Endoplasmic reticulum stress and oncoviral therapy

内质网应激和肿瘤病毒治疗

• 批准号: 9262357
• 负责人: Steffan T Nawrocki
• 金额: $ 27.67万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262357
• 关键词: Endoplasmic; reticulum; stress; oncoviral; therapy

 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.

 描述（由申请方提供）：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/高危疾病，因此是一个有吸引力的治疗靶点。我们之前证明了一种用于癌症治疗的新型呼肠孤病毒制剂，称为Reolysin，是MM患者的一种有前途的新药，因为它在细胞系，原代患者细胞和疾病的小鼠模型中表现出显着的活性。然而，介导MM细胞中呼肠孤病毒敏感性的机制还不清楚。我们的初步数据表明，Reolysin可能对具有高MYC活性的MM患者和/或硼替佐米难治的MM患者特别有效，因为这些细胞对Reolysin诱导的细胞死亡表现出超敏反应。我们假设组成性MYC活性通过内质网（ER）应激介导的机制使难治性/高危MM细胞对Reolysin具有独特的敏感性。在目标1中，我们将确定MYC作为Reolysin敏感性调节剂的作用。将评估MYC、PKR活性和ER应激之间的潜在联系。在目标2中，我们将研究获得性硼替佐米耐药性的演变赋予对Reolysin敏感性增加的机制。最后，在目标3中，我们将确定ER应激诱导的自噬作为Reolysin介导的细胞死亡的调节剂的作用。在这些研究结束时，我们将显着扩展有关促进复发/高风险MM细胞中呼肠孤病毒疗效改善的机制的知识，并将产生最佳利用Reolysin治疗晚期和药物难治性MM所需的关键新信息。