Monitoring therapeutic response to TKIs in breast cancer by use of imaging peptides

Abstract

11002 Background: Rapid assessment of cancer response to a therapeutic regimen can determine efficacy early in the course of treatment. Here we simultaneously assess response in all sites of disease within days of starting therapy by use of peptide ligands selected for their ability to discern responding from non-responding cancers. Methods: MDA-MB-231 breast cancer was studied in the cerebrum, lung, Liver and axilla of nude mice. The tumor bearing mice were treated with VEGFR TKIs for one hour. Cy7-labeled HVGGSSV peptide was injected intravenously 4 hours after treatment. The peptide binding (relative radiance) was correlated to tumor response (tumor volume fold change). mice were treated with SU11248 doses of 0, 4 or 40 mg/Kg daily for 14 days. Tumor volumes were measured by use of calipers. Peptide was imaged by use of near infrared (NIR) using Xenogen IVIS. Results: HVGGSSV peptide binding was not detected in untreated tumors. Tumors treated with TKIs showed NIR imaging of peptide binding within 24 hours of injection. The NIR images show Cy7 labeled peptide binding within treated tumors but no binding to untreated control tumors. All tumors showed significant increase in radiance compared to untreated controls (p<0.05). The sensitivity of detecting responsive tumors was 40 out of 42 responding mouse tumors detected by HVGGSSV radiance. In comparison, 0 of 26 non-responding or untreated tumors showed increased peptide radiance within tumors (p<0.001). To determine whether radiance from peptide binding in tumors correlated with tumor response, we studied the dose-dependent response to SU11248 in MDA-MB231. Tumors responded to high dose treatment (40 mg/kg SU11248), but not 4 mg/kg, when treated with SU11248 alone. After the first treatment, Cy7-labeled peptide was injected intravenously into tumor-bearing mice. NIR images were captured and radiance from peptide binding in tumors was measured. A linear correlation (R2=0.8684) was found for peptide binding and tumor response to treatment. Conclusions: Rapid noninvasive assessment of cancer response promises to speed drug development and minimize the duration of treatment with ineffective regimens in cancer patients. No significant financial relationships to disclose.