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 tumors in particular. The use of massively parallel RNA 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 from non-canonical start sites and spliced from non-canonical exon junctions, as well as gain-of-function post-translational modifications, such as those induced by mutant enzymes and aberrant metabolic products.

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. To enable their facile profiling, we are leveraging ultra-sensitive high-accuracy mass spectrometry to develop the Quantitative Cancer Proteomics Atlas. This technology should have wide uses in oncology and human biology.