Radiovirotherapy for Multiple Myeloma

描述（由申请人提供）：2006年多发性骨髓瘤导致超过12000名美国人死亡，目前的治疗方法仍然无法治愈。MV-NIS是一种重组麻疹病毒，以骨髓瘤浆细胞为靶点，编码人甲状腺碘化钠同调体NIS。MV-NIS感染的细胞在其表面膜上表达NIS蛋白，从而浓缩放射性碘。在这项资助的前五年，我们使用无创成像技术研究MV-NIS在异种骨髓瘤移植模型中的扩散，并使用I-131实现协同肿瘤细胞杀伤（放射病毒治疗）。我们还将NIS基因引入溶瘤性水泡性口炎病毒（VSV）平台，并将VSV-NIS用于原位同基因5TGM1骨髓瘤模型的放射病毒治疗。MV-NIS目前正在多发性骨髓瘤患者的I期临床试验中进行测试，我们计划（在未来5年的某个时候）继续进行后续临床试验，在MV-NIS之后将给予治疗剂量的I-131。在接下来的五年里，我们的目标是开发临床可行的方法，提高放射病毒治疗的治疗指数。为实现这一目标，我们提出以下具体目标：测定骨髓瘤沉积物放射性碘外排率，这些骨髓瘤沉积物感染了编码NIS的病毒，加上或减去抑制CLC(N)2氯离子通道表达的shRNA。假设放射性碘通过氯离子通道CLC(N)2从大多数哺乳动物细胞中逃逸，并通过限制该通道的表达而更有效地保留在骨髓瘤细胞中。目标2。目的：探讨地塞米松是否能改善I-131的骨髓毒性。假设是，地塞米松与放射病毒治疗一起使用将显著降低治疗的骨髓毒性，而不会阻碍病毒的繁殖或骨髓瘤细胞中NIS的表达，从而改善治疗结果。目标3。为了确定蛋白酶体抑制剂硼替佐米（一种批准的抗骨髓瘤药物，使骨髓瘤细胞对电离辐射的致死效应敏感）是否可以增强使用MV-NIS或VSV-NIS放射病毒治疗的溶瘤效力。假设硼替佐米与放射病毒治疗一起使用将显著增强肿瘤的放射敏感性，而不会阻碍病毒的繁殖或骨髓瘤细胞中NIS的表达，从而改善治疗结果。尽管采用了新的治疗方法，多发性骨髓瘤仍然无法治愈。在这项拨款中进行的研究结合了有前途的溶瘤病毒治疗新方法和使用放射性碘治疗这种疾病。

DESCRIPTION (provided by applicant): Multiple myeloma was responsible for the deaths of more than 12,000 Americans in 2006 and remains incurable with current therapy. MV-NIS is a recombinant measles virus that targets myeloma plasma cells and codes for the human thyroidal sodium iodide symporter, NIS. MV-NIS infected cells express the NIS protein on their surface membrane and therefore concentrate radioiodine. During the first five years of this grant we used noninvasive imaging techniques to study the spread of MV-NIS in myeloma xenograft models, and used I-131 to achieve synergistic tumor cell killing (radiovirotherapy). We also introduced the NIS gene into an oncolytic vesicular stomatitis virus (VSV) platform and used VSV-NIS for radiovirotherapy in the orthotopic syngeneic 5TGM1 myeloma model. MV-NIS is now being tested in a phase I clinical trial in patients with multiple myeloma and we plan to proceed (sometime in the next five years) to a follow-on clinical trial in which a therapeutic dose of I-131 will be administered after MV-NIS. Our goal during the next five years of this grant is to develop clinically viable approaches that will enhance the therapeutic index of radiovirotherapy. With this goal in mind, we have the following specific aims: Aim 1