While new therapeutic agents have made major progress in extending lifespans for multiple myeloma patients, this plasma cell malignancy unfortunately remains incurable. A significant interest of our group is identifying methods by which to overcome this continuing clinical conundrum. To do this, we aim to combine methods including RNA-seq, translational profiling via ribosome profiling, quantitative proteomics, and functional genomics.
Using a combination of these "omics" approaches, we initially found that very few proteins are upregulated during rapid cell death induced by the proteasome inhibitor bortezomib, a first-line therapeutic administered to almost all myeloma patients. We hypothesized that the acute stress response proteins, including numerous heat shock response proteins, that did "break through" may be related to PI resisistance (Wiita et al., eLife, 2013). We next used targeted proteomic approaches to specifically monitor the synthesis of new protein molecules in this system, developing a quantitative model to relate absolute protein molecules per cell to mRNA transcript abundance in the context of drug treatment (Liu and Huang et al., Cell Systems (2017)).
More recently, we have collaborated with the group of Jason Gestwicki at UCSF to evaluate the role of their novel allosteric HSP inhibitors (originally described by Shao et al, J Med Chem (2018)) as myeloma therapeutics. Remarkably, these molecules are indeed much more potent versus proteasome-inhibitor resistant models of myeloma (see Figure). We have further evaluated the mechanism behind this increased efficacy, finding strong genetic co-dependency between the proteasome and HSP70 system, as well as using pulsed-SILAC proteomics to reveal an interaction between PI resistance and vulnerability to mitochondrial perturbation (Ferguson et al., BioRxiv). These results validate HSP70 inhibition as a promising strategy to overcome PI resistance.
We are also studying drug response and resistance at the level of the cell surface proteome. Surface proteomic profiling of PI-resistant cell line models have identified dysregulation of numerous cell surface proteins, which may serve both as novel biomarkers and immunotherapeutic targets (Ferguson et al., BioRxiv). In addition, in collaboration with Martin Kampmann's lab UCSF, we are using CRISPR interference to deeply explore transcriptional regulation of the surface protein CD38 in myeloma, the target of the monoclonal antibody daratumumab. Loss of CD38 may be a key factor in resistance to this agent and discovering new ways to modulate this surface target may provide a way to re-sensitize tumors. We have recently described one strategy to increase CD38 expression and overcome daratumumab resistance - co-administration of DNA methyltransferase inhibitors (Choudhry et al., Leukemia 2020) - and now have moved this strategy into a clinical trial with Drs. Nina Shah and Swetha Kambhampati.