High-accuracy mass spectrometry for the discovery and drugging of cancer proteomes

Epigenetic dysregulation is becoming increasingly recognized as an important driver of human cancer, and childhood cancers in particular. The use of massively parallel DNA sequencing is beginning to reveal the extent of non-canonical transcription and splicing in eukaryotic cells but remains hindered by limited genome annotation and inability to discriminate coding reading frames, which in turn precludes their therapeutic targeting.

To investigate non-canonical proteomes directly, we are developing high-accuracy mass spectrometry approaches for the analysis of non-canonical proteomes. In particular, we are investigating neomorphic gene products, as transcribed and spliced from non-canonical start sites and exon junctions, as well as gain-of-function post-translational modifications, such as those induced by mutant enzymes and aberrant metabolic products. In particular, we recently developed ultra-sensitive methods for high-accuracy quantitative proteomics and comprehensive techniques for cancer proteomics, including the scalable ProteomeGenerator2.

We hypothesize that these neomorphic proteome activities are required for aberrant cancer cell growth and survival, and that their identification and rational targeting will lead to improved targeted therapies, including immune targeting. To enable their facile and clinical profiling, we developed the Quantitative Cancer Proteomics Atlas, with immediate applications in biology and diagnostics.

Using molecular mechanics modeling, protein engineering and synthetic chemistry techniques, we are developing a modular platform technology to enable specific and efficient intracellular delivery of macromolecular drugs, including peptidomimetics to control protein interactions, synthetic tumor suppressors, and genome-editing enzymes. This approach leverages libraries of peptide barcodes that we have recently developed to enable functional proteomics screening for discovery of peptide-based ligands, probes, and biologic therapeutics.