Treatment of transplanted and established multiple myeloma using oncolytic myxoma

描述(申请人提供)：作为一名科学家，我的兴趣是研究病毒与宿主之间的相互作用。目前，我感兴趣的是一种名为粘液瘤病毒(MYXV)的兔痘病毒，以及它如何与正常细胞和癌细胞相互作用。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和癌变的造血细胞。我们已经提出，在移植到患者体内之前，这种区分可以被用来特异性地消除污染自体干细胞样本的多发性骨髓瘤癌细胞。通过提供一种安全有效的治疗方法，这种疗法有可能改善多发性骨髓瘤患者的生存和生活质量。然而，在MYXV在临床环境中用作清除剂之前，必须阐明MYXV在不影响正常干细胞植入的情况下诱导骨髓瘤细胞凋亡的能力的基础。此外，必须确定有效的受体免疫系统对体外净化和已建立的多发性骨髓瘤疾病治疗的潜在影响。这项建议旨在推进将MYXV用作体外病毒治疗的理论基础，并通过几种潜在的机制测试其治疗已建立的恶性肿瘤的潜力。在短期内，我的目标是开展这项K22资助中建议的实验，并推进针对MM等癌症的溶瘤病毒疗法的科学基础。我认为这项K22资助中建议的工作相当于大约两年的研究，因此代表了在这项资助过程中可以完成的工作。我觉得我有潜力成为一名强大的独立调查员。我拥有成功开展拟议工作所需的专业知识、领导能力和动力。我以前的出版物获得了多个奖项和表彰，证明了它的高质量以及学术界的兴趣。我还成功地从多个来源获得了自己的资金。我曾指导过几位研究生和本科生研究人员，并发起了与其他研究人员的合作，这可能会导致多本同行评议的电子出版物和成功的拨款申请。作为这些经历的结果，我觉得我完全有能力：制定和执行研究计划，领导他人完成这个计划，并获得继续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一种称为粘液瘤病毒的兔特异性痘病毒进行体外治疗来清除。我们现在证明，这种治疗方法通过诱导细胞快速凋亡，在清除污染的多发性骨髓瘤细胞方面也是有效的。这项建议旨在阐明粘液瘤治疗如何导致骨髓瘤细胞凋亡的机制(S)，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.