively inexpensive reactors, and others, such as copper − 64 and fluorine − 18, which have longer half-lives, can be shipped from remote sites. The lack of spatial resolution in PET has been compensated to some extent by the introduction of combined PET/CT scanners [18], in which CT provides high-resolution anatomical detail that can be co-registered with the PET image. This has increased diagnostic accuracy, compared to PET alone [19], and has led to an improvement in patient management [20]. Dosimetry is another limiting issue in PET (see Section 2). Whereas, with MRI, several different types of image can be acquired within the same patient examination, the use of different isotopes within a single PET exam may be limited by dosimetry considerations. MRI has good depth penetration and can provide highresolution anatomical information, including good soft tissue delineation and, in addition, can provide functional information on such things as vascular permeability, tissue oxygenation and, using MR spectroscopy, cellular metabolism [21–23]. The technique can thus allow co-registration of molecular-based information with high-resolution anatomical detail within the same imaging modality. The main limitation of MRI is its low

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Table 1 Molecular imaging agents in cancer diagnosis Agent

Company/[Ref]

[18F]-FDG (MetaTrace FDG®) §05 [18F]-FLT #

CTI Molecular Compound Imaging (USA) GE Healthcare (USA) Compound

Feridex (Ferumoxide®) §96

Advanced Magnetics (USA) Advanced Magnetics (USA)

Ferumoxtran-10 (Combidex®, Sinerem®) [p1],[p2] Gadofosveset trisodium (Vasovist®) ∈05 Gadoxetic acid disodium (Primovist®, formerly Eovist®) ∈04 Indocyanine green (IC-green®) §59 FITC-labeled RPMC peptides [90Y]-Ibritumomab tiuxetan (Zevalin®) §02 Somatostatin analogues (Sandostatin® and others) §98 [99mTc]-Arcitumomab or IMMU-4 (CEA-Scan®) §96 [111In]-Capromab pendetide or CYT-356 (ProstaScint®) §96 [99mTc]-Nofetumomab (Verluma®) §96 [123I]-MIBG (Scintiscan®) §94 [111In]-Satumomab pendetide or CYT-103 (OncoScint CR/OV®) §92 [99mTc]-MIBI or SestaMIBI (Miraluma®, Cardiolite®) §90 [99mTc]-Votumumab (Humaspect®) ∈98-03 [99mTc]-Tecnemab KI® ∈96

Backbone

SPIO (80–150 nm) SPIO (20–40 nm)

Target

Modality

Application/detection

Glucose transporters and hexokinases Thymidine kinase 1 (DNA synthesis) Phagocytes

PET

MRI

Tumor cell proliferation and metabolism Tumor cell proliferation and metabolism Liver cancer

Phagocytes

MRI

Lymph node imaging

Albumin

MRI

EPIX Pharmaceuticals Compound (USA) and Schering (GER) Schering (GER) Compound

Hepatocytes

Akorn (USA) [24]

Unspecific

[25] Biogen Idec (USA)

Compound/ Dye Peptide Antibody

Novartis (USA)

Compound

Immunomedics (USA) Antibody Cytogen (USA)

Antibody

Boehringer Ingelheim/ Antibody NeoRx (USA) A.D.A.M. (USA) Compound Cytogen (USA) Antibody Bristol-Myers Squibb (USA) Organon Teknika (USA) Sorin (Ita)

Compound Antibody Antibody

[111In]-Indimacis 125 (Igovomab®) ∈96 [99mTc]-AFP-Scan® [p1]

CIS Bio/Schering Antibody (Fra) Immunomedics (USA) Antibody

Annexin A5 [p1] (a) Bombesin-, (b) Estrogenand (c) Folate -based probes #

[239] [200], [205], [201].

α5β1 integrin CD20 antigen on B-cell non-Hodgkin’s lymphoma sst-2/sst-5 receptors Carcinoembryonic antigen (CEA) Prostate-specific membrane antigen (PSMA) Carcinoma-associated antigen Adrenergic receptors Glycoprotein (TAG-72) P-glycoprotein, MDR-1, mitochondria Cytokeratin tumor-associated antigen High molecular weightmelanoma-associated antigen (HMW-MAA) Tumor-associated antigen CA 125) Alpha-fetoprotein

Protein PtdS on apoptotic cells Peptides (a) and Bombesin, estrogen and compounds (b, c) folate receptors

PET

Blood pool agent (anti-vascular/ anti-angiogenic therapies) MRI Liver conditions (tumors, cysts, other malignant or benign lesions) Optical/NIR Diffuse optical tomography (DOT) of breast cancer Optical/NIR Colon cancer NI/SPECT Certain types of non-Hodgkin’s lymphoma NI/SPECT Neuroendocrine tumours NI/SPECT NI/SPECT NI/SPECT NI/SPECT NI/SPECT

Recurrent and/or metastatic colorectal carcinoma Prostate carcinoma and soft tissue metastases Small-cell lung cancers (SCLCs)

NI/SPECT

Neuroendocrine tumours Adenocarcinomas (colorectal, ovarian, breast) Breast carcinoma and multidrugresistant lung cancer Colon adenocarcinoma

NI/SPECT

Cutaneous melanoma lesions

NI/SPECT

Ovarian adenocarcinoma

NI/SPECT

Primary liver and germ-cell cancer staging Assess tumor response to therapy (a) Many cancers, (b) Breast, (c) Ovarian

NI/SPECT

NI/SPECT NI/SPECT

(§,∈) = year approved by the FDA or the EU, respectively; NI = Nuclear Imaging; NIR = Near Infra Red Imaging; PET = Positron Emission Tomography; SPECT = Single Photon Emission Tomography; MRI = Magnetic Resonance Imaging; FLT = 3′-Deoxy-3′-[18F]fluorothymidine; MIBI = Methoxyisobutyl-isonitrile; [p1], [p2] = completed phase-1 or phase-2 clinical trials, respectively; # = used in humans; MIBG = Metaiodobenzylguanidine; PtdS = phosphatidylserine; FITC = Fluorescein isothiocyanate; SPIO = Superparamagnetic iron oxide particles; Ref = references. Data sources: U.S. Food and Drugs Administration (FDA)-http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm; European Medicines Agency (EMA)http://www.emea.europa.eu/htms/human/epar/eparintro.htm; Molecular Imaging and Contrast Agent Database-http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid= micad.TOC&depth=2; Magnetic Resonance Technology Information Portal-http://www.mr-tip.com/.

sensitivity, when compared with the nuclear imaging methods. This low sensitivity can be overcome to some extent by using targeted agents that give a large signal amplification (see Sections 5, 6 and 7). Several MI agents have been designed for MRI and used in a variety of preclinical and clinical applications (see Table 1). Photonic MI methods make use of fluorescent or bioluminescent probes. The use of near-infrared (NIR) fluorescence, in particular, which shows reduced tissue scattering, attenuation and autofluorescence, has allowed

greater tissue penetration depths (up to 10 cm) [24]. Photonic MI techniques do not involve ionizing radiation, are relatively inexpensive and high throughput. Limited tissue penetration, however, is a limitation and possibly the main reason for the lack of clinical applications to date. Photonic techniques, nevertheless, may enable the development of a new generation of MI agents to be used in the future for endoscopic measurements of the mucosal surfaces of the body [14,25], where a significant number of human cancers arise [26].

