This grant is funded by Carol Klein and Nancy Moses through their annual Afternoon Tea event.
The proteasome inhibitor bortezomib (Velcade®) is an important new drug for the treatment of myeloma. Based on this success, novel combination therapies with bortezomib are being tested for efficacy and for their potential in circumventing drug resistance in myeloma. The reovirus is a naturally occurring virus that is non-pathogenic and has been reported to preferentially replicate in cancer cells, but not in normal tissue. This observation prompted the development of the reovirus-based anticancer agent Reolysin®, which has already demonstrated promise in early preclinical and clinical studies. However, the mechanism by which Reolysin induces tumor cell death remains unclear. Myeloma cells have remarkably high rates of protein synthesis to produce large amounts of immunoglobulins. Therefore, it has been suggested that these cells may be hypersensitive to endoplasmic reticular (ER) stress. Dr. Nawrocki and colleagues hypothesize that Reolysin preferentially induces the accumulation of viral products in myeloma cells and that this selectively stimulates ER stress-mediated cell death. Since abnormal protein accumulation can trigger cancer cell death, the simultaneous induction of different types of protein buildup (ubiquitin-conjugated and viral) may be a promising anticancer strategy. Moreover, the high protein synthesis rates of myeloma cells (compared with low protein synthesis rates of normal cells) may render them uniquely sensitive to proteotoxicity-mediated cell death. Dr. Nawrocki will investigate this possibility by evaluating the benefit of a bortezomib and Reolysin combination therapeutic strategy. The knowledge gained from this research will be rapidly translated into a clinical trial and has the potential to significantly impact myeloma therapy.