Issue No. 15, March 2018
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.     
The Challenge of Multiple Myeloma (MM) and Targeting Cell Death Pathways in MM

  • Multiple myeloma (MM) is an accumulative disease involving mature plasma cells that afflicts approximately 30,000 new patients annually in the United States.
  • MM remains an incurable and ultimately fatal disease in most cases despite encouraging progress in development and approval of several new agents for these patients e.g., proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies.
  • MM cells are impaired in their capacity to initiate apoptosis, resulting in the accumulation of malignant plasma cells in the bone marrow and other sites.
  • Venetoclax (ABT-199, AbbVie) specifically and potently targets BCL-2, an anti-apoptotic protein that protects MM and other cells from the lethal effects of multiple anti-MM agents.
  • Venetoclax has recently been approved for use by the FDA for patients with a high-risk sub-type of chronic lymphocytic leukemia (CLL) and has shown encouraging results in several other hematologic malignancies including follicular lymphoma and acute myelogenous leukemia. 
Limitations of Venetoclax in MM

Because MM, like CLL, is a B-cell malignancy, evaluating venetoclax in this disease was a logical step to take. Interestingly, pre-clinical studies found that venetoclax is effective against MM cells, but primarily against a sub-set of cells with favorable karyotypic features e.g., the t(11;14) translocation. In contrast, venetoclax was relatively ineffective against MM cells exhibiting high-risk features e.g., cells displaying the t(4;14) translocation. Significantly, responding cells exhibited high expression ratios of BCL-2 to MCL-1, another anti-apoptotic protein implicated in myelomagenesis. Interestingly, similar results were observed in MM patients receiving venetoclax e.g., low-risk patients tended to respond but high-risk patients did not. The problem is that low-risk patients have multiple other therapeutic options while high-risk patients are generally refractory to most therapeutic strategies. These findings raised the possibility that the efficacy of venetoclax may be limited to a sub-set of patients who have a variety of alternative therapeutic possibilities.
 
Restoring Venetoclax Activity in High-Risk MM Patients

In a study recently reported in the British Journal of Cancer (*1), Steven Grant, MD, VIMM physician-scientist, Associate Director for Translational Research and Co-Leader of the Developmental Therapeutics Program of the VCU Massey Cancer Center and his colleagues described a new strategy potentially capable of restoring venetoclax sensitivity in otherwise resistant high-risk MM cells. This strategy was based in part on earlier findings by this group demonstrating that certain cyclin-dependent kinase inhibitors e.g., the CDK9 inhibitor flavopiridol (alvocidib), lower the threshold for cell death by pan-BH3-mimetics in MM cells (2), and that CDK9 inhibitors potently down-regulate MCL-1 triggering cell death in these cells (3). This strategy stems from evidence that CDK9 inhibitors, in addition to their anti-proliferative effects, inhibit transcription by blocking phosphorylation of the carboxy-terminal domain of RNA polymerase II by positive translation elongation factor b (TEFb). Disruption of transcription by this mechanism leads to down-regulation of multiple short-lived proteins, including MCL-1, which has a half-life of 2-3 hours. Thus, co-administration of flavopiridol has the potential to reverse the BCL-2/MCL-1 ratio of venetoclax-resistant cells and in so doing, restore their sensitivity to this agent. Indeed, as shown in Figure 1 , co-administration of flavopiridol and venetoclax sharply increased cell death in both low-risk as well as high-risk primary, patient-derived MM cells, whereas individual exposure had little effect. Importantly, co-administration of flavopiridol and venetoclax exerted minimal toxicity, but very significantly increased animal survival in a xenograft model of high-risk MM (Figure 2) .
Figure 1. Flavopiridol and venetoclax potently induce apoptosis in standard- and high-risk primary multiple myeloma cell specimens.

Figure 2. Xenograft model of MM (U266) following treatment with flavopridol and venetoclax C. Body weight was monitored twice weekly during treatment.
Conclusions and Implications

Together, these findings indicate that transcriptional repression by a CDK9 inhibitor such as flavopiridol can potentially restore venetoclax sensitivity in otherwise resistant MM cells by modifying the balance between apoptotic regulatory proteins. They also raise the possibility that this strategy may be successful in high-risk MM patients who have few satisfactory therapeutic options available to them. Based on the present findings, discussions are currently underway with AbbVie and Genentech (venetoclax) as well as Tolero (flavopiridol) with the goal of initiating a phase I trial of venetoclax and flavopiridol in patients with relapsed/refractory high-risk MM. This trial would be carried out in connection with a Multiple Myeloma SPORE in collaboration with MD Anderson Cancer Center and the Johns Hopkins Sidney Kimmel Cancer Center.
Support and Collaborations
This work was supported by CA205607 and Multiple Myeloma SPORE award 1P50CA142509-01 from the NCI. Collaborators included Dr. Deepak Sampath (Genentech) and Dr. Joel Leverson (AbbVie).

Publications:



About the Investigators : Steven Grant, MD, is Professor of Hematology-Oncology, Internal Medicine, VCU School of Medicine, Associate Director for Translational Research
Program and Shirley Carter and Sture Gordon Olsson Chair in Cancer Research, and Full Member of the VCU Institute of Molecular Medicine (VIMM).