Treatment of transplanted and established multiple myeloma using oncolytic myxoma

描述（由申请人提供）：作为一名科学家，我的兴趣涉及病毒-宿主相互作用的研究。目前，我感兴趣的是一种名为粘液瘤病毒（MYXV）的兔特异性痘病毒的研究，以及它如何与正常细胞和癌细胞相互作用。以前，我们的实验室已经证明粘液瘤特异性区分正常和癌性造血细胞。我们已经提出，这种区分可以用于在移植到患者体内之前特异性地消除污染自体干细胞样本的癌性多发性骨髓瘤细胞。这种疗法有可能通过提供安全有效的治疗来改善多发性骨髓瘤患者的生存和生活质量。然而，在MYXV可以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诊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，并通过几种潜在机制测试其治疗已确定的恶性肿瘤的潜力。在短期内，我的目标是开展K22资助中提出的实验，并推进开发针对MM等癌症的溶瘤病毒疗法的科学原理。我认为K22资助中提出的工作相当于大约2年的研究，因此代表了在该资助期间可以完成的工作。我觉得我有潜力成为一个强大的独立调查员。我具备成功开展拟议工作所需的专门知识、领导能力和动力。我以前的出版物已经获得了多个奖项和表彰，证明它是高质量的，以及学术界的兴趣。我也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，并与其他研究人员开展合作，这可能会导致多篇同行评议的出版物和成功的资助申请。由于这些经验，我觉得我完全有能力：制定和执行研究计划，通过这个计划领导他人，并获得继续我的研究所需的额外资金。我们以前已经证明，急性髓性白血病细胞污染自体干细胞移植样品可以清除离体治疗与兔特异性痘病毒称为粘液瘤病毒。我们现在证明，这种治疗也是有效的净化污染的多发性骨髓瘤细胞诱导快速细胞凋亡。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建立的骨髓瘤。

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.