KRAS mutations are among the most common oncogenic drivers in pancreatic, colorectal, and lung cancers, with nearly all early pancreatic lesions carrying alterations in the KRAS G12 codon. These mutations generate peptide neoantigens that can be presented by diverse HLA molecules, offering a compelling but unrealized opportunity for highly specific tumor detection. Current approaches have been limited by the dependence of antibodies and T cell receptors on rare HLA allotypes and by the low abundance of peptide HLA complexes on tumor cells. This project addresses these challenges by leveraging a new class of engineered binding proteins known as TRACeRs, which can be designed to recognize KRAS G12X neoantigens across multiple HLA variants with high specificity.
The investigators have already created TRACeRs that bind KRAS G12V peptides presented on several HLA alleles, and preliminary studies show strong discrimination against self-peptides. Building on this platform, the team will convert the G12V binders into radioligand conjugates and evaluate their ability to image KRAS G12V-positive pancreatic tumor cells in vivo. They will extend the approach to G12D and G12R neoantigens through protein design, structural analysis, and functional characterization. Together, these studies will establish a versatile strategy for detecting KRAS-driven cancers in genetically diverse patient populations. The work has the potential to introduce a new diagnostic modality for pancreatic cancer, with future applications in colorectal and lung cancer and the possibility for extension into radiotherapeutic development.