Treatment of transplanted and established multiple myeloma using oncolytic myxoma

使用溶瘤粘液瘤治疗移植和建立的多发性骨髓瘤

• 批准号: 8300521
• 负责人: Eric Carter Bartee
• 金额: $ 15.39万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300521
• 关键词: Acute Myelocytic Leukemia; Affect; Apoptosis; Applications Grants; Autologous; Autologous Transplantation; Award; Binding; Biological Models; Biology; Bone Marrow; Bone Marrow Stem Cell; Cancerous; Cell Extracts; Cells; Clinical; Collaborations; Communities; Data; Diagnosis; Discrimination; Disease; Disease remission; Engraftment; Event; Funding; Goals; Grant; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Immune system; Induction of Apoptosis; Leadership; Life; Life Expectancy; Malignant Neoplasms; Mediating; Mentors; Molecular; Motivation; Multiple Myeloma; Myeloid Cells; Myxoma; Myxoma virus; Oncolytic; Oncolytic viruses; Oryctolagus cuniculus; Patient Care; Patients; Pharmaceutical Preparations; Plasma; Poxviridae; Process; Publications; Recurrent disease; Relapse; Research; Research Personnel; Residual Tumors; Residual state; Sampling; Scientific Advances and Accomplishments; Scientist; Source; Specificity; Stem cell transplant; Stem cells; Surface; Survival Rate; Testing; Transplantation; Viral; Virus; Work; base; cancer cell; cancer therapy; chemotherapy; design; experience; improved; in vivo; interest; member; novel; outcome forecast; peer; purge; research study; stem; virus host interaction

DESCRIPTION (provided by applicant): My interests as a scientist involve the study on virus-host interactions. Currently, I am interested in the study of a rabbit specific poxvirus called myxoma virus (MYXV) and how it interacts with normal and cancerous cells. Previously, our lab has demonstrated that myxoma specifically discriminates between normal and cancerous hematopoietic cells. We have proposed that this discrimination can be used to specifically eliminate cancerous multiple myeloma cells contaminating autologous stem cell samples prior to transplant into patients. This therapy has the potential to improve both the survival and quality o life of multiple myeloma patients by providing a safe and effective cure. Before MYXV can be used as a purging agent in a clinical setting, however, the basis of MYXV's ability to induce apoptosis in myeloma cells while not affecting engraftment of normal stem cells must be elucidated. Additionally, the potential impact of a functional recipient immune system on both ex vivo purging as well as treatment of established MM disease must be determined. This proposal is designed to advance the rationale for using MYXV as an ex vivo virotherapeutic as well as test its potential to treat established malignancy through several potential mechanisms. In the short term, my goal is to carry out the experiments proposed in this K22 grant and advance the scientific rationale for developing oncolytic virotherapy against cancers such as MM. I feel that the work proposed in this K22 grant corresponds to around 2 years of research and therefore represents work that can be accomplished during the course of this grant. I feel that I have the potential to become a strong independent investigator. I have the expertise, leadership and motivation necessary to successfully carry out the proposed work. My previous publications have received multiple awards and commendations proving that it is of high quality as well as interest to the academic community. I have also been successful in obtaining my own funding from multiple sources. I have mentored several graduate and undergraduate researchers and initiated collaborations with other researchers which are likely to result in multiple peer-reviewe publications and successful grant applications. As a result of these experiences, I feel that I am fully capable of: developing and executing a research plan, leading others through this plan, and obtaining the additional funding needed to continue my research. We have previously demonstrated that acute myeloid leukemia cells contaminating autologous stem cell transplant samples can be purged by ex vivo treatment with a rabbit specific poxvirus called myxoma virus. We now demonstrate that this treatment is also effective at purging contaminating multiple myeloma cells by inducing rapid cellular apoptosis. This proposal is designed to elucidate the mechanism(s) of how myxoma treatment results in myeloma cell apoptosis and whether the virus can also be used to reduce established myeloma.

描述（由申请人提供）：作为一名科学家，我的兴趣涉及病毒与宿主相互作用的研究。目前，我对研究一种称为粘液瘤病毒（MYXV）的兔子特异性痘病毒及其如何与正常细胞和癌细胞相互作用感兴趣。此前，我们的实验室已经证明粘液瘤可以特异性地区分正常造血细胞和癌性造血细胞。我们提出，这种区分可用于在移植到患者体内之前特异性消除污染自体干细胞样本的癌性多发性骨髓瘤细胞。该疗法有可能通过提供安全有效的治疗来提高多发性骨髓瘤患者的生存率和生活质量。然而，在 MYXV 在临床环境中用作净化剂之前，必须阐明 MYXV 诱导骨髓瘤细胞凋亡而不影响正常干细胞植入的能力的基础。此外，必须确定功能性受体免疫系统对离体清除以及已确定的 MM 疾病治疗的潜在影响。该提案旨在推进使用 MYXV 作为离体病毒治疗剂的基本原理，并测试其通过几种潜在机制治疗既定恶性肿瘤的潜力。短期内，我的目标是开展 K22 资助中提出的实验，并推进开发针对多发性骨髓瘤等癌症的溶瘤病毒疗法的科学原理。我认为这项 K22 拨款中提出的工作相当于大约 2 年的研究，因此代表了在这笔拨款期间可以完成的工作。我觉得我有潜力成为一名强有力的独立调查员。我拥有成功开展拟议工作所需的专业知识、领导力和动力。我之前的出版物已获得多项奖项和表彰，证明其质量很高并且引起了学术界的兴趣。我还成功地从多个来源获得了自己的资金。我指导过几位研究生和本科生研究人员，并与其他研究人员展开合作，这可能会导致多篇同行评审出版物和成功的资助申请。由于这些经历，我觉得我完全有能力：制定和执行研究计划，领导其他人完成该计划，并获得继续我的研究所需的额外资金。我们之前已经证明，污染自体干细胞移植样本的急性髓系白血病细胞可以通过用一种称为粘液瘤病毒的兔特异性痘病毒进行离体处理来清除。我们现在证明，这种治疗还可以通过诱导快速细胞凋亡来有效清除污染的多发性骨髓瘤细胞。该提案旨在阐明粘液瘤治疗如何导致骨髓瘤细胞凋亡的机制，以及该病毒是否也可用于减少已形成的骨髓瘤。