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We describe in the following sections some of the main applications of MI to assess and guide therapy in cancer. 2. Tumor cell proliferation and metabolism Tumors generally have high rates of aerobic glycolysis [27]. This intrinsic property has been exploited extensively in PETbased imaging to detect tumors and their responses to treatment. The glucose analogue, 2-( 18 F)-Fluoro-2-deoxy-D-glucose (FDG), is transported into cells by a family of glucose transporters and phosphorylated by hexokinase to give 2-(18F)Fluoro-2-deoxy-D-glucose-6-phosphate (FDG-6P). These two families of proteins (glucose transporters and hexokinases) are frequently overexpressed in tumors [28–30]. FDG-6P cannot be metabolized further and thus the tracer accumulates in cells at a rate proportional to glucose metabolism [31]. High glucose uptake rates, however, are not specific to tumors [32]. Brain [33], cardiac [34], infected and inflamed tissue [35] can also show increased rates of FDG uptake. Nevertheless, even though FDG is not a tumor-specific tracer, FDG-PET has become a powerful and quantitative tool in clinical oncology [36], which allows the detection and staging of disease by identifying and localizing tumors with high glucose metabolism. Surveys of the literature have shown that FDG-PET has a >90% sensitivity and specificity for the detection of metastases of most epithelial cancers [37,38]. Furthermore, it can also be used to predict the outcome of therapy, since a decrease in FDG uptake can indicate a positive response to treatment [39]. Qualitative visualization of PET scans is often sufficient to assess tumor response after therapy. However, in order to use the technique in a continuing follow-up, a quantitative analysis of tumor metabolic activity, based on FDG uptake, is often required [5]. The standardized FDG uptake rate (normally termed Standardized Uptake Value, or SUV) is the most often used parameter to quantify uptake. As a general empirical rule, a SUV value greater than three is normally associated with malignancy [20]. SUV values, however, can be affected by a variety of different factors. These include tumor size relative to the scanner resolution (the error in the estimates of FDG uptake of tumors smaller than 3 cm can be very large [5]), partial volume effects caused by tumor heterogeneity, radioisotope decay, temporal resolution (tracer uptake continues after administration for more than 2 h [40]), patient glucose levels (known to affect tracer uptake [41]) and imaging acquisition and processing (e.g. image filtering may contribute to an underestimate of SUV values [42]). The further development and validation of methods to assess quantitatively the response to cancer therapy are currently thought to represent the greatest unmet need in the clinical use of PET [36]. Over the last few years, FDG-PET has been shown to be able to detect early response to neoadjuvant or preoperative chemo/ radiotherapy in patients with various types of cancer, including advanced breast cancer [43,44], melanoma [45], gastric carcinoma [46], non-small-cell lung cancer [47,48], aggressive lymphoma [49–52], cervical [53], colorectal [54,55], central nervous system (CNS) [56], head and neck [57], prostate [58] and esophageal cancer [59]. This has improved patient

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management by avoiding ineffective therapy and predicting progression-free survival. In a clinical study involving forty patients with advanced adenocarcinomas of the esophagastric junction, FDG-PET was used prior to, and 14 days after therapy with cisplatin-based chemotherapy. PET imaging was able to differentiate responding from non-responding tumors early in the course of treatment. Tumor regression, assessed histopathologically, also correlated with metabolic response, evaluated by FDG uptake [60]. In a similar study, the response of patients with esophageal squamous carcinoma to chemoradiotherapy was significantly correlated with changes in tumor glucose metabolism, evaluated by FDG-PET, histopathology and patient survival [61]. The use of integrated PET/CT, in particular, has been proposed as a method to improve the accuracy of response evaluation in esophageal cancer, and the development of individualized therapeutic regimens [62]. 3′-Deoxy-3′-(18F)-fluorothymidine (or FLT) is an alternative PET tracer to FDG, which is currently under clinical investigation. FLT accumulates in proliferating tissues following phosphorylation, by S-phase specific thymidine kinase-1 (TK1), to FLT-monophosphate (FLT-MP). FLT has been shown to produce high contrast in tumors and in bone marrow [63,64] and is more selective in detecting brain tumors, compared to FDG, which is non-specifically retained in brain tissue, due to its high glucose metabolism. In a recent comparative study, Chen et al. used FDG- and FLT-based PET, on consecutive days, to assess brain tumor cell proliferation in a group of twenty-five patients with newly diagnosed or previously treated gliomas. FLT, 30 min after injection, was shown to be more sensitive than FDG for imaging recurrent high-grade tumors, and a better predictor of progression and disease-free survival [65]. In a similar study, Barthel et al. investigated the facility of FDG- and FLT-based PET to assess tumor response to antiproliferative treatment with 5-fluouracil, in a mouse model of radiation-induced fibrosarcoma. FLT uptake was correlated with proliferating cell nuclear antigen (PCNA) expression, and a more pronounced decrease in FLT uptake was observed compared to FDG uptake, following chemotherapy [66]. In another study of tumor cell proliferation, this time in lung, increased FLT uptake was found exclusively in malignant tumors. The correlation with cell proliferation was better than that observed with FDG, indicating that FLT has better potential as a marker for malignant cell proliferation [67]. Inflammation, and its associated increase in glucose metabolism, is one of the major sources of interference in clinical FDG-PET, and the main source of false-positive findings in oncology [68]. Van Waarde et al. used a rodent model of C6 rat glioma and sterile inflammation, to evaluate the ability of FDG and FLT to distinguish between these lesions. There was increased FDG uptake in both tumor and inflamed tissue, whereas FLT uptake was selective for tumor tissue in this animal model [69]. ( 18 F)-fluorocholine ( 18 F-FCh), ( 18 F)-fluoroethilcholine 18 ( F-FECh) and (11C)-choline (11C-Ch) have also been used as PET-detectable markers of tumor cell proliferation and metastatic potential, particularly in prostate [70,71] and brain

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[72] tumors. It is known that many tumors overexpress choline kinase-I, an enzyme that phosphorylates choline to phosphocholine in the pathway of phosphatidylcholine biosynthesis. Similarly to FDG and FLT, the phosphorylated versions of these choline-based tracers accumulate in cells at a rate proportional to the rate of cell proliferation. In a study involving sixteen patients with primary prostate cancer, 18F-FECh was shown to give slightly higher spatial resolution, compared with 11C-Ch, which was attributed to the shorter positron range of 18F [73]. The use of PET/CT with tracers that are indicative of cell proliferation has become a powerful clinical tool. However, issues concerning standardization of quantitative protocols and spatial/temporal resolution need to be addressed at an international level, in order to facilitate the use of such technologies in multi-center clinical trials of cancer therapies [5,18]. Magnetic resonance spectroscopy (MRS) has been used for many years to study the metabolism of tumor cells in vitro and in vivo (reviewed in [74,75]). A particular focus has been the levels of the phospholipid metabolites, phosphocholine (PC) and phosphoethanolamine (PE), which are frequently elevated in proliferating tumor cells and decreased in concentration in tumors responding to treatment. The increases in phosphocholine levels are thought to be due to increases in choline kinase activity and phospholipase C-mediated catabolism [75]. In serial measurements of nineteen patients with breast cancer, a decrease in the phosphomonoester peak in the 31P-MRS spectrum, which includes PC and PE, was significantly associated with stable or responding disease and an increase in PME was associated with disease progression [76]. In a 1H-MRS study of breast tumors seven of ten malignant lesions showed detectable levels of choline-containing metabolites whereas the remaining six patients with benign processes showed no detectable choline signal [77]. The use of 1H-MRS to characterize breast lesions has been reviewed [78]. In the prostate, pre- and post-therapy studies have demonstrated the potential of spectroscopic imaging to provide a direct measure of the presence and spatial extent of prostate cancer after therapy, a measure of the time course of response, and information concerning the mechanism of therapeutic response [79]. Studies in preclinical model systems have demonstrated the potential of spectroscopic measurements to detect the action of new therapeutic agents non-invasively. An anticancer drug that inhibits heat shock protein-90 (Hsp90), 17-Allylamino,17-demethoxygeldanamycin (17AAG), was shown in 31P-MRS studies of cultured tumor cells and tumor xenografts to increase the concentration of phosphocholine. It was suggested that these measurements have the potential to act as noninvasive pharmacodynamic markers for analyzing tumor response to treatment with 17AAG or other Hsp90 inhibitors [80]. Similar studies have been performed with other anticancer drugs, including a choline kinase inhibitor and a mitogen-activated protein kinase (MAPK) signaling inhibitor. Again, it was the level of phosphocholine that provided a pharmacodynamic marker for assessing tumor response [81,82]. A problem with these MRS measurements, particularly the 31PMRS measurements, is their lack of sensitivity, which leads to long data acquisition times and poor spectral resolution. This problem may be addressed to some extent in the future by the

