As part of the UCSF Stephen and Nancy Grand Multiple Myeloma Translational Initiative, one of our goals is to develop and evaluate novel therapeutic strategies for this disease. We aim to develop these strategies from hypotheses developed in our lab as well as via collaborations with others in academia and industry. Our goal is to advance these theapeutics into clinical trials to provide new options for myeloma patients.
For example, we recently used a combination of quantitative phosphoproteomics, alternative splicing analysis of RNA-seq (in collaboration with Angela Brooks at UC Santa Cruz), and bioinformatics to show that carfilzomib modulates the splicing machinery and the spliceosome represents a unique therapeutic vulnerability in myeloma (Huang et al, Nature Communications (2020); see Figure).
In collaboration with Casey Greene at UPenn and Larry Boise at Emory, we have also recently used quantitative phosphoproteomic profiling and machine learning approaches applied to publicly-available RNA-seq data to suggest new strategies by which to employ kinase inhibitors in myeloma trials (Lin et al, Blood Adv 2019).
In collaboration with biotechnology companies Sutro Biopharma and TeneoBio, we have also preclinically evaluated novel immunotherapies targeting the cell surface markers CD74 (Abrahams et al, Oncotarget (2018)) and BCMA (Force Aldred et al, mAbs (2019)). These molecules have now proceeded into Phase I clinical trials led by UCSF MMTI physicians.
Overcoming Drug Resistance in Multiple Myeloma
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., Cell Chem Biol 2022). 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.