Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy

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PROJECT SUMMARY/ABSTRACT This NCI Supplement to Promote Diversity is designed to support the career development of Ms. Audrey Kishishita, a second year student in the Chemistry and Chemical Biology Graduate Program at the University of California, San Francisco. Ms. Kishishita is of Latina descent and a first-generation college student who completed her undergraduate studies with high accolades at California State University-Los Angeles. The supplement is related to R01 CA226851, whose PI is Arun Wiita, MD, PhD. Dr. Wiita, an Associate Professor in the Dept. of Laboratory Medicine at UCSF, will serve as Ms. Kishishita's primary mentor for this proposal. The research plan of the Supplement directly relates to Aim 2 of the R01, which is focused on studying the role of alternative splicing in the blood cancer multiple myeloma. Specially, a major goal of this Aim in the R01 is to identify new ways to modulate splicing that may be beneficial either to perturb myeloma biology or potentially as a therapeutic. Here, Ms. Kishishita proposes experiments to develop novel recombinant protein fusion constructs that can enter myeloma cells and specifically degrade subunits of the spliceosome. She will first work to validate the principle of these degraders using GFP as a test substrate and then move on to engineering nanobody recognition elements for targeted splicing factors. She will further use mass spectrometry-based proteomics and mRNA-seq to evaluate downstream effects of this degradation. To complement the expertise of the primary mentor in myeloma biology, proteomics, splicing, and nanobody engineering, the co-mentor, Dr. Charles Craik, is a University Professor at UCSF with a >30 year track record of mentorship. Dr. Craik is also a leading expert in protein engineering and protein degradation, directly relevant to the proposal here. Drs. Wiita and Craik have worked with Ms. Kishishita to craft a comprehensive training plan including experiential learning, a series of both internal and external didactic courses, opportunities to present scientific work to receive feedback, experience in grant- and paper-writing, and opportunities for networking with peers and more experienced scientists. This training plan is designed to provide Ms. Kishishita with a unique skillset and scientific experience to carry her forward into her post-doctoral work and ultimately into an independent faculty position. We are excited to complete the proposal here to support the career development of a scientific trainee with outstanding potential.