introduction of dynamic nuclear hyperpolarization (DNP) techniques, which can increase the sensitivity of the MR experiment by more than 10,000-fold [83]. The introduction of, for example, a (13C)-labeled cell substrate, in which the 13C nucleus has been hyperpolarized, will allow the direct imaging of the location of this molecule in the body and, more importantly, its enzyme-catalyzed interconversion into other species. This exciting technique promises unprecedented insights into tissue function in vivo and may offer new ways to detect the responses of tumors to therapy. There remain however some significant technical problems with its implementation. The polarization is relatively short-lived (tens of seconds), which necessitates fast delivery of the labeled molecule into the cell and the use of very fast imaging methods. These problems limit the number of molecules that can be effectively polarized and used in vivo, nevertheless some preliminary studies have demonstrated the potential of this methodology [84–86]. 3. Alterations in tumor angiogenesis and vascular function For a tumor to grow beyond 1–2 mm in diameter there is a requirement for the growth of new blood vessels to supply essential nutrients, in particular oxygen [87]. In a nonmenstruating adult, significant angiogenesis, the formation of new blood vessels from pre-existing larger vessels [88], is normally only found in neoplastic tissues [89]. Angiogenesis is also an essential mechanism for tumor invasion and metastasis [90] and increased tumor angiogenesis is normally associated with poor disease prognosis. The development of therapeutic agents that can reduce or inhibit angiogenesis (anti-angiogenic drugs) or destroy the neovasculature of tumors (anti-vascular drugs) has received considerable interest. One possible advantage of such drugs, compared to conventional chemotherapy, is their potential for reduced susceptibility to acquired drug resistance (ADR). This is a major clinical problem observed in about 30% of cancer patients undergoing chemotherapy and results from the intrinsic genetic instability and heterogeneity of tumor cells [91]. Endothelial cells, on the other hand, on which anti-vascular and anti-angiogenic drugs act, are genetically more stable and more homogeneous and are thus presumed to be not so susceptible to ADR. Our growing understanding of the molecular mechanisms underlying angiogenesis, including the role of several growth factors that regulate the process, has enabled the development of a large number of drug candidates against vascular-specific targets [92] that can inhibit angiogenesis [93]. Low-molecular-weight anti-angiogenic compounds include those developed against the vascular endothelial growth factor (VEGF) family and their tyrosine kinase receptors (VEGFR), both of which are overexpressed in many solid tumors [94]. Low-molecular-weight anti-vascular compounds include the combretastatins [95], anti-angiogenic tubulin-binding agents that resemble colchicine, and flavone acetic acid (FAA) and 5,6dimethylxanthenone-4-acetic acid (DMXAA), which are also anti-angiogenic but have an anti-vascular mode of action as well. Both groups of anti-vascular agents are currently in

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clinical trials [96–98]. Several imaging modalities have been used to evaluate the effects of anti-angiogenic or anti-vascular drugs. Conventional morphological imaging techniques (e.g. CT) are not normally used since these drugs usually only arrest tumor growth and stabilize disease, rather than effect tumor regression [93,99]. Therefore, imaging modalities that are specifically sensitive to vascular function have been developed. We used dynamic contrast agent enhanced MRI (DCE-MRI) measurements of tumor perfusion to assess the anti-vascular effects of combretastatin A-4 phosphate (CA4P), a drug that is toxic to proliferating endothelial cells in vitro [100]. The drug showed efficacy at 10% of its maximum tolerated dose, inducing severe disruption of tumor blood flow and hemorrhage within 2 h of administration in a murine tumor model [101]. Further work on a range of murine and human xenografted tumors showed that the susceptibility to CA4P was correlated with vessel permeability, measured by DCE-MRI with a macromolecular contrast agent [102] (Fig. 1). Vascular permeability measured in this way is considered to be a surrogate marker of angiogenesis [103], and thus the correlation between vessel permeability and drug susceptibility was consistent with its toxic effects on proliferating endothelial cells. However Jordan et al., have observed a disconnection between VEGF levels and vascular permeability measured using a macromolecular MRI contrast agent. Drug-inhibition of the hypoxia-inducible transcription factor, HIF-1α, decreased VEGF levels within 2 h, which returned to control values by 8 h after treatment, however, vascular permeability was still reduced at 24 h [104]. DCE-MRI was used to evaluate the efficacy of CA4P in a phase-I clinical trial involving patients with advanced solid malignancies. Tumor perfusion, measured by DCE-MRI, was found to decrease in eight out of ten patients treated with the drug in a 5-day schedule. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices

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[105,106]. In another recent phase-I trial with patients with refractory disease, the administration of CA4P 1 h after a chemotherapeutic drug (carboplatin®) was shown to increase drug cytotoxicity by altering its pharmacokinetics [96]. The combined used of the two classes of drugs may prove to be advantageous in future trials [98]. Recommendations have been made for assessing vascular response from DCE-MRI data in order to ensure comparability between studies performed at different institutions [107]. Response should be assessed from a measured decrease in Ktrans, a kinetic parameter describing the transendothelial transport of low molecular weight contrast medium into the extravascular– extracellular space, or by a decrease in the area under the contrast agent uptake curve. The latter phenomenological parameter, has the virtue that it does not require any fitting of contrast agent uptake to a kinetic model and is, therefore, more robust. The interpretation of Ktrans depends on the tissue under examination. If blood flow to the tissue is insufficient then Ktrans approximates to tissue perfusion per unit volume, whereas if tissue perfusion is sufficient, and transport of the contrast agent out of the vasculature does not deplete the intravascular concentration, then Ktrans will provide some measure of vascular permeability. In a tumor both conditions may apply and therefore vessel permeability is better measured using macromolecular contrast agents, which leak more slowly out of the vasculature [103]. Macromolecular agents may become available for use in the clinic in the future. PET can also be used in the clinic to assess tumor perfusion and vascular volume. H2(15O) is normally used to estimate perfusive flow as the tracer diffuses freely into and out of the tumor interstitium, and is frequently used to assess malignant angiogenesis and response to treatment [108]. The half-life of 15 O, however, is very short (ca. 2 min), and therefore the procedure must be repeated at short intervals. Spatial resolution

Fig. 1. Effect of the anti-vascular drug, combretastatin A4-phosphate, on tumor perfusion. Tumor perfusion was assessed from the initial rate of inflow of Gd3+-based contrast agent (GdDTPA), using T1-weighted MR imaging, for five different tumor models. The tumors were implanted subcutaneously in mice. The images shown are parameter maps from the tumors in which intensity is proportional to the rate of contrast agent inflow. The images were acquired before (A) and 3 h after drug administration (B). Loss in signal intensity, corresponding to a reduction in perfusion, is observed for LoVo (i) and RIF-1 (ii) tumors, whereas this occurs to a lesser extent in SaS (iii), SaF (iv), and HT29 (v) tumors. The figure is reproduced from Beauregard et al. [102], with permission.

