Deciphering Complex Regulation of the Proteome To Treat Disease

Significant effort in cancer research has been directed towards understanding the composition of the cancer genome. This work has produced a great deal of insight into cancer biology. However, less is known about how global protein-level dynamics interface with genomic alterations and therapeutic perturbations, despite the fact that proteins are the functional units of cancer cells that carry out biological function. To attempt to bridge this knowledge gap, we aim to apply chemical biology and mass spectometry-based strategies to answer specific questions within biology relating to transcriptional regulation, translational regulation, protein turnover, and signaling. We primarily focus on these problems in the context of blood cancers, with a particular emphasis on multiple myeloma. The goal of our laboratory is to understand the basic biology of proteome-level regulation in cancer - whether at the level of protein abundance, post-translational modification, protein-protein interaction, or localization - as well as develop new therapeutic and diagnostic strategies based on this knowledge.

For example, we have recently sought to evaluate both post-translational modifications and the cancer cell surface in response to therapeutic or genomic perturbation. We are particularly interested in applying these methodologies to discover new therapeutic stratagies not only using novel small molecules but also immunotherapy approaches. Importantly, these findings integrate with our work as part of the UCSF Stephen and Nancy Grand Multiple Myeloma Translational Initiative where we use state-of-the-art in vitro and in vivo models of myeloma to evaluate the preclincal efficacy of new therapies for this blood cancer.

In a link to Dr. Wiita's clinical work, we have also recently begun to apply our proteomic methods to the study of phenotypic effects of copy number variation in constitutional genetics. The link between genome and proteome has been largely ignored in the field of genetics but may carry major implications for diagnosis, prognosis, and therapy.

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