Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 28, 2008


Contents

Imaging of Tumor Characteristics for Tailored Therapy
Executive Editor: Erik de Vries



Editorial: Pp. 2912-2913


Individualized Treatment Planning in Oncology: Role of PET and Radiolabelled Anticancer Drugs in Predicting Tumour Resistance Pp. 2914-2931
A.A.M. van der Veldt, G. Luurtsema, M. Lubberink, A.A. Lammertsma and N.H. Hendrikse
[Abstract] [Purchase Article]


Imaging of Tumor Hypoxia to Predict Treatment Sensitivity Pp. 2932-2942
H. Minn, T.J. Grönroos, G. Komar, O. Eskola, K. Lehtiö, J. Tuomela, M. Seppänen and O. Solin
[Abstract] [Purchase Article]


Imaging of Integrins as Biomarkers for Tumor Angiogenesis Pp. 2943-2973
W. Cai, G. Niu and X. Chen
[Abstract] [Purchase Article]


Monitoring of Treatment-Induced Apoptosis in Oncology with PET and SPECT Pp. 2974-2982
F.G. Blankenberg
[Abstract] [Purchase Article]


Imaging of EGFR and EGFR Tyrosine Kinase Overexpression in Tumors by Nuclear Medicine Modalities Pp. 2983-2998
E. Mishani, G. Abourbeh, M. Eiblmaier and C.J. Anderson
[Abstract] [Purchase Article] [View Article on PubMed]


Imaging of HER-2 Overexpression in Tumors for Guiding Therapy Pp. 2999-3019
V. Tolmachev
[Abstract] [Purchase Article]


PET Imaging of Steroid Receptor Expression in Breast and Prostate Cancer Pp. 3020-3032
G.A.P. Hospers, F.A. Helmond, E.G.E. de Vries, R.A. Dierckx and E.F.J. de Vries
[Abstract] [Purchase Article]


Nuclear Imaging of Prostate Cancer with Gastrin-Releasing Peptide-Receptor Targeted Radiopharmaceuticals Pp. 3033-3047
H.J.K. Ananias, I.J. de Jong, R.A. Dierckx, C. van de Wiele, W. Helfrich and P.H. Elsinga
[Abstract] [Purchase Article]


Imaging Virus-Associated Cancer Pp. 3048-3065
D-X. Fu, C.A. Foss, S. Nimmagadda, R.F. Ambinder and M.G. Pomper
[Abstract] [Purchase Article]




Abstracts


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Editorial: Imaging of Tumor Characteristics for Tailored Therapy

Despite significant improvement in treatment efficacy, cancer is still a major cause of morbidity and mortality. The treatment of cancer patients is variable and it is more and more dependent on specific tumor characteristics, such as the expression of distinct receptors, enzymes and transcription factors. Usually these tumor characteristics are determined by biopsy of the primary tumor at diagnosis. In metastatic disease, however, tumor characteristics can be discordant between lesions in a single patient. Tumor characteristics can also changes during the course of the disease or in response to treatment. Consequently, some patients receive ineffective treatment, whereas other patients are withheld treatment that could have been effective. For optimal treatment decision-making, tumor characteristics should ideally be measured in all lesions throughout the course of the disease, but repeated biopsies of multiple lesions are not feasible in clinical practice.

Nuclear imaging techniques, like PET and SPECT, offer the opportunity to repetitively and non-invasively monitor relevant biochemical and physiological parameters in patients. In the past decades, the clinical applications of these molecular imaging techniques in oncology have expanded from tumor detection and staging to therapy evaluation and imaging of specific tumor markers. Although the latter application of molecular imaging is still in its infancy, it could potentially improve therapy management by allowing clinicians to adjust treatment according to the specific tumor profile of the individual patient. With the introduction of expensive anti-cancer drugs, such as monoclonal antibodies, nuclear imaging also could help to control the vast increase in healthcare costs in developed countries by providing a tool for selection of patients that will actually benefit from these expensive therapies. Furthermore, imaging of specific tumor characteristics may not only be relevant for treatment management, but it might also aid drug development. Imaging would allow the selection of a homogenous study population and thus reduce the variation in clinical outcome. In addition, imaging of a specific tumor target could provide a suitable surrogate marker for determining the efficacy of a new drug. Such a surrogate marker may allow earlier and more sensitive prediction of drug efficacy than clinical tests of therapy outcome.

In this thematic issue of Current Pharmaceutical Design, the developments in nuclear imaging of specific tumor characteristics that are relevant for clinical treatment decision-making and drug development are discussed. In the first article of this issue, Van der Veldt and coworkers discuss the mechanisms of anti-cancer drug resistance [1]. Drug resistance can be caused by multiple factors, like impaired drug delivery, metabolism or the absence of the drug target. Imaging with radiolabeled anti-cancer agents can help to reveal the cause of drug resistance and could allow selection of patients eligible to treatment.

One of the phenomena associated with therapy resistance is hypoxia. Hypoxic tumors usually respond poorly to radiation therapy or chemotherapy. Several tracers for PET imaging of hypoxia have been developed. In the second article, Minn et al. give their view on the latest developments in imaging of hypoxia and discuss several factors that are important in the development of hypoxia markers [2]. Hypoxia is caused by insufficient blood supply to the tumor. Generation of new blood vessels (angiogenesis) is a prerequisite for tumor progression. Integrins are a family of adhesion molecules that play a pivotal role in the angiogenesis process. In the third review, Cai and coworkers give an overview of the field of imaging of angiogenesis and focus specifically on the development of radiopharmaceuticals for molecular imaging of integrins [3]. Several new drugs that inhibit tumor angiogenesis–and thus tumor growth– are approved for clinical use now. For optimal patient management, early monitoring of therapy efficacy is desirable. This is not only the case for anti-angiogenetic drugs, but for every kind of therapy. Programmed cell death (apoptosis) is the major elimination route of tumor cells that were successfully treated with radiation or chemotherapy. Thus, imaging of apoptosis could provide a useful tool for monitoring early treatment response. Radiopharmaceuticals that target extracellular phosphatidylserine exposure or the caspase-3 cascade in apoptotic cells are available now. An overview of the radiopharmaceuticals for nuclear imaging of apoptosis is presented in the paper by Blankenberg [4].

The next four papers in this issue deal with receptors that play a pivotal role in signaling pathways that are involved in tumor growth. These receptors are interesting targets for intervention, as inhibition of the overactive signaling pathways can stop tumor growth. The epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) are members of the growth factor receptor family. Overexpression of these receptors stimulates tumor progression and correlates with poor prognosis. Binding of a ligand to the extracellular binding domain of EFGR or HER2 induces activation of the intracellular tyrosine kinase domain of the receptor, which activates the downstream signaling cascade. Most drugs that target the growth factor receptors are either monoclonal antibodies that bind to the extracellular binding domain or small molecules that inhibit the tyrosine kinase activity. Several radiopharmaceuticals that are base on these drugs are currently being evaluated for imaging. The article by Mischani et al. surveys the recent developments in nuclear imaging of the EGFR and EGFR tyrosine kinase [5], whereas the subsequent article by Tolmachev reviews the radiolabeled compounds that have been developed for imaging of HER2 [6]. In breast and prostate cancer, steroid hormone receptors, such as estrogen, progesterone and androgen receptors, play a prominent role in disease progression. When a hormone binds to the steroid receptor, the receptor will act as nuclear transcription factor, which stimulates the expression of oncogenes and inhibits the expression of tumor-suppressor genes. Blocking the hormone receptor signaling pathway is usually the first line of treatment in breast and prostate cancer. However, therapy resistance will occur eventually. Imaging techniques could be applied to refine treatment and stratify therapy resistant patients for another line of treatment. Hospers et al. provide an overview of the current status of steroid hormone receptor imaging using PET and suggest potential applications of these PET imaging methods [7]. The next review by Ananias et al. focuses on radiopharmaceuticals for imaging of the gastrin-releasing peptide receptor (GRPR) [8]. Ligands of the GRPR, such as gastrin-releasing peptide and bombesin, were found to stimulate tumor growth. The GRPR is expressed in several types of cancer, including prostate and lung cancer, and could therefore be a good marker for tumor detection and staging. In addition, this receptor seems an attractive aim for targeted-therapy, as the GRPR is specifically overexpressed in tumors. Although this approach is still in its infancy, bombesin analogs that were conjugated with drugs, toxins or radioisotopes have been evaluated as anti-tumor agents.

In the final article in this issue, Fu et al., focus on molecular-genetic imaging of malignancies that are caused by a viral infection [9]. A surprisingly large proportion of the cancers is estimated to be of infectious origin (about 20%). In virus-associated cancer, tumors express specific viral genes that are not present in any other tissue in the body, which makes them attractive targets for treatment. Since viruses are usually present in the tumor in a latent state, pharmacological activation may be required. Tumor cells, in which the virus is activated, have become sensitive for anti-viral therapy. Activation of the virus can be monitored by imaging of a viral protein, such a viral thymidine kinase. Fu and coworkers have expanded the imaging paradigm to develop a new therapeutic approach, in which the radionuclide in the viral thymidine kinase-specific nucleoside for imaging is replaced with a radionuclide with therapeutic properties [9].

Taken together, the articles in this issue provide a broad overview of the current status of nuclear imaging of specific tumor characteristics that are relevant for treatment and drug development. Although some of these nuclear medicine methods still need to be validated in clinical trials, they have the potential to become important tools for image-guided individualized therapy and early decision-making in drug development.


References

[1] Van der Veldt AAM, Luurtsema G, Lubberink M, Lammertsma AA, Hendrikse NH. Individualized Treatment Planning in Oncology: Role of PET and Radiolabelled Anticancer Drugs in Predicting Tumour Resistance. Curr Pharm Des 2008; 14(28): 2914-2931.

[2] Minn H, Grönroos T, Komar G, Eskola O, Lehtiö K, Tuomela J, Seppänen M, Solin O. Imaging of Tumor Hypoxia to Predict Treatment Sensitivity. Curr Pharm Des 2008; 14(28): 2932-2942.

[3] Cai W, Niu G, Chen X. Imaging of Integrins as Biomarkers for Tumor Angiogenesis. Curr Pharm Des 2008; 14(28): 2943-2973.

[4] Blankenberg FG. Monitoring of Treatment-induced Apoptosis in Oncology with PET and SPECT. Curr Pharm Des 2008; 14(28): 2974-2982.

[5] Mishani E, Abourbeh G, Eiblmaier M, Anderson CJ. Imaging of EGFR and EGFR Tyrosine Kinase Overexpression in Tumors by Nuclear Medicine Modalities. Curr Pharm Des 2008; 14(28): 2983-2998.

[6] Tolmachev V. Imaging of HER-2 Overexpression in Tumors for Guiding Therapy. Curr Pharm Des 2008; 14(28): 2999-3019.

[7] Hospers GAP, Helmond FA, De Vries EGE, Dierckx RA, De Vries EFJ. PET Imaging of Steroid Receptor Expression in Breast and Prostate Cancer. Curr Pharm Des 2008; 14(28): 3020-3032.

[8] Ananias HJK, De Jong IJ, Dierckx RA, Van de Wiele C, Helfrich W, Elsinga PH. Nuclear Imaging of Prostate Cancer with Gastrin-Releasing-Peptide-Receptor Targeted Radiopharmaceuticals. Curr Pharm Des 2008; 14(28): 3033-3047.

[9] Fu D-X, Foss CA, Nimmagadda S, Ambinder RF, Pomper MG. Imaging Virus-associated Cancer. Curr Pharm Des 2008; 14(28): 3048-3065.


Erik de Vries
Department of Nuclear Medicine and Molecular Imaging
University Medical Center Groningen
University of Groningen
The Netherlands
E-mail: e.f.j.de.vries@ngmb.umcg.nl


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Individualized Treatment Planning in Oncology: Role of PET and Radiolabelled Anticancer Drugs in Predicting Tumour Resistance
A.A.M. van der Veldt, G. Luurtsema, M. Lubberink, A.A. Lammertsma and N.H. Hendrikse

Tumour resistance to anticancer agents remains a challenge in oncological practice, because it results in exposure to toxicities, unnecessary costs and, most importantly, delay of a potentially more effective treatment. Drug uptake by tumours may be impaired by several resistance pathways. Reasons for primary resistance may be that the drug is not delivered to the tumour or that its uptake by the tumour is not sufficient. Drug delivery depends on its distribution within the body, its bioavailability in the circulation and its transport to the tumour. Binding of drugs to circulating cells and proteins, formation of inactive metabolites as well as a rapid drug clearance may limit bioavailability. Furthermore, drug delivery to tumours is regulated by tumour vascularisation. Finally, tumour targets such as hormone receptors and efflux pumps also influence drug uptake by tumours.

The use of specific PET tracers such as radiolabelled anticancer drugs (e.g. [¹⁸F]fluoropaclitaxel and [¹⁸F]5-fluorouracil) provide a unique means for individualized treatment planning and drug development. Combining these specific tracers with other less specific tracers, such as tracers for blood flow (e.g. [¹⁵O]H₂O) and efflux (e.g. [¹¹C]verapamil), may provide additional information on drug resistance mechanisms. Furthermore, radiolabelled anticancer agents may be valuable to evaluate the optimal timing of combination therapies. This review will focus on how PET can reveal different mechanisms of tumour resistance and thus may play a role in drug development and prediction of tumour response.


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Imaging of Tumor Hypoxia to Predict Treatment Sensitivity
H. Minn, T.J. Grönroos, G. Komar, O. Eskola, K. Lehtiö, J. Tuomela, M. Seppänen and O. Solin

Non-invasive detection of tumor hypoxia using radiolabeled 2-nitroimidazoles has been a major effort during the last two decades. Recent years have witnessed the introduction of several new compounds which are chemically related to [¹⁸F]fluoromisonidazole (FMISO) but show slight but distinct differences in biodistribution and metabolic clearance. Although [¹⁸F]FMISO has shown clinical potential it suffers from suboptimal oxygen dependent tissue contrast and newer agents seek to improve this essential feature. The limited data on other interesting tracers keeps the investigators busy at demonstrating the potential advantages over [¹⁸F]FMISO while efforts should start to concentrate on proving the clinical significance of such techniques in the form of outcome data from image-guided therapy modification. We review here our experiences with two hypoxia-avid agents [¹⁸F]fluoroerythronitromidazole (FETNIM) and [¹⁸F] 2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) and focus on the similarities and differences of these two tracers in comparison to other radiolabeled 2-nitroimidazoles. It is recognized that only [¹⁸F]FMISO has thus far shown clinical utility and newer tracers need to be tested against this circumstance.


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Imaging of Integrins as Biomarkers for Tumor Angiogenesis
W. Cai, G. Niu and X. Chen

The integrin family plays important roles during tumor angiogenesis, the formation of new blood vessels from pre-existing vasculature. Traditional structural and functional imaging techniques are not sufficient for early lesion detection, patient stratification, or monitoring the therapeutic efficacy against cancer. Molecular imaging, the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems, can fulfill these goals. In this review article, we will summarize the current state-of-the-art of imaging integrin (α₂β₁, α₃β₁, α₄β₁, α_vβ₃, and α_vβ₆) expression using either single molecular imaging modality (magnetic resonance imaging, untrasound, optical, single photon emission computed tomography, and positron emissiom tomography) or a combination of different modalities. For clinical translation, radionuclide-based imaging will have broad potential applications in cancer patients and the currently available clinical data (exclusively on integrin α_vβ₃ so far) will be discussed in detail. The design, optimization, and characterization of imaging agents targeting integrins will be presented and areas needing extensive future research effort will be discussed. In the new era of personalized medicine, fast clinical translation and incorporation of integrin imaging into anti-cancer clinical trials will be critical for the maximum benefit of cancer patients.


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Monitoring of Treatment-Induced Apoptosis in Oncology with PET and SPECT
F.G. Blankenberg

The early assessment of a solid tumor’s response to conventional or new drug therapy to complement or replace current RECIST (or other clinical) criteria remains an elusive goal. The work horse PET tracer ¹⁸F-FDG, may represent the most immediate method to track individual tumor response to therapy for many types of cancer. Newer radiotracers such as radiolabeled annexin V, have also shown the ability to selectively localize to tumor cells undergoing apoptosis (programmed cell death) in response to successful treatment in vivo. In this article we will review therapy reduced tumor apoptosis and the radiotracers used to date to image this process in both animal models and clinical trials.


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Imaging of EGFR and EGFR Tyrosine Kinase Overexpression in Tumors by Nuclear Medicine Modalities
E. Mishani, G. Abourbeh, M. Eiblmaier and C.J. Anderson

Protein tyrosine kinases (PTKs) play a pivotal role in signal transduction pathways and in the development and maintenance of various cancers. They are involved in multiple processes such as transcription, cell cycle progression, proliferation, angiogenesis and inhibition of apoptosis. Among the PTKs, the EGFR is one of the most widely studied and has emerged as a promising key target for the treatment of cancer. Indeed, several drugs directed at this receptor are FDA-approved and many others are at various stages of development. However, thus far, the therapeutic outcome of EGFR-targeted therapy is suboptimal and needs to be refined. Quantitative PET molecular imaging coupled with selective labelled biomarkers may facilitate in vivo EGFR-targeted drug efficacy by noninvasively assessing the expression of EGFR in tumor, guiding dose and regime by measuring target drug binding and receptor occupancy as well as potentially detecting the existence of a primary or secondary mutation leading to either drug interaction or failure of EGFR recognition by the drug. This review describes the attempts to develop labelled EGFR molecular imaging agents that are based either on low molecular weight tyrosine kinase inhibitors or monoclonal antibodies directed to the extracellular binding domain of the receptor to be used in nuclear medicine modalities.


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Imaging of HER-2 Overexpression in Tumors for Guiding Therapy
V. Tolmachev

Human epidermal growth factor receptor type 2 (HER2) is a transmembrane tyrosine kinase receptor, which is overexpressed in a large fraction of breast, ovarian, urinary bladder and a number of other carcinomas. Overexpression of HER2 is associated with poor prognosis. Treatment of patients with HER2-expressing breast cancer with a humanized anti-HER2 monoclonal antibody trastuzumab has resulted in improved survival. Several kinds of other anti-HER2 therapies are under development. Radionuclide molecular imaging of HER2 expression may influence patient management by selecting patients, who would benefit form anti-HER2 therapy. Other applications, such as therapy response monitoring and followup are also possible. In this case, the use of radionuclide imaging may overcome problems associated with biopsies, including sampling errors and discordance of expression between primary tumors and metastases. Important preconditions for development of a successful tracer for radionuclide imaging are high affinity of a targeting agent and suitable chemistry of labeling. The paper reviews information concerning major classes of HER2-targeting agents, including full-length monoclonal antibodies, their enzymatically produced fragments, engineered immunoglobulin based tracers, and alternative high affinity binders. Available information suggests that Affibody molecules or other small non-immunoglobulin based tracers have the best potential for development of high-contrast imaging agents for visualization of HER2 in vivo.


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PET Imaging of Steroid Receptor Expression in Breast and Prostate Cancer
G.A.P. Hospers, F.A. Helmond, E.G.E. de Vries, R.A. Dierckx and E.F.J. de Vries

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.


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Nuclear Imaging of Prostate Cancer with Gastrin-Releasing Peptide-Receptor Targeted Radiopharmaceuticals
H.J.K. Ananias, I.J. de Jong, R.A. Dierckx, C. van de Wiele, W. Helfrich and P.H. Elsinga

Prostate cancer is one of the most common causes of cancer in men. Evaluating the different stages of prostate cancer with conventional imaging techniques still proves difficult. Nuclear imaging might provide a technique that is able to evaluate prostate cancer, but clinical application has been limited due to lack of accuracy of current radiopharmaceuticals.

The development of radiopharmaceuticals that can be targeted to specific antigens, overexpressed in prostate cancer, but sparse in normal tissue, is crucial. Peptides are of particular interest because of their favourable characteristics, leading to increased attention for nuclear imaging of the gastrin-releasing-peptide-receptor (GRPR) with radiolabelled bombesin-like peptides. Several derivatives of bombesin and its truncated form have been prepared for imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET), thereby delivering potent candidates for further clinical evaluation.

This article provides an overview of the development and preclinical evaluation of radiolabelled bombesin analogues for in vivo targeting of GRPR in prostate cancer. The effect of the radionuclide, chelator, spacer and unnatural amino acids on affinity, metabolic stability and image quality are discussed, as well as agonistic or antagonistic properties. Potent candidates are proposed based on these selection criteria: (I) high affinity for GRPR, with rapid and specific tumour uptake (II) high hydrophilicity resulting in the preferred renalurinary mode of excretion and low hepatobiliary excretion, (III) high stability, but relatively rapid clearance from blood. Also, a summary is made of clinical studies that report on the detection of prostate cancer with GRPR targeted radiopharmaceuticals.


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Imaging Virus-Associated Cancer
D-X. Fu, C.A. Foss, S. Nimmagadda, R.F. Ambinder and M.G. Pomper

Cancer remains an important and growing health problem. Researchers have made great progress in defining genetic and molecular alterations that contribute to cancer formation and progression. Molecular imaging can identify appropriate patients for targeted cancer therapy and may detect early biochemical changes in tumors during therapy, some of which may have important prognostic implications. Progress in this field continues largely due to a union between molecular genetics and advanced imaging technology. This review details uses of molecular-genetic imaging in the context of tumor-associated viruses. Under certain conditions, and particularly during pharmacologic stimulation, gammaherpes-viruses will express genes that enable imaging and therapy in vivo. The techniques discussed are readily translatable to the clinic.