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is another major limitation, and signal intensity may be dominated by large blood vessels, which may render difficult the analysis of small capillaries in tumors. Measurement of circulatory parameters, including blood volume, can also be performed by inhaling trace amounts of carbon monoxide (CO), labeled with either 11C or 15O, which binds tightly to hemoglobin in red blood cells, and is thus partially distributed in relation to blood volume [109]. However, CO is also distributed according to hematocrit1, which can be highly variable in tumors [110]. The design of imaging agents targeted at the αvβ3 integrin, which is upregulated on the surface of proliferating endothelial cells, is another promising avenue to monitor the effects of antiangiogenic drugs [111]. MRI probes that recognize this target have been generated using gadolinium-labeled antibodies that recognize the integrin [112], and integrin-binding peptides, containing the arginine–glycine–aspartic acid (RGD) motif, labeled with paramagnetic nanoparticles [113–115]. Integrinbinding (RGD-containing) peptides have also been labeled with a positron-emitting isotope for detection using PET [116]. Photonic imaging-based methods can also been used to assess tumor angiogenesis [117]. Quantum dot (QD) imaging, for example, is a relatively new technology based on fluorescent nanoparticles with a size range of ca. 10–20 nm, which, compared to small organic fluorophores, give very bright and stable fluorescence [118–120]. Conjugation of these particles to targeting moieties may enable the visualization of cell/tissuespecific targets in tumor tissue [121]. Cai et al. recently reported the use of QD-labeled RGD peptides to image tumor vasculature in athymic nude mice bearing subcutaneous human glioblastoma tumors [122]. This novel near-infrared imaging platform for detecting angiogenesis may have an important future role in identifying and validating new therapeutic targets in animal models [123], and may also provide an alternative route to monitor clinically drug response in GI tract tumors, via endoscopy [124,125]. The development of imaging methods to assess the efficacy of anti-vascular and/or anti-angiogenic drugs has enabled the assessment of new drugs in early stage clinical trials and has assisted in the selection of drug dosages for later stage trials. Some of these drugs have now reached phase-II clinical trials (e.g. CA4P) and may potentially provide a future alternative or complementary route for cancer treatment. However, in order to allow comparison of MR imaging data of vascular function from different centers, the standardization and validation of clinical protocols and the reproducibility of measurements, in particular the analysis of tumor heterogeneity, are important issues that need to be addressed [107]. 4. Gene expression The treatment of cancer using gene therapy approaches continues to attract significant interest [126,127]. For this reason the development of methods capable of imaging vector

1 The hematocrit (HCT) is the percent of whole blood that is composed of red blood cells, being a measure of both the number and size of red blood cells.

delivery and subsequent gene expression have received particular attention in the last few years. Several reporter gene systems have been proposed for nuclear [128,129], photonic [130] and MR imaging [131–133]. These have used either constitutive or inducible promoters. The former, by driving the expression of a gene product that generates an imaging signal, have typically been used to monitor vector delivery and expression. The latter are generally used to monitor changes in cellular or physiological processes in tumors, which affect the activity of the inducible promoter and thus the concentration of an imaging-detectable marker. Gene reporter imaging can thus be made cell or tissue specific, providing a valuable insight into the specific molecular/genetic machinery of tumors. The most common reporter gene systems are based on: (1) green or red fluorescence proteins; (2) luciferases that can enzymatically activate a non bioluminescent substrate; (3) the herpes simplex virus-1 thymidine kinase [134], that can enzymatically modify an imaging probe molecule which then accumulates in the transfected tissue or (4) a cell surface receptor that binds or mediates the endocytosis of a labeled ligand, that is detectable by imaging [135]. Green (GFP) and red (RFP) fluorescent proteins have been very widely used in studies of cell biology [136–138] and a full discussion of their use is beyond the scope of this review. They have been used to study gene expression patterns and to monitor the localization of labeled fusion proteins. In the more limited context of this review, the following examples illustrate the type of measurements that can be performed using these systems. Oncolytic adenoviral activity was monitored in mice, by fusing a minor capsid protein with RFP. The fusion had only a minor effect on viral replication, encapsidation, cytopathicity, thermostability and adenoviral receptor binding [139], offering a promising route for monitoring oncolytic activity of adenovirusmediated gene therapy. Mayer-Kuckuk et al. evaluated antifolate therapy by exploiting the rapid increase in dihydrofolate reductase activity (DHFR) upon exposure of cells to anti-folates [140]. Mouse cells transfected with a DHFR–GFP fusion protein and exposed subsequently to the anti-folate trimetrexate (TMTX), showed increased expression of the fusion protein. Tissue autofluorescence in the emission range of these fluorochromes and low tissue penetrance (1–2 mm) can be serious limitations, reducing the sensitivity and specificity of whole-body imaging [127]. However, background autofluorescence can be deconvolved using multispectral imaging [141]. Bioluminescence-based imaging (BLI) reporters, in particular those based on luciferases (firely-fLuc, Renilla-rLuc and Gaussia-gLuc) [142,143], are unaffected by background and can be more sensitive techniques for whole-body animal imaging than fluorescence-based imaging. Bioluminescence provides a simple, robust, inexpensive and very sensitive method to image biological processes in vivo [134]. However, luciferase activity requires the systemic delivery of reporterspecific substrates (e.g. luciferin and coelenterazine, for fLuc and rLuc respectively) and also Mg and ATP, as co-factors, in the case of fLuc. Transport of coelenterazine by the multidrug resistance-1 P-glycoprotein complex (MDR1-Pgp) has been exploited to monitor the activity of this drug transporter. In cells

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stably transfected with a codon-humanized Rluc reporter, coelenterazine-mediated bioluminescence was increased by MDR1-Pgp expression and this could be reversed by Pgp inhibitors, thus providing a potential route for the highthroughput screening of drug resistance pathways in cancer [144]. In another application of BLI-based gene reporter imaging, the growth and therapy-induced cell death of gliosarcoma-derived rat brain tumors, was investigated by transfecting the cells to express fLuc. Tumor cell death, evaluated by MRI measurements of tumor volume, was highly correlated with the BLI measurements [145]. However, the requirement to transfect cells with luciferases, deliver a bioluminescent substrate and the limited tissue penetration of the emitted light means that these approaches are unlikely to find direct clinical application, and are likely to be used largely in preclinical animal studies. A wide range of applications has been proposed based on the herpes simplex virus-1 thymidine kinase (HSV1-tk). This gene reporter system can be used to modify enzymatically an imaging probe molecule that selectively accumulates in the transfected tissue and/or to convert a low-toxicity prodrug into its cytotoxic counterpart. Replication-competent vectors expressing HSV1tk, that do not induce neuropathogenicity, have been developed and validated for safety and efficacy in several mouse models and in phase-I clinical trials [146,147]. Oncolytic HSV1-based vectors expressing genes that induce cell suicide [148] or produce immunostimulatory [149] factors have been designed to induce tumor destruction [150]. HSV1-tk [129], and a mutant variant (HSV1-sr39tk) [151] have been used as a pro-drug converting enzyme for a number of anticancer gene therapy approaches [152]. Viral thymidine kinase has broader substrate specificity compared to its endogenous mammalian homologue, and can convert the low-toxicity pro-drug ganciclovir (GCV) into toxic compounds that result in selective cell death. Gambhir et al. synthesized an (18F)-labelled version of ganciclovir ((18F)ganciclovir or FGCV) and demonstrated in a mouse model, that FCGV could be phosphorylated by viral HSV1-tk, similarly to the unlabelled substrate, and accumulated in transfected cells expressing the viral kinase [153]. More recently the same authors have proposed an alternative PET tracer, (18F)-fluoropenciclovir (FPCV), with improved sensitivity compared with FGCV, as a reporter probe for imaging low levels of HSV1-tk expression in vivo [154]. Approaches to prevent a possible immune response to viral thymidine kinases are being investigated [155]. Radiolabeled synthetic somatostatin analogues (see Section 6) have been used routinely in clinical imaging of gastroenteropancreatic neuroendrocrine tumors for more than a decade [156]. The somatostatin type-2 receptor (SSTr2) has been used more recently as a reporter probe for radionuclide and PET imaging of gene transfer. Rogers et al. used a somatostatin analogue (demotate-1) chelated to 94m-Tc as a targeting agent to assess, using micro-PET, the adenoviral-mediated expression of SSTr2 in a mouse model [157]. The uptake of (94m-Tc)demotate-1 in transfected tumors was significantly greater than the uptake in other tissues. The label was also efficiently cleared via the kidneys, suggesting that this could be a highly sensitive method to evaluate SSTr2-based reporter gene expression.

