Advances in biology, genomics, epigenetics, and immunity have transformed our understanding of the etiology and pathogenesis of multiple myeloma (MM). Using these technologies, we have defined at an unprecedented level the genetic heterogeneity and genomic instability of MM, as well as the clonal evolution underlying the progression of the disease from monoclonal gammopathy of undetermined significance to smoldering MM and then to active MM. In parallel, we have developed in vitro and in vivo models of MM in its bone marrow (BM) milieu, which have facilitated the identification of mechanisms mediating MM cell homing to the BM; growth, survival, and drug resistance; as well as egress to extramedullary sites. Altogether, these advances have allowed for the identification of vulnerabilities in MM that can be exploited, directly leading to a transformation in therapeutic efficacy and marked improvement in patient outcome. We are focusing on five major areas to achieve a curative outcome:
Genomics
Using the latest -omic technologies, we are assessing myeloma cells for broad changes to their genomes, epigenomes, transcription factor networks, and proteomes and correlating those changes to clinically relevant phenotypes such as cancer subtype, patient survival, and patient response to therapies. We are particularly interested in the mechanisms of mutation, clonal heterogeneity, and transcriptional control programs. By combining genomics, transcriptomics, proteomics, and epigenomics, we are attempting to reconstruct how a plasma cell initially transforms into a myeloma cell, how it mutates to survive and multiply, and how current therapies may alter these processes. By learning how myeloma cells broadly adapt to become resistant to therapy, we are developing new approaches to therapy and making current therapies more effective. Novel targets currently identified, as well as those identified in the above genomic analyses, are being validated in both high throughput screens and in in vitro and in vivo models of myeloma in the bone marrow microenvironment. We are especially interested in investigating high-risk myeloma to develop targeted therapies and strategies to control such aggressive disease. We have focused our attention on t(4;14) and t(14;16) myeloma and are in the process of further studying del 17p and amp1q myeloma.
Cell Signaling
How a myeloma cell interacts with other nearby cells can affect when it multiplies, if it can avoid cell death, and other internal pathways that regulate everything from cell metabolism to DNA damage. We are interested in finding the protein mediators of these pathways, fully assessing their function, and investigating ways to therapeutically target them.
RNA-based Therapeutics
Long Noncoding RNAs (lncRNAs) play fundamental roles in the growth of multiple myeloma. These RNA molecules provide essential chromatin scaffolds for protein interactions that contribute to the epigenetic and transcriptional reprogramming of tumor cells. Therefore, inhibiting specific lncRNAs could be an avenue for novel and more effective treatments. We have identified 14 lncRNAs that are correlated with progression-free survival independent of cytogenetic, ISS, or MRD status. We are currently conducting high-throughput screens to identify functionally important lncRNAs in multiple myeloma and performing validation studies on the most promising candidates to develop targeted therapeutics.
Genome Stability
The instability of a myeloma cell’s genome dictates how easily it can avoid cell death, adapt to therapy, and evolve new capabilities and aggressive phenotypes. We are researching not only how instability (and subsequent mutations) correlate with patient survival and response to therapy, but the mechanisms of how, when, and to what degree the genome becomes unstable. We are particularly interested in investigating the mechanisms of DNA repair and how these mechanisms become dysregulated, thus promoting instability and cancer aggressiveness. We are looking at targeting these mechanisms, either to prevent instability or to encourage it enough to kill the cancer cell.
Immune System
Inducing and maintaining immune activity against tumor cells is a constant struggle in multiple myeloma, where immune suppression and exhaustion is common. The loss of a competent immune system worsens patient survival by allowing the growth of tumor cells and by weakening the impact of immunotherapy. We are profiling the immune system to assess how it changes in response to myeloma cells and to therapy. We are particularly interested in finding suitable proteins for vaccines, ways to boost immune function, and how current therapies rejuvenate or repress the immune system. Building on the recent success of cellular therapies such as CAR T cells, we hope to further develop novel immune-based therapies and to tweak the current therapies to beneficially interact with the immune system.