Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

Abstract

Targeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the 'correct', biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response.

Figure 1

Intrapatient heterogeneity in the expression of α_Vβ₃ integrin imaged by PET with the α_Vβ₃ ligand [¹⁸F]galacto-RGD. The primary tumor, a soft tissue sarcoma of the thigh (arrow in the CT image in A), demonstrates intense uptake of [¹⁸F]galacto-RGD, indicating high expression levels of α_Vβ₃ integrin (arrow in B). Uptake of [¹⁸F]galacto-RGD is much less pronounced in a bone metastasis in the pelvis and a right-sided lung metastasis (arrows in D). The bottom image in C shows the pelvic metastasis on CT (arrows). A left-sided lung metastasis, shown on CT (C, top) is negative on the [¹⁸F] galacto-RGD PET scan (D). Permission obtained from the Society of Nuclear Medicine © Beer AJ et al. (2005) Biodistribution and pharmacokinetics of the α_Vβ₃-selective tracer 18F-galacto-RGD in cancer patients. J Nucl Med 46: 1333–1341. Abbreviations: RGD, arginine–glycine–aspartic acid; SUV, standardized uptake value.

Figure 2

New approaches for imaging expression of the target protein. (A) Imaging of the expression of carcinoembryonic antigen (CEA) with radiolabeled antibody fragments in mice. Mice were implanted with a CEA-expressing tumor at the left shoulder and CEA-negative tumor at the right shoulder. An [¹²⁴I]-labeled anti-CEA antibody (top row) accumulates in the CEA-positive tumor (solid arrow), but the background and CEA-negative tumor (open arrow) have relatively low levels of CEA expression. The contrast is much higher for sc-Fv-Fc antibody fragments (bottom row) owing to faster blood clearance. Permission obtained from Nature Publishing Group © Wu AM and Senter PD (2005) Nat Biotechnol 23: 1137–1146. (B) Multiplexed optical imaging using quantum dots. Quantum dots of three different colors were subcutaneously injected into the back of a mouse and imaged simultaneously. The right side of the panel shows microscopic images of the injected quantum-dot-encoded microbeads (diameter 0.5 µm). Permission obtained from Nature Publishing Group © Gao X et al. (2004) Nat Biotechnol 22: 969–976. (C) Optical fluorescence tomography of the expression of cathepsin B in a mouse bearing an orthotopic human glioma xenograft in the right hemisphere of the brain (arrow). The top panel shows the reconstructed optical image (cross-section) obtained after injection of an activatable optical probe that is cleaved by cathepsin B. The bottom panel shows an overlay of the optical image and an MRI scan. Permission obtained from Nature Publishing Group © Ntziachristos V et al. (2002) Nat Med 8: 757–760.

Figure 3

Monitoring of target inhibition by PET imaging. (A) Blockade of α_Vβ₃ integrin by the cyclic pentapeptide c(RGDfV). Mice were implanted with an α_Vβ₃-positive tumor on the left shoulder. Pretreatment with the α_Vβ₃ ligand c(RGDfV) leads to a dose-dependent decrease in the uptake of the radiolabeled imaging probe [¹⁸F]galacto-RGD. Permission obtained from the American Association for Cancer Research © Haubner R et al. (2001) Noninvasive imaging of α_Vβ₃ integrin expression using 18F–labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 61: 1781–1785. (B) Monitoring of Hsp90 inhibition by PET imaging with ⁶⁸Ga-labeled anti-HER2 antibody fragments. Mice were implanted on the left shoulder with a tumor that overexpressed HER2 (arrows). Treatment with the Hsp90 inhibitor 17-AAG leads, within 24 h, to a marked reduction of the uptake of anti-HER2 antibody fragments, indicating downregulation of HER2 expression. Downregulation of HER2 expression was confirmed by immunoblots of the tumor tissue. Permission obtained from Nature Publishing Group © Smith-Jones PM et al. (2004) Nat Biotechnol 22: 701–706. Abbreviations: 17-AAG, 17-allylaminogeldanamycin; HER2, human epidermal growth factor receptor 2; Hsp90, heat shock protein 90; RGD, arginine–glycine–aspartic acid.

Figure 4

Monitoring of target inhibition by dynamic contrast-enhanced MRI. At baseline (top row), the multiple liver metastases (arrows) demonstrate intense contrast enhancement. Following treatment with the VEGF receptor protein kinase inhibitor PTK/ZK, the liver metastases demonstrate no visible contrast enhancement, indicating a marked decrease in vascular permeability or perfusion. Permission obtained from the American Society of Clinical Oncology © Morgan B et al. (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 21: 3955–3964.

Figure 5

Treatment monitoring with fluorodeoxyglucose (FDG) PET and CT in a patient with locally advanced distal esophageal cancer (arrows). In each image set, the image on the left is a longitudinal section from the neck to the pelvis and the image on the right is a cross-section through the plane containing the tumor. The tumor demonstrates intense FDG uptake before therapy (day 0). FDG uptake decreases markedly on day 14 of the first chemotherapy cycle. Quantitatively, FDG uptake by the tumor decreased from a standard uptake value of 9.2 to 4.2. After completion of preoperative chemotherapy, the tumor was resected. Histopathology demonstrated less than 10% of viable tumor cells in the resected specimen. Permission obtained from the American Society of Clinical Oncology © Weber WA (2006) Positron emission tomography as an imaging biomarker. J Clin Oncol 24: 3282–3292.