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We here aim to dissect the molecular landscape of MM that is acquiring resistance to the most active PI, carfilzomib (CFZ) in vivo. We therefore here extend our model to orthotopic growth conditions of MM in murine bone marrow under continuous selection pressure with CFZ. We build on our long-term experience and established experimental tools as an international leader in dissecting the mechanisms of PI-resistance in MM cell lines in vitro, together with established single-cell global mRNA expression analysis to characterize the molecular and sub-clonal landscape and evolution of PI-resistance in MM in the bone marrow-niche in situ, and to further explore the most prominent findings on a functional level. Towards this, we shall compare single cell RNA profiling of both murine and human MM cell lines that acquire CFZ-resistance under selection pressure of
the drug either in vitro or in vivo, as well as primary human MM cells obtained from patients progressing under CFZ-based therapy (Aim 1,2). The most prominent changes in the CFZ-resistant population shall be validated by immunohistochemistry, as well as functionally by genetic manipulation using CRISPR-Cas9 technology established for MM (Aim 3). This shall reveal candidate genes and pathways for mediating CFZ-resistance in vivo, which we aim to target with molecular targeting drug compounds identified from the public drug repurposing database at the broad institute (Aim 4) towards targeted elimination of such CFZ-resistant MM.
Overall, this study aims to deliver a first comprehensive picture of CFZ-resistant MM arising in the bone marrow environment in vivo, and to identify and evaluate biology-driven new treatment strategies and lead drugs to treat CFZ-resistant MM.