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The Na/I symporter (NIS) is responsible for iodide uptake in the thyroid and salivary glands and in the gastric mucosa [158]. Groot-Wassink et al. used the human NIS gene (hNIS) as a reporter, showing that expression of hNIS, following adenoviral gene delivery, can be monitored in vitro after incubation with 125 I. Iodide uptake in the transduced cells was directly correlated with the levels of gene expression [159]. Subsequent experiments in live mice, using PET and 124I as the tracer, demonstrated that quantitative information on NIS gene expression could be also obtained in vivo [160]. Several MRI-based gene reporters have been described. Louie et al. described a Gd3+ chelate, in which the paramagnetic Gd3+ ion was shielded from water by a galactose residue. Cleavage of the galactose residue from the chelate, by β-galactosidase, a gene reporter that is often used in biology, resulted in an increase in the relaxivity of the agent and a consequent increase in signal intensity in T1-weighted MR images [132]. Weissleder et al. used the transferrin receptor as the reporter in conjunction with a transferrin molecule labeled with paramagnetic nanoparticles. Expression of the reporter (the transferrin receptor) led to increased uptake of the paramagnetic transferrin and loss of signal intensity in T2*-weighted MR images [133]. More recently, Genove et al., have used the ferritin gene as the reporter. Expression of the gene leads to production of the ironbinding protein, ferritin, which is paramagnetic and leads to loss of signal intensity in T2*-weighted MR images [131]. Gene reporter systems, such as those described above, could provide valuable information in assessing the delivery, primary transduction and subsequent expression of gene therapy vectors. Alternatively, inducible vectors can be used to assess cellular or physiological processes, in which these processes affect the activity of an inducible promoter and consequently drive expression of a reporter protein that leads to tissue retention of an imaging probe molecule. These can be a valuable tool in cancer for studying the dynamics of disease progression and/or the outcome of different therapies. For example, p53 is the most commonly mutated gene in human cancer [161] and its expression is closely linked to disease progression. A retroviral dual reporter gene vector was constructed using HSV1-tk and GFP (TK-GFP) and used to monitor transcriptional activation of p53-dependent genes [162]. The TK-GFP sequence was placed under control of an artificial cis-acting p53-specific enhancer and the resulting vector used to transduce p53 wild-type (p53+/+) and mutant cells (p53−/−), which were then implanted to form tumor xenografts in rats. Drug-induced DNA damage induced upregulation of p53 transcriptional activity, which could be detected in the p53+/+ tumors through both an increase in GFP fluorescence and by increased trapping of the PET tracer ( 124 I)-FIAU [2*-fluoro-2*-deoxy-1-b-D-arabinofuranosyl-5(124I)iodouracil] [162]. This approach could be used to evaluate novel therapies that target the p53 pathway or to study activation of this signaling pathway in different experimental models of the disease. The ability to image in real-time and non-invasively endogenous gene expression would also be a powerful asset in clinical practice, as it could provide a tool for probing the gene expression profiles of various tumors and for assessing the

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outcome of tumor therapy. An approach, which may allow this concept to become a reality in the clinic in the future, is based on the use of peptide nucleic acid (PNA) anti-sense oligonucleotide probes that recognize particular mRNA sequences in the cytoplasm of targeted cells [163]. Single-stranded oligonucleotide probes can be designed as anti-sense chemotherapies to block or reduce the expression levels of specific oncogenes and also labeled with a positron or single-photon radionuclide emitter to enable imaging of specific transcript levels in tumor cells [164]. MYC and the insulin-like growth factor-1 receptor (IGFR1) are frequently overexpressed in estrogen-positive breast cancer cells [165]. A PNA probe designed to target MYC mRNA, was labeled with 99m-Tc and used to assess, noninvasively using radionuclide imaging, the levels of expression of this transcript in human MCF7 breast cancer xenografts in nude mice [166]. An IGF1 peptide was conjugated to the Cterminus of the PNA probe and used to deliver the PNA into the cell via IGFR1. Suzuki et al. designed a PNA probe, labeled with 111In, that was antisense to rat caveolin-1-alpha (CAV) mRNA, which is upregulated in brain tumors, in order to selectively image its expression in brain glioma. The delivery system in this case employed a murine monoclonal antibody against the rat transferrin receptor. The murine antibody was conjugated to streptavidin and subsequently attached to the biotinylated PNA [167]. 5. Cell tracking and immunotherapy imaging Several novel cellular therapies, in particular those based on stem cells, are currently being tested in the clinic for autoimmune and degenerative diseases and also as immunotherapies for cancer [168,169]. The latter are promising cell-based therapies that involve activation of the patients' immune cells ex vivo against particular tumor-specific antigens. These activated immune cells are then injected back into the patient, thus promoting an immune response against the tumor. For example, adoptive T-cell therapy involves infusing a large number of activated tumor-specific T-cells into patients, in an approach that was first demonstrated in animal models [170]. However, this potentially powerful cancer therapy has so far shown limited efficacy in early stage clinical trials, where reported response rates have been in the range of 10–25% [171]. These modest rates are thought to be due mainly to limitations in the numbers of tumor cells collected and the intrinsic difficulty of expanding tumor antigen-specific T-cells ex vivo. Several soluble factors (e.g. cytokines, interleukins) have been used to minimize the de-differentiation of T-cells in vitro [172] and to boost their activity after immunization [173]. Imaging of labeled T-cells post-implantation could make an important contribution to the development of this approach [174]. Cells can be labeled using a variety of different agents, in particular radioisotope-labeled probes [175,176] for PET and SPECT and bioluminescent probes for optical imaging [177]. MRI of cells labeled with iron oxide-based nanoparticles is also proving to be a very effective method for cell tracking in vivo [178–180]. These nanoparticles often have little or no effect on cell function and can allow the tracking of single cells, even at

