New version page

Strategies for Molecular Imaging

Upgrade to remove ads

This preview shows page 1 out of 4 pages.

View Full Document
Premium Document
Do you want full access? Go Premium and unlock all 4 pages.
Access to all documents
Download any document
Ad free experience

Upgrade to remove ads
Unformatted text preview:

FOCUS ON MOLECULAR IMAGINGStrategies for Molecular Imaging ofEpidermal Growth Factor Receptor TyrosineKinase in CancerEyal Mishani and Aviv HagoolyCyclotron Unit, Department of Nuclear Medicine, Hadassah Hebrew University Hospital, Jerusalem, IsraelA wealth of research has focused on developing targeted cancertherapies by specifically inhibiting epidermal growth factor re-ceptor tyrosine kinase (EGFR-TK). However, the outcome ofmost EGFR-TK–targeted drugs that were approved by theFood and Drug Administration or entered clinical trials hasbeen only moderate. Enhancement of EGFR-targeted therapyhinges on a reliable in vivo quantitative molecular imagingmethod. Such a method would enable monitoring of receptordrug binding and receptor occupancy in vivo; determination ofthe duration of EGFR inhibition in vivo; and, potentially, identifi-cation of a primary or secondary mutation in EGFR leading todrug interaction or loss of EGFR recognition by the drug. This re-view analyzes the most recent strategies to visualize and quantifyEGFR-TK in cancer by nuclear medicine imaging and describesfuture directions.Key Words: EGFR; PET; cancer; imaging; tyrosine kinase;cetuximab; gefitinibJ Nucl Med 2009; 50:1199–1202DOI: 10.2967/jnumed.109.062117Because of the enhanced cell proliferation characteristic ofmany cancers, most of the first anticancer drugs developed werebased on nonspecific agents that inhibited pathways related toRNA and DNA synthesis. This approach, although making asignificant contribution at the onset, had limited ultimate successbecause of toxicities, side effects, and insufficient and unpredictableresponses. The strategic turning point for the treatment of malig-nancies commenced in the mid-1990s with the discovery thatmutation, constitutive activation, and aberrant expression of a set ofgenes (oncogenes) coding for proteins regulating cell proliferation,cell differentiation, and apoptosis were implicated in cancerpathogenesis and may serve as markers for specific and targetedtreatment of cancer (1). In parallel, the emerging chemical andbiochemical technologies served as essential adjuncts for anticancerdrug development directed at these markers and resulted in morespecific targeted approaches for treating cancer.One such valid approach focused on inhibiting protein tyrosinekinases (PTKs), including the epidermal growth factor receptortyrosine kinase (EGFR-TK), that interfere with crucial signalingpathways that are dysregulated in malignant cells (1–4). The role ofPTKs appears to be crucial in signal transduction pathways thatregulate both intracellular signaling and multicellular communication,and regulated signaling is pivotal to the development and survival ofnormal and cancer cells. PTKs catalyze the transfer of phosphate inadenosine triphosphate (ATP) to specific tyrosine residues withinproteins, thereby altering their structure and function. PTKs areinvolved in multiple processes such as metabolism, cell movement,cell proliferation, angiogenesis, and inhibition of apoptosis. PTKdysregulation, such as overexpression of the TK receptor and itsligand, dimerization of PTK receptors (RTKs) or cellular PTKs with arelated protein, or various mutations in the PTK itself, leads toenhanced and constant stimulation, culminating in various diseases,including cancer (1–4). Hence, PTKs, whether receptors or cellularproteins, have become valid targets to combat cancer , and theepidermal growth factor family of membrane receptors (a member ofsubclass I of the RTK superfamily) is one of the most relevant markersin this class. EGFR comprises 3 regions: an extracellular bindingdomain, a single hydrophobic transmembrane reg ion, and theintracellular domain that harbors TK activity. EGFR activationnormally occurs by a 3-step mechanism. The first step is binding ofspecific ligands such as EGF, amphiregulin, or TGF-a to theextracellular ligand binding domain of the receptor. The second stepis dimerization of the ligand-bound receptor with one of the subclass IRTKs (HER1–HER4), leading to the third step, intracellular binding ofATP molecules and autophosphorylation of specific tyrosine residueswithin the TK domain of the receptor. These phosphotyrosine moietiesserve as docking sites for further downstream signal transductionmolecules, thus resulting in the various processes mentioned above .EGFR-TARGETED THERAPYTwo approaches were attempted to inhibit EGFR in cancer. Thefirst was based on small organic molecules targeting the internal TKdomain and inhibiting autophosphorylation, The second approachused antibodies targeting the extracellular ligand binding site andinhibiting cancer cell growth by any of several direct processes,including interruption of EGFR signaling by blockage of its ligandbinding, leading to inhibition of cell cycle progression or DNArepair, deceleration of angiogenesis or induction of apoptosis, orindirect processes mediated by the immune system. However, mostof these drugs that have been approved by the Food and DrugReceived Mar. 15, 2009; revision accepted May 21, 2009.For correspondence or reprints contact: Eyal Mishani, Department ofNuclear Medicine, Hadassah University Hospital, P.O. Box 12000, Jerusalem,Israel 91120.E-mail: [email protected] Editor: Caius Radu, UCLA Crump InstituteCOPYRIGHT ª 2009 by the Society of Nuclear Medicine, Inc.TYROSINE KINASE EPIDERMAL CANCER IMAGING • Mishani and Hagooly 1199Administration or have entered clinical trials have not yielded thepredicted positive outcome (5–7). For example, the small organicmolecules directed at the tyrosine kinase domain of the receptor,gefitinib and erlotinib, which exhibited promising results in preclin-ical studies, had only a moderate outcome clinically and wereeffecti ve in only a subset of non–small cell lung cancer patients whoexpressed well-defined EGFR-activating mutations (8–10). More-over, patients who initially responded to these drugs occasionallybecame resistent totherapy(11,12). Another example is cetuximab, anIgG1 class mAb that had positive clinical results in head and neckcancer overexpressing EGFR but insufficient effects in EGFR-overexpressing breast cancer and only a moderate response in coloncancer regardless of EGFR expression. Thus, patient response tocetuximab could not be predicted solely on the basis of EGFRexpression, although it is a prerequisite for initiation of treatment(13–15). These results could be due to several factors, includinginappropriate

Download Strategies for Molecular Imaging
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...

Join to view Strategies for Molecular Imaging and access 3M+ class-specific study document.

We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Strategies for Molecular Imaging 2 2 and access 3M+ class-specific study document.


By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?