Targeting EGFR and VEGFR2 tyrosine kinases with positron emission tomography : evaluation of two radiotracers

Receptor tyrosine kinases (RTKs) are commonly involved in the development, growth and spread of cancer. Targeted therapy with tyrosine kinase inhibitors (TKIs) has proven a successful treatment strategy against cancers in which growth is dependent on the expression of these receptors. Increased effectiveness of treatment can potentially be achieved by individual characterizations of the disease, enabling tailoring of the therapy directed at the specific targets found.

Positron emission tomography (PET) is a non-invasive imaging technique that allows characterization of biochemical processes and quantification of targets such as RTKs. In PET, the distribution of radiolabeled molecules in the body is traced by the emission of photons produced after the decay of the radionuclide that is incorporated in the tracer molecule. Drugs and other xenobiotics are often metabolized in the body to facilitate excretion. A PET tracer can be metabolized into radioactive metabolites, which often display pharmacokinetic behaviors different than that of the parent molecule. It is therefore pivotal to characterize the metabolism of novel PET tracers before accurate estimations of biological target levels, based on radioactivity uptakes, can be performed.

This doctoral thesis focuses on the preclinical evaluation of two tracer molecules, [11C]PD153035 and [11C]PAQ, each targeting a specific RTK known to play important roles in cancerogenesis. Both tracers are based on TKIs and have been proven to be potent RTK inhibitors in vitro. In papers I and III, the in vitro and in vivo metabolism, respectively, of [11C]PD153035 was investigated. We found that the tracer was extensively metabolized by cytochrome P450 enzymes into several different radioactive metabolites. Furthermore, the results indicate that the metabolism impairs quantification of the target RTK, the epidermal growth factor receptor (EGFR).

In papers II and IV the pharmacokinetics and angiogenesis detection properties of (R,S)-[11C]PAQ and (R)-[11C]PAQ were assessed in various models of cancer in mice. The results show that the tracer is metabolically stable and that areas with increased angiogenic activity, based on vascular endothelial growth factor receptor 2 expression (VEGFR2), can be visualized with PET. Uptake of radioactivity correlated well to areas with high expression of the receptor both with the labeled racemate and the R-isomer. In addition, high focal uptake was observed with (R)-[11C]PAQ in lungs with metastases that exhibited high expression levels of the VEGFR2.

In summary, we conclude that [11C]PD153035 is metabolized very rapidly in rat and that a similar metabolism in humans would imply serious limitations if the tracer is used in patient stratification for EGFR targeted therapy. (R)-[11C]PAQ, on the other hand, is a promising tracer that, pending positive results in further validation studies, can prove to be a valuable tool for personalizing cancer treatment based on expression levels of VEGFR2.

List of scientific papers

I. Samén E, Thorell JO, Fredriksson A and Stone-Elander S. The tyrosine kinase inhibitor PD153035: implication of labeling position on radiometabolites formed in vitro. Nucl Med Biol. 2006 33(8): 1005-1011.
https://doi.org/10.1016/j.nucmedbio.2006.09.008

II. Samén E, Thorell JO, Lu L, Tegnebratt T, Holmgren L and Stone-Elander S. Synthesis and preclinical evaluation of [11C]PAQ as a PET imaging tracer for VEGFR-2. Eur J Nucl Med Mol Imaging. 2009 36(8): 1283-1295.
https://doi.org/10.1007/s00259-009-1111-3

III. Samén E, Arnberg F, Lu L, Hagg Olofsson M, Tegnebratt T, Thorell JO, Holmin S and Stone-Elander S. Metabolism of the epidermal growth factor receptor targeting probe [11C]PD153035: impact on biodistribution and tumor uptake in rats. J Nucl Med. 2013 Oct;54(10):1804-1811.
https://doi.org/10.2967/jnumed.113.120493

IV. Samén E, Lu L, Mulder J, Thorell JO, Damberg P, Tegnebratt T, Holmgren L, Rundqvist H, Stone-Elander S. Visualization of angiogenesis during cancer development in the polyoma middle T breast cancer model: molecular imaging with (R)-[11C]PAQ. [Submitted]