clinical magnetic field strengths [179,181]. Kircher et al. used MRI to monitor the trafficking of CD8+ T-cells into an immunogenic melanoma tumor model, expressing a model tumor antigen, chicken ovalbumin [182]. The T-cells were harvested from OT-1 mice, which possess T-cells that express a transgenic T-cell receptor that recognizes ovalbumin. The cells were activated in vitro, by treatment with an ovalbumin peptide and antigen-presenting cells that had been treated with IL-2, and then labeled using a Tat peptide-derivatized nanoparticle. The Tat peptide promotes cell uptake of the nanoparticle by endocytosis. In a similar study, we monitored T-cell infiltration of a lymphoma tumor model expressing ovalbumin. In this case a heterogeneous T-cell preparation from wild-type mice was used, in which activated CD8+ T cells recognizing ovalbumin were obtained from animals that had rejected a lymphoma tumor expressing relatively high levels of ovalbumin. In this case the cells were labeled with a citrated iron oxide-based magnetic nanoparticle, which is readily taken up by endocytosis following addition to the culture medium [183]. In both studies a heterogeneous pattern of T-cell recruitment to the tumors was observed between 24 and 144 h after cell injection (see Fig. 2). As well as immune cell infiltration, immune rejection in this lymphoma model was also accompanied by an increase in vascular volume, which could be detected using DCE-MRI [184]. We suggested that DCE-MRI might be usable clinically to detect the early signs of tumor immune rejection. Dendritic cells have also been used in the development of cell-based vaccines for cancer immunotherapy [168,185,186]. The cells are harvested from the patient's blood or bone marrow, exposed in vitro to patient-specific tumor antigens and then cultured in vitro to produce large numbers. These amplified and activated dendritic cells are then injected back into the patient, where the delivery and subsequent migration of the dendritic cells to regional lymph nodes is essential for stimulation of Band T-lymphocytes. De Vries et al. used MRI and dendritic cells labeled with magnetic nanoparticles to detect very low numbers of these cells in lymph nodes of patients with melanoma, allowing the assessment of dendritic cell delivery and lymph node-associated cell migration [181]. Neural progenitor cells (NPCs) have also been proposed as potential new forms of cancer treatment, primarily due to their ability to infiltrate tumors [187]. These cells can be used as delivery agents for retroviral- or herpes simplex virus-mediated cytotoxic gene therapies (see Section 4). The migratory capacity of NPCs towards brain tumors has been investigated in a nude mouse model of intracranial glioblastoma. NPCs were transfected with the fLuc gene and implanted in different brain locations, or injected intravenously (i.v.) or intraperitoneally (i.p.). Cell migration and accumulation at the tumor site were observed, using serial bioluminescence imaging, when the cells were implanted directly into the brain or injected i.v. [188]. Zhang et al. labeled NPCs and bone marrow stromal cells (MSCs) with lipophilic dye-coated superparamagnetic particles and transplanted these cells into rats bearing 9L-gliosarcomas, via the cisterna magna and tail vein, respectively. Gradient echo T2*-weighted images revealed dynamic migration of NPCs and MSCs, where tumor infiltration of labeled cells was observed

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Fig. 2. Magnetic resonance imaging of the trafficking of labeled T-cells into implanted lymphoma tumors in mice. The T-cells were labeled with iron-oxide nanoparticles and detected using T2*-weighted MR imaging. The images were acquired before (i, ii) and 2 days after injection of the labeled T-cells (iii, iv). The presence of labeled cells is observed as regions of hypointensity (arrowed) in the images (iii, iv). The figure is reproduced from Hu et al. [183], with permission.

through loss of signal in specific tumor areas. Histological analysis, using Prussian blue staining, showed that the grafted cells targeted tumor areas in the brain that corresponded to areas that showed loss of MRI signal [189]. MRI using iron oxide nanoparticles may become an important tool in the future for monitoring the efficacy of stem cell transplantation therapies in the clinic [178]. A problem with iron oxide-based MRI labels, however, is that these are detected through the negative contrast that they produce in T2*weighted images. This may make them difficult to detect in tissues, like tumors, that show preexisting heterogeneous contrast. Although there are techniques to convert this negative contrast into positive contrast [190,191], it may in some circumstances be preferable to use alternative labels that produce positive contrast, such as Gd(III)-chelates in T1-weighted images [192]. An alternative MR-detectable cell label was recently proposed by Ahrens et al., who used a fluorinated contrast agent to label dendritic cells ex vivo [193]. (19F)-MRI was used subsequently to track the labeled cells non-invasively in live mice and the images acquired were subsequently superimposed on conventional proton MR images, which provided an anatomical context. The fluorinated agent was retained by the cells, with minimal loss of cell activity. 6. Receptor imaging The targeting of cancer-specific receptors expressed on the surface of tumor cells has received considerable attention. Many of these receptors are involved in signaling pathways that regulate tumor cell division, proliferation and death. The development of

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novel, potentially less toxic, therapeutic drugs that can block, with high affinity and specificity, these receptors is a major research area in cancer drug development [194]. MI provides a means for the non-invasive assessment of receptor expression in patients' tumors, and therefore provides a unique opportunity to study receptor-mediated pathways in cancer. Several receptor-specific probes have been proposed for PET/SPECT [195], optical imaging [196,197] and MRI [198,199]. Some of these receptorspecific probes are in clinical use (see Table 1). The somatostatin [156], bombesin [200] and folate [201] receptors, in particular, are over-expressed in a variety of human cancers, including breast, pancreatic, small cell lung, prostate and thyroid [202,203]. Several radiolabeled probes that can detect the expression of these receptors in tumors have been approved for clinical use (see Table 1). For example, patients with progressive metastatic or recurrent thyroid cancer, that show high levels of the somatostatin receptor on scintigraphy, can be selected for targeted radionuclide therapy using labeled peptides [204]. (18F)-fluorinated progestins, estrogen [205] and androgens [206], have also been used as targeted contrast agents (CAs) for imaging receptor-positive breast and prostate tumors, respectively. In breast cancer, estrogen-receptor (ER) expression can be imaged using (18F)-fluoroestradiol (FES)-based PET. FES targets the ER and is able to predict response to tamoxifen®, a drug that blocks the ER, preventing the proliferation-inducing action of estrogens. Linden et al. tested the ability of FES-PET imaging to predict response to hormonal treatment in refractory metastatic breast cancer patients, previously treated with aromatase inhibitors. Quantitative FES-PET was able to predict response to hormonal therapy. In this particular study [205], the use of the technique to guide treatment selection would have increased the rate of response from 23% to 34% overall, and from 29% to 46% in a subset of patients lacking Her2/Neu receptor overexpression (see below). Endothelial growth factor (EGF) receptor over-expression also occurs in a variety of human breast cancer cells [207]. A fluorescent optical probe, based on conjugation of EGF to the Cy5.5 fluorochrome (EGF-Cy5.5), has been used for detection of the EGF receptor (EGFr) in breast cancer xenografts [208]. Thus, in this tumor model, EGF-Cy5.5 may be used for noninvasive imaging of the response of the tumor to EGFr-targeted therapies. The Her2/Neu receptor is a member of the EGFr family and another important cancer-related receptor that is over-expressed in several human tumors, notably on a subset of breast cancer cells [209]. Artemov et al. imaged the Her2/Neu receptor in a mouse model of breast cancer, using a two-stage approach, in which administration of a biotinylated Her2/Neu-specific antibody was followed by the administration of Gd3+-labeled avidin [199]. This technology provides a tool for assessing the expression levels of the receptor in breast cancer patients, and potentially the selection of a patient subset that should benefit from antibody-based therapy against the Her2/Neu receptor. However, the intrinsically low sensitivity of MRI, may be an important clinical limitation in the assessment of low levels of receptor expression.

