Abstract 4534: Mutant KRAS2 mRNA PET imaging in spontaneous transgenic lung cancers.

Abstract

Abstract Treatment of lung cancer with anti-EGFR antibodies or tyrosine kinase inhibitors (TKIs) fails when KRAS2 cancer gene is activated by mutation. Mutation of the KRAS2 12th codon from the wild type GGU that encodes glycine (G) to a mutant GAU that encodes aspartate (D) occurs in some lung cancers. For this reason, we hypothesize that determining KRAS2 mutation status in vivo by external mRNA PET imaging will enable physicians to decide on alternatives to EGFR-directed therapy. To test the hypothesis, we designed wild type and mutant KRAS2 hybridization agents based on peptide nucleic acid (PNA), due to its strong, specific basepairing, and resistance to nucleases and proteases. At the C-terminus, we included a cyclized tetrapeptide based on insulin-like growth factor 1 (IGF1) to enable IGF1R-mediated cellular uptake. We included an N-terminal N2S2 chelator in order to bind 64Cu. We then administered the 64Cu-labeled agents by tail vein into mutant KRAS2 transgenic mice that develop spontaneous lung tumors. We demonstrated sequence-specific positron emission tomography (PET) imaging and quantitation of mutant KRAS2 G12D mRNA in the mice. The wild type control agent, differing by one base in the middle of the 12th codon, showed neglible images in the same mice. Wobble base agents with a hypoxanthine to detect either G12D or G12V KRAS2 mutants are under investigation. Supported by NIH CA148565; IP owned by EW/MLT, licensed to MTTI. Citation Format: Eric Wickstrom, Chang-Po Chen, Bishnuhari Paudyal, Matthew E. Wampole, Kaijun Zhang, Antican Wang, Bo Lu, Mathew L. Thakur. Mutant KRAS2 mRNA PET imaging in spontaneous transgenic lung cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4534. doi:10.1158/1538-7445.AM2013-4534