Lung cancer cells often express mutated KRAS2 mRNA. Imaging mutated KRAS2 mRNA in lung cancer would rule out interventions targeting EGFR or B-Raf. We have demonstrated significant tumor image contrast in breast cancer and pancreatic cancer xenografts with peptide nucleic acid (PNA) dodecamers coupled to imaging reporters and receptor-targeting peptides. Multiple mutants in the 12th codon of KRAS2 mRNA, most frequently G12D, G12V, or G12C, complicate the use of single imaging sequences. Hypoxanthine substitutions might allow a single PNA to bind multiple mutant mRNAs. We are developing a set of force fields to predict the binding energies of various PNA constructs, including hypoxanthines to bind redundant RNA bases, to mutant and wild type KRAS2 RNAs, prior to synthesis. These force fields are standardized against our previously measured melting temperatures. Calculated enthalpies vary predictably with G:C content. Supported by NIH CA148565; IP owned by EW/MLT, licensed to MTTI.

Computational design of peptide nucleic acid conjugates for imaging oncogenic <i>KRAS2 </i>mRNA in vivo

244th National Meeting (2012)

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Computational design of peptide nucleic acid conjugates for imaging oncogenic KRAS2 mRNA in vivo