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Orlova et al. have recently reported the radioiodination of a Her2/Neu-specific affibody2, a small protein with picomolar affinity for the receptor [210]. The labeled affibody was tested in vivo, and showed high-contrast visualization of Her2/Neu-expressing xenografts in mice, 6 h post-injection. The tumor uptake at 4 h post-injection increased 4-fold, with 9% of the injected dose accumulating in the tumor tissue. Affibody molecules represent a promising novel class of targeting molecules that could be used as relatively small, high-affinity, cancer-specific ligands, and that are well suited for tumor MI, providing a possible new route for imaging tumor-specific receptors. 7. Cell death Apoptosis, or programmed cell death, is an integral part of the development of multicellular organisms [211]. This highly regulated and genetically defined cellular process constitutes the main mechanism by which cells die, both in healthy and diseased tissues. The other well-recognized form of cell death, necrosis, is an accidental and unregulated form of cell death that normally occurs as a result of a physicochemical insult. Cell death is now recognized as a complex continuum of mechanisms, which include the apoptotic pathways, necrosis and autophagy [212]. The latter being an alternative form of cell death that occurs normally in some cell types following nutrient deprivation. These different forms of cell death cannot easily be distinguished as dying cells can display a wide range of characteristics, some of which are predominantly necrotic while others are symptomatic of apoptosis. This makes imaging of apoptosis, and its separation from other forms of cell death difficult in vitro and nearly impossible in vivo. From a clinical point of view, however, it is important to detect cell death in all its forms [212,213]. Preclinical and clinical studies have shown that the detection of apoptosis, or cell death in general, can potentially be used to provide an early indication of the success of therapy, providing prognostic information and guiding the course of subsequent treatment [214,215]. Specific and sensitive detection of apoptosis in the clinic, using MI techniques, may thus in the future provide an alternative or complementary technique to FDG- or FLT-based PET (see Section 2) for detecting the early responses of tumors to treatment. A range of non-invasive imaging techniques have been developed to detect apoptosis in vivo, including MRI and MRS [216,217], nuclear imaging, in particular SPECT [218], and photonic imaging [219]. The application of PET applications in this area has been more limited, nevertheless, a (18F)-labelled annexin V has been used recently for the detection of apoptosis [220]. Ultrasound has also been used to detect apoptosis at relatively high resolution [15] and has the important advantages of relatively low cost and availability at the bedside. In the field of magnetic resonance, early attempts to detect apoptosis focused on identifying metabolic markers of the process using spectroscopic techniques [221,222]. We used (31P)-MRS to detect metabolic markers in different tumor cell 2 Affibodies® are 6-kDa proteins that mimic antibodies and are derived from one of the IgG-binding domains of Protein A.

lines in culture. These markers included cytidine diphosphocoline (CDP-choline) and fructose 1,6-biphosphate (FBF) [223,224]. However, these MR spectroscopic measurements are limited in their ability to detect apoptosis non-invasively in vivo. This is mainly due to lack of spectral resolution, and also lack of sensitivity, the latter resulting in low spatial resolution and long data acquisition times. Proton MRS has also been used to detect apoptosis by monitoring the accumulation of cytoplasmic mobile lipid droplets, which give rise to relatively intense and high-resolution signals in the (1H)-MR spectrum. These measurements, which were first made on apoptotic cells in culture [225], were used subsequently to detect apoptosis in a gene therapy model of rat brain glioma [226]. We have shown recently that the technique can also be used to detect apoptosis in a murine lymphoma in vivo, in mice treated with a cocktail of chemotherapeutic drugs [227]. However, the utility of this method for detecting apoptosis is compromised, to some extent, by possible contamination with signal from adjacent fat deposits and by the presence of pre-existing lipid droplets in many tumor cells. Nevertheless, it has the virtue that it is completely noninvasive and so could be used in the clinic today. Other MR parameters have also been proposed as surrogate markers for generalized tumor cell death following therapy (reviewed recently by Kettunen and Brindle [217]). Perhaps the most promising of these parameters is the apparent diffusion coefficient (ADC) of water, which increases markedly following induction of tumor cell death and is most likely the result of changes in tissue density [228,229]. Diffusion-weighted MRI, which is sensitive to changes in water ADC, is already widely used clinically and although changes in water ADC are not specific for apoptosis, measurements of ADC have significant clinical potential to assess therapy-induced cell death. This is especially the case in brain tumors, which are largely unaffected by movement, which can significantly compromise these measurements in other areas of the body. Hamstra et al. examined thirty-four patients with malignant glioma by diffusion MRI before and after treatment. Functional diffusion maps were calculated from the differences in tumor–water diffusion values. These images were found to be strongly correlated with patient radiographic response, time-to-progression, and overall survival [230], providing a route to individualization of treatment or evaluation of clinical response. ADC has also been used to predict tumor responses in a group of thirteen patients with metastatic liver lesions, that originated from breast cancer [231]. ADC values and tumor volumes were estimated from MR images obtained prior to, and at 4, 11, and 39 days following chemotherapy. Diffusion MRI was able to predict response by 4 or 11 days after initiation of therapy, the highest concordance being observed in smaller tumor metastases (less than 8 cm3 in volume at presentation). Caspases are intracellular cysteine aspartyl-specific proteases that play a crucial role in the early stages of programmed cell death [232] and are therefore a good target for the development of MI techniques to detect apoptosis. Using fLuc-based bioluminescence imaging in nude mice, Laxman et al. developed a caspase-cleavable reporter probe able to detect tumor apoptosis following chemotherapy [233]. Although not relevant clinically,

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this approach could allow high-throughput screening of pro/antiapoptotic drugs, either in cell lines or in transgenic animals. An early event in apoptosis, that closely follows activation of caspase-3, is the externalization on the cell surface of an abundant phospholipid, phosphatidylserine (PS), which is normally confined to the inner leaflet of the plasma membrane bilayer. The early exposure of PS on the cell surface serves as an important signal to neighboring macrophages that the cell is committed to the death pathway and must be removed from the tissue. PS exposure has been arguably the most pursued target for the detection of cell death using MI methods. The 40-kDa vesicle-associated protein, Annexin V (AnxV), which has been the most widely used PS-targeting moiety, binds PS in a calciumdependent manner and with high (nanomolar) affinity. Initially AnxV was coupled to fluorescent dye molecules and used as an apoptosis detection reagent for fluorescence microscopy and flow cytometry [234]. Subsequently AnxV was coupled to a radionuclide ( 99m Tc) and used to detect apoptosis noninvasively in animals [218] and in the clinic [235,236] using radionuclide imaging techniques. Early stage clinical studies using radio-labeled AnxV (99mTc/HYNIC3/AnxV) [237,238], however, have had limited success, due mainly to poor clearance and biodistribution, which emphasizes the crucial importance of these parameters in CA development. The elevated accumulation of the CA in the liver and kidneys is a particular challenge, which may require the use of alternative chelating agents or radionuclides [239]. However, there are currently no clinical trials using radionuclide-labeled AnxV, to further evaluate its potential to assess the outcome of cancer therapy. Photonic imaging methods have also been used to image AnxV labeled with fluorochromes [240] or NIR fluorochromes [241] in animal tumor models. These techniques may become particularly useful in the future in the screening of novel drugs in preclinical studies. We have used a smaller PS targeting agent, based on the C2A domain (14.2 kDa) of another vesicle-associated protein, synaptotagmin-I, which also binds PS with nanomolar affinity and in a calcium-dependent manner. After verifying initially that a fluorescently-labeled version of C2A would bind apoptotic cells, using flow cytometry, we went on to label the protein with SPIO nanoparticles and demonstrated that this reagent would allow MRI-detection of apoptotic cells in vitro and in vivo, in a murine lymphoma tumor model treated with chemotherapeutic drugs [242]. Regions of extensive apoptosis, identified by conventional histological staining of tumor sections obtained post mortem, were correlated with regions of hypointensity in T2*-weighted MR images of the corresponding tumor sections in vivo. A similar approach, based on SPIO-labeled AnxV, was also developed by Schellenberger et al. [243]. Clinical MRIbased detection of PS exposure would have several advantages over radionuclide-based methods. MRI does not involve exposure to ionizing radiation, has typically a much higher spatial resolution (ca. 0.5 mm in the clinic), typically ca. 10-fold better than clinical SPECT or PET [14], and provides coregistered complementary anatomical information within the 3

HYNIC = hydrazinonicotinamide, a common chelator for

99m

-Tc.

