Endoplasmic Reticulum Stress and Oncoviral Therapy

Activation of the oncogene MYC is a frequent event in multiple myeloma (MM) that contributes to refractory/high-risk disease and is therefore an attractive therapeutic target. We previously demonstrated that a novel reovirus formulation for cancer therapy called Reolysin is a promising new agent for patients with MM as it exhibits significant activity in cell lines, primary patient cells, and mouse models of the disease. However, the mechanisms that mediate reovirus sensitivity in MM cells are not well understood. Our preliminary data indicate that Reolysin may be particularly effective for MM patients with high MYC activity and/or those that are refractory to bortezomib as these cells exhibit hypersensitivity to Reolysin-induced cell death. We hypothesize that constitutive MYC activity renders refractory/high-risk MM cells uniquely sensitive to Reolysin through an endoplasmic reticulum (ER) stress-mediated mechanism. In Aim 1, we will determine the role of MYC as a regulator of Reolysin sensitivity. A potential link between MYC, PKR activity, and ER stress will be evaluated. In Aim 2, we will investigate the mechanisms by which the evolution of acquired bortezomib resistance confers increased sensitivity to Reolysin. Finally, in Aim 3 we will determine the role of ER stress-induced autophagy as a regulator of Reolysin-mediated cell death. At the conclusion of these studies, we will have significantly expanded our knowledge regarding the mechanisms that promote improved reovirus efficacy in relapsed/high- risk MM cells and will have generated critical new information required to optimally utilize Reolysin for the treatment of advanced and drug-refractory MM. PUBLIC HEALTH RELEVANCE: Increased activity of the oncogene c-MYC is a well-described event in multiple myeloma (MM) pathogenesis that leads to constitutive endoplasmic reticulum (ER) stress. Therapeutic agents that specifically target MYC expressing cells could have direct applications for the treatment of patients with high- risk/refractory disease, for whom few options currently exist. Reoviruses are commonly found in the respiratory and gastrointestinal tract of humans, but are considered to be non-pathogenic. Recent studies have shown that reoviruses selectively replicate in malignant cells and this has led to the development of a reovirus-based formulation for cancer therapy called Reolysin. We previously demonstrated that Reolysin has significant anti- MM activity in MM cell lines, primary specimens from MM patients, and in both syngeneic and xenograft mouse models of the disease. However, the mechanisms that control the selective activity of Reolysin against MM cells remain to be elucidated. Our preliminary data demonstrate that Reolysin preferentially replicates in MM cells with high MYC activity, induces ER stress, and is significantly more efficacious against bortezomib- resistant cell lines and refractory patient specimens than their drug-sensitive counterparts. Our major goals are to investigate the mechanisms that control the hypersensitivity of refractory/high-risk MM cells to reovirus- induced cell death and to further evaluate Reolysin as a novel therapy for patients with high-risk disease. We hypothesize that constitutive MYC activity renders refractory/high-risk MM cells uniquely sensitive to Reolysin through an ER stress-mediated mechanism. Collectively, our proposed research will define the role of MYC as a regulator of Reolysin sensitivity, determine the mechanisms involved in the evolution of bortezomib resistance that confer acquired sensitivity to Reolysin, and will provide critical information required to optimally develop reovirus-based tr