Endoplasmic reticulum stress and oncoviral therapy

内质网应激和肿瘤病毒治疗

• 批准号: 8910821
• 负责人: Steffan T Nawrocki
• 金额: $ 3.68万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910821
• 关键词: Apoptosis; Apoptotic; Autophagocytosis; Bone Marrow; Bortezomib; Cell Adhesion Molecules; Cell Death; Cell Line; Cells; Chloroquine; Data; Development; Disease; Drug Formulations; Drug resistance; Drug-sensitive; Event; Evolution; Exhibits; Gastrointestinal tract structure; Genes; Genetically Engineered Mouse; Goals; Hematologic Neoplasms; Human; Hypersensitivity; Immunocompetent; Immunoglobulins; In Vitro; Knowledge; Link; Lucanthone; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Modeling; Multiple Myeloma; Neoplastic Plasma Cell; New Agents; Nutrient; Oncogene Activation; Oncogenes; Oncolytic viruses; Organelles; PMAIP1 gene; Pathogenesis; Patients; Pharmaceutical Preparations; Predisposition; Protein Biosynthesis; Proteins; Recycling; Refractory; Refractory Disease; Relapse; Reoviridae Infections; Reovirus; Research; Resistance; Respiratory System; Respiratory tract structure; Role; Solid Neoplasm; Source; Specimen; Stress; System; Testing; Therapeutic; Therapeutic Agents; Transcription Factor AP-1; Treatment Failure; Up-Regulation; Viral; Xenograft procedure; base; cancer cell; cancer therapy; cellular targeting; chromatin immunoprecipitation; clinically relevant; direct application; endoplasmic reticulum stress; high risk; improved; in vivo; in vivo Model; inhibitor/antagonist; junctional adhesion molecule; mouse model; mutant; novel; overexpression; public health relevance; receptor; research study; small hairpin RNA; theories; therapeutic target; treatment strategy

 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（由申请人提供）：癌基因 MYC 的激活是多发性骨髓瘤 (MM) 中的常见事件，会导致难治性/高风险疾病，因此是一个有吸引力的治疗靶点。我们之前证明，一种名为 Reolysin 的用于癌症治疗的新型呼肠孤病毒制剂对于多发性骨髓瘤患者来说是一种有前途的新药，因为它在该疾病的细胞系、原代患者细胞和小鼠模型中表现出显着的活性。然而，MM 细胞中介导呼肠孤病毒敏感性的机制尚不清楚。我们的初步数据表明，Reolysin 对于 MYC 活性高的 MM 患者和/或对硼替佐米耐药的患者特别有效，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，组成型 MYC 活性通过内质网 (ER) 应激介导机制使难治性/高风险 MM 细胞对 Reolysin 独特敏感。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进化导致对 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 介导的细胞死亡调节剂的作用。在这些研究结束时，我们将显着扩展我们对促进复发/高风险 MM 细胞中呼肠孤病毒疗效提高的机制的了解，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。