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same imaging modality. PET and SPECT normally require MRI, or more frequently CT, to provide anatomical information, which must then be co-registered with the radionuclide image. However, as mentioned previously, MRI is much less sensitive, typically requiring CA concentrations 5–10 orders of magnitude greater than those required for PET or SPECT (typically mM versus nM to pM, respectively) [10]. Furthermore, the use of SPIO-based CAs, that generate hypointense areas in MR images, suffer from a number of limitations. Although SPIO particles are sensitive to detection, the negative signal that they produce can be difficult to distinguish from other sources of hypointensity, such as hemorrhage in tumors. SPIO particle size, normally in the range of 20–50 nm (hydrodynamic diameter), can also limit CA extravasation into tissue. In the case of tumors, however, the tumor microvasculature is often sufficiently leaky [109] to allow permeation of the SPIO-based agent into the interstitium. For these reasons we have recently started to develop gadolinium ion (Gd3+)-based CAs that are both smaller and can generate positive contrast (hyperintensity) in MR images. (Gd3+)-based macromolecular agents are normally produced by chemical modification of the targeting molecule with small molecular weight chelating agents (e.g. diethylenetriaminepentaacetate, or DTPA), which are capable of binding this extremely toxic metal ion with very high affinity. Positive macromolecular CAs based on Gd3+ are usually much smaller than SPIO-based agents. However, a large number of Gd3+ ions are required to generate detectable contrast using T1-weighted MRI. A minimum tissue Gd3+ concentration of 100 μM has been estimated to be necessary to generate detectable contrast [192]. This concentration, albeit relatively high, is within the range of PS concentrations expected in tumors following therapy-induced apoptosis [217]. We are currently developing a new generation of smaller apoptosis detection agents that give positive contrast, by conjugating C2A to (Gd3+)-chelates [244]. Experiments in vivo with these (Gd3+)-based agents have shown a statistically significant decrease in tumor T1 over 24 h in animals treated with a chemotherapeutic drug, and injected with active CA, compared with untreated control animals or treated animals that had been injected with an inactive version of the CA [245]. The sensitivity to detection of a targeted (Gd3+)-based agent can be increased by increasing the (Gd3+)-payload. One approach to doing this is to conjugate the targeting agent to a moiety containing multiple (Gd3+)-chelates, for example Gd-loaded liposomes [246]. These reagents, however, have the intrinsic limitation of a large size (10–100 nm). An alternative to liposomes is to conjugate the (Gd 3+)-chelates to polyamidoamine (PAMAM) dendrimers [247]. These hyperbranched, protein-sized spherical polymers have a high density of reactive surface amino groups that can be used to attach (Gd3+)-chelates and can also be cross-linked to targeting agents [248]. Another alternative is to use the avidin/ biotin system, which may allow signal amplification by multiple biotinylation of the targeting agent. We have shown recently that by conjugating one or more biotinylated C2A molecules to (Gd3+)-labeled avidin (AvGd), we can produce CAs with increased affinity for PS [249]. In conclusion, there is still a need for sensitive and specific methodologies for detecting and monitoring tumor cell death

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following cancer therapy in the clinic. These methodologies will need to be evaluated in comparison with methods that detect tumor cell death indirectly, such as FDG, and that are already well established in the clinic. 8. Staging, detection of recurrence and drug resistance MI techniques have enormous potential for staging cancer, monitoring and planning treatment and subsequently in detecting disease recurrence and resistance to therapy. FDGPET, in particular, has become one of the most important clinical imaging modalities in the management of Hodgkin's lymphoma [250], complementing anatomical data from CT and MRI and providing valuable prognostic information. FDG-PET can also be very helpful to evaluate occult recurrence in breast cancer patients [43]. In the U.S., PET is currently also approved for clinical restaging of colorectal, esophageal, head and neck and non-small-cell lung cancers and melanoma [68]. Multi-drug resistance (MDR) is a major problem in cancer therapy with significant repercussions for patient care. One of the best-known mediators of MDR is the complex MDR1 P-glycoprotein (Pgp), which can pump chemotherapeutic drugs out of cells, acting as a transport barrier to cancer chemotherapeutics (see Section 4) [251]. MI probes capable of evaluating Pgp-mediated drug transport could provide valuable insights in planning and guiding cancer therapy [252]. PET- and SPECTbased clinical probes (e.g. (99mTc)-Sestamibi®, see Table 1) have been used to image Pgp-mediated transport activity in human tumors [253]. Other MI probes have been proposed to assess the expression of Pgp and other MDR-related proteins. Most of these were designed for PET and have been reviewed recently [254]. 9. Clinical drug development and evaluation Medicine is entering a new era in which genetic and pharmacological information are being combined to provide patientspecific therapy, which has greater efficacy and fewer side effects. However, drug development is very expensive and this is particularly true for new cancer treatments. It is estimated that more than 80% of new cancer drugs entering clinical development do not get regulatory approval, due to previously unseen safety and/or efficacy issues, frequently as late as at phase-III clinical trials [255]. The total cost of taking a new drug from concept to market is currently estimated at ca. US$ 1.7 billion [256], over typically 10–15 years. Therefore, the establishment of effective molecular response biomarkers, or end-points, capable of defining critical parameters, such as the genetic makeup of tumors and their metabolic and signaling states could provide faster and less expensive routes to evaluate drug efficacy and to define patient sub-groups that are more likely to benefit from the novel therapies. Drug efficacy evaluation, normally performed by studies of pharmacokinetics/pharmacodynamics (PK/PD) 4 4 Pharmacokinetics and pharmacodynamics studies establish the global mechanisms by which the body metabolizes a drug and the modes of action of a drug in the body, respectively.

should therefore benefit substantially from the introduction of MI techniques, based on probes designed to detect drug targets or on modified labeled drug or prodrug analogues [194]. The development of drugs that may both prevent and treat cancer could benefit also from the wider implementation of MI techniques [254]. The progress of oncologic drug development using MI tools has been reviewed recently [17]. The extremely high sensitivity of PET, for example, can be exploited in preclinical studies and phase-I trials to detect drug biodistribution at pharmacological doses, by administering sub-pharmacological doses of drug analogues labeled with PET tracers. This concept, termed microdosing [39], is currently being tested in humans [257]. The principle of microdosing relies on the linearity of drug pharmacokinetics over a wide range of dosages. However, this needs to be validated for different drug classes. 10. Future challenges and directions The potential of MI techniques to assess response to cancer therapy is now undeniable. There is, however, still a need for new methods that are capable of providing quantitative, sensitive and spatially accurate information, in a minimally invasive manner, and to develop new probes against critical biomarkers for assessing drug response in early stage clinical trials. There is also a need to validate and standardize international clinical MI protocols for diagnosing disease, guiding therapy and detecting recurrence and drug resistance. Acknowledgments The molecular imaging work in KMB's laboratory is funded by grants from Cancer Research UK and by a collaboration with GE Healthcare. References [1] R. Weissleder, U. Mahmood, Molecular imaging, Radiology 219 (2001) 316–333. [2] A.B. Miller, B. Hoogstraten, M. Staquet, A. Winkler, Reporting results of cancer treatment, Cancer 47 (1981) 207–214. [3] P. Therasse, S.G. Arbuck, E.A. Eisenhauer, J. Wanders, R.S. Kaplan, L. Rubinstein, J. Verweij, M. Van Glabbeke, A.T. van Oosterom, M.C. Christian, S.G. Gwyther, New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada, J. Natl. Cancer Inst. 92 (2000) 205–216. [4] J.D. Hainsworth, J.A. Sosman, D.R. Spigel, D.L. Edwards, C. Baughman, A. Greco, Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib, J. Clin. Oncol. 23 (2005) 7889–7896. [5] W.A. Weber, Use of PET for monitoring cancer therapy and for predicting outcome, J. Nucl. Med. 46 (2005) 983–995. [6] L. Aabakken, Endoscopic tumor diagnosis and treatment, Endoscopy 35 (2003) 887–890. [7] D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (2000) 57–70. [8] J.G. Paez, P.A. Janne, J.C. Lee, S. Tracy, H. Greulich, S. Gabriel, P. Herman, F.J. Kaye, N. Lindeman, T.J. Boggon, K. Naoki, H. Sasaki, Y. Fujii, M.J. Eck, W.R. Sellers, B.E. Johnson, M. Meyerson, EGFR

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