Cancer stratification by molecular imaging

Abstract

The lack of specificity of traditional cytotoxic drugs has triggered the development of anticancer agents that selectively address specific molecular targets. An intrinsic property of these specialized drugs is their limited applicability for specific patient subgroups. Consequently, the generation of information about tumor characteristics is the key to exploit the potential of these drugs. Currently, cancer stratification relies on three approaches: Gene expression analysis and cancer proteomics, immunohistochemistry and molecular imaging. In order to enable the precise localization of functionally expressed targets, molecular imaging combines highly selective biomarkers and intense signal sources. Thus, cancer stratification and localization are performed simultaneously. Many cancer types are characterized by altered receptor expression, such as somatostatin receptors, folate receptors or Her2 (human epidermal growth factor receptor 2). Similar correlations are also known for a multitude of transporters, such as glucose transporters, amino acid transporters or hNIS (human sodium iodide symporter), as well as cell specific proteins, such as the prostate specific membrane antigen, integrins, and CD20. This review provides a comprehensive description of the methods, targets and agents used in molecular imaging, to outline their application for cancer stratification. Emphasis is placed on radiotracers which are used to identify altered expression patterns of cancer associated markers.

Figure 1

Cancer stratification by molecular imaging allows patients clustering according to the expected outcome of a therapeutic approach by visualizing an expressed biomarker. The resulting patient subgroups can subsequently be treated with the most promising therapy [6].

Figure 2

Chemical structure of 2-Deoxy-2-(¹⁸F)fluoro-glucose ([¹⁸F]-FDG). [¹⁸F]-FDG is taken up by the glucose transport system. As many cancer types show higher metabolic glucose turnover, [¹⁸F]-FDG uptake is increased, leading to its accumulation in cancer tissue. Subsequently, imaging with positron emission tomography (PET) is possible due to the β⁺ emitting radionuclide ¹⁸F.

Figure 3

Chemical structure of l-[3-¹⁸F]-α-methyl-tyrosine, a PET tracer specifically taken up via amino acid transporters, which are overexpressed in many types of cancer.

Figure 4

Chemical structure of [⁶⁸Ga]-DOTATOC (DOTA(0)-Phe(1)-Tyr(3))octreotide). It shows high affinity to SSTR2 (Somatostatin Receptor 2)—a receptor overexpressed in neuroendocrine tumors. The blue portion of the molecule is responsible for the SSTR2 specificity, whereas the radionuclide ⁶⁸Ga contained in the chelator DOTA (red) acts as the signal source for PET imaging. For reasons of clarity, chelation bonds are omitted.

Figure 5

Chemical structure of [⁶⁸Ga]-NOTA-c(RGDyK) (NOTA-Cyclo [Arg-Gly-Asp-d-Tyr-Lys]), which is used for the molecular imaging of α_vβ₃ integrin overexpressing tumors. ⁶⁸Ga functions as the signal source for molecular imaging and is chelated to NOTA (red) to prevent displacement of the imaging moiety. The RGD-motif (Arg-Gyl-Asp, blue) is responsible for the integrin interaction. Insertion of d-tyrosine and cyclization reduce the protease digestibility of the compound, while lysine enables the correct positioning of the imaging moiety. For reasons of clarity, chelation bonds are omitted.

Figure 6

(a) Chemical structure of etarfolatide. It is used to image folate receptor positive cancers with SPECT. It contains folate (blue) to target the compound to the FR and chelated ^99mTc in order to allow imaging (red); (b) Chemical structure of vintafolide, which is used to treat folate receptor positive ovarian cancer. It also contains folate as targeting moiety (blue). Additionally, a hydrophilic peptide linker with a cleavable disulfide bond (green) is incorporated to allow the release of deacetylvinblastine monohydrazide (red), which exhibits the cytotoxic effect. For reasons of clarity, chelation bonds are omitted.

Figure 7

¹¹¹In-ibritumomab-tiuxetan (Zevalin^®). The monoclonal antibody ibritumomab (grey) is highly specific for CD20, which is overexpressed by many different lymphomas. The chelator tiuxetan (red) is able to bind ¹¹¹In, as well as ⁹⁰Y. This allows molecular imaging and the subsequent therapy of CD20 positive lymphomas. For reasons of clarity, chelation bonds are omitted.

Figure 8

Chemical structure of [⁶⁸Ga]-PSMA-HBED-CC. The Glu-urea-Lys sequence (blue) is responsible for the targeting properties of the tracer. It is linked to the ⁶⁸Ga-labeledchelator HBED-CC (red) via an aminocaproic acid linker (green). For reasons of clarity, chelation bonds are omitted.