PROJECT SUMMARY/ABSTRACT
We propose to create a multidisciplinary Mayo Clinic Center for Clinical Proteomics with the overarching goal
of identifying and validating proteomic biomarkers for treatment response in multiple myeloma. This center is a
unique alliance comprising of two teams within the Mayo Clinic umbrella and one team at Brigham Young
University. This team of physicians and scientists at Mayo Clinic with expertise in multiple myeloma
diagnosis, treatment, clinical trials and basic research as well as technologies such as mass
spectrometry, genomics, transcriptomics, bioinformatics and clinical assay development will be joined
by a world expert in novel instrument/platform development at Brigham Young University to create a
unique center. Multiple myeloma is a complex disease with several distinct cytogenetic subtypes. A recently
developed class of drugs designated immunomodulatory imide drugs (IMiDs) has become a mainstay of
treatment of multiple myeloma although relapses among patients is high mainly due to drug resistance. The
primary target of IMiDs is cereblon (CRBN), which is absolutely required for its anti-cancer and immune activity.
IMiDs activate the enzymatic activity of the CRBN E3 ubiquitin ligase complex leading to ubiquitylation and
degradation of transcription factors IKZF1 and IKZF3, thereby regulating tumor survival and immune response
through downregulation of IRF4 and MYC. For the preclinical arm, our interdisciplinary team will undertake
discovery studies involving comprehensive proteogenomic characterization (proteome, phosphoproteome,
ubiquitylome, genome, transcriptome) of multiple myeloma models (genetically engineered cell lines, humanized
mouse models and patient samples) to identify molecular markers of IMiD resistance. Given the centrality of
CRBN-mediated pathways in IMiD resistance, we will jumpstart our targeted proteomics efforts by
focusing on developing targeted assays for CRBN and its downstream effectors. In parallel, we anticipate
identifying additional candidate proteins through our discovery studies, for which targeted assays will also be
developed. Finally, Dr. Vincent Rajkumar, a co-investigator on this proposal, will provide access to samples from
three NCI-sponsored clinical trials specifically designed to look at effects of IMiDs enabling validation of
candidates through a targeted approach. By incorporating continuous development of multiple technology
platforms including CyTOF, we will ensure that we maintain agility over the duration of the proposal.
With an established advanced infrastructure, personnel experienced in the development of CAP/CLIA assays,
dedicated instrumentation, high analytical capacity and existing pipelines for QC, data handling and
bioinformatics, the proposed Mayo Clinic Center for Clinical Proteomics is poised for success to discover and
validate proteomic markers of IMiD resistance in multiple myeloma.