Imaging of EGFR and EGFR tyrosine kinase overexpression in tumors by nuclear medicine modalities

Abstract

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.

Fig. (1)

Mechanism of action of anti-EGFR mAb-based drugs.

Fig. (2)

Chemical structure of PTKS drugs

Fig. (3)

Preparation of ⁶⁴Cu-DOTA-cetuximab for PET imaging of EGFR-positive tumors.

Fig. (4)

Labelled EGFR bioprobes.

Fig. (5)

In vivo inhibition of phosphorylation of the EGFR in U87MG.wt EGFR xenografts is attained after administration of an excess of ML04 to mice.

Fig. (6)

Preferential uptake of [18F]-ML04 in U87MG.wt EGFR over U138MG tumors.

Scheme. (1)

Labelling of ML09, ML10 and ML11.