Molecular Imaging of Nonsmall Cell Lung Carcinomas Expressing Active Mutant EGFR Kinase Using PET with [124I]-Morpholino-IPQA

Skye Hsin-Hsien Yeh,Ren-Shyan Liu,Juri G Gelovani,Ya-Ju Hsieh,Chien-Feng Lin,Hsin-Ell Wang,Fan-Lin Kong

doi:10.1155/2013/549359

Abstract

Mutations in the kinase domain of epidermal growth factor receptor (EGFR) have high levels of basal receptor phosphorylation and are associated with clinical responsiveness to Iressa in patients with nonsmall cell lung cancer (NSCLC). This study aimed to assess the feasibility of morpholino-[124I]IPQA derivative as an in vivo PET imaging tool for the expression of different EGFR mutants in NSCLC. In vitro radiotracer accumulation and washout studies demonstrated a rapid accumulation and progressive retention after washout of morpholino-[131I]IPQA derivative in high EGFR-expressing H1299 NSCLC derivative cell lines (L858R and E746-A750 del cell lines), but not in EGFR-transfected H1299 cell line and vector-transfected H1299 cell line. Using the morpholino-[124I]IPQA derivative, we obtained noninvasive microPET images of EGFR activity in L858R and E746-A750 del subcutaneous tumor xenografts, but not in subcutaneous tumor xenografts grown form control cell line. Different EGFR mutant (activity) tumors have a different morpholino-[∗I]IPQA derivative uptake. However, it still needs to modify the structure of IPQA to increase its water solubility and reduce hepatobiliary clearance. Morpholino-[124I]IPQA derivative may be a potential probe for selection of the candidate patients suffering from NSCLC for the small molecule tyrosine kinase inhibitor therapy (e.g., Iressa) in the future.

Highlights

Nonsmall cell lung cancer (NSCLC) represents the majority of lung cancers [1]
Predicting the expression of epidermal growth factor receptor (EGFR) mutation through noninvasive positron emission tomography (PET) imaging with a specific EGFR kinase radiotracer would provide an assessment for the NSCLC patients who may be benefit from EGFR inhibitors therapeutic regiment
Our collaborator reported that the PET imaging with morpholino-[124I]IPQA, which could irreversibly and bind to active form of EGFR kinase, allowed for identification of tumors with high EGFR kinase signaling activity (i.e., A431 highly expressing EGFR in NSCLC and U87 del EGFR cells expressing EGFRvIII mutants in brain gliomas) [28]

Summary

Introduction

Nonsmall cell lung cancer (NSCLC) represents the majority of lung cancers [1]. Lung cancer treatment depends on several factors including tumor type, size, and patient’s health. Radiation therapy, and chemotherapy using tumor specific targeted agents such as vascular endothelial growth factor (VEGF) inhibitor bevacizumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) are the primary tools for treating lung cancer. These targeted agents are initially effective in certain small subpopulations of patients, but eventually most patients turn out to be resistant to the further treatments [2]. EGFR overexpression is observed in tumors of more than 60% of patients with metastatic NSCLC and correlates with poor prognosis [5] These observations have provided a rationale for the development of novel anticancer agents that target EGFR. The mutational status of EFGR kinase could be considered as a positive predictive biomarker of response to NSCLC [20, 21]

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