Endoplasmic reticulum stress and oncoviral therapy

 描述(由申请人提供)：癌基因MYC的激活是多发性骨髓瘤(MM)的常见事件，导致难治性/高风险疾病，因此是一个有吸引力的治疗靶点。我们先前证明了一种名为溶血素的新型呼肠孤病毒制剂是治疗多发性骨髓瘤患者的一种有前途的新制剂，因为它在多发性骨髓瘤的细胞系、原代患者细胞和小鼠模型中显示出显著的活性。然而，在MM细胞中介导呼肠孤病毒敏感性的机制还不是很清楚。我们的初步数据表明，溶血素可能对MYC活性高的MM患者和/或对Bortezomib无效的患者特别有效，因为这些细胞对溶血素诱导的细胞死亡表现出超敏反应。我们假设，结构性MYC活动通过内质网(ER)应激调节机制，使难治/高危MM细胞对溶血素唯一敏感。在目标1中，我们将确定MYC作为溶血素敏感性调节因子的作用。MYC、PKR活性和内质网应激之间的潜在联系将被评估。在目标2中，我们将研究获得性Bortezomib耐药性的演变使其对溶血素的敏感性增加的机制。最后，在目标3中，我们将确定内质网应激诱导的自噬作为溶素介导的细胞死亡的调节因子的作用。在这些研究的结论中，我们将大大扩展我们关于促进复发/高危MM细胞中呼肠孤病毒疗效提高的机制的知识，并将产生关键的新信息，以最佳地利用溶血素治疗晚期和药物难治性MM。

 DESCRIPTION (provided by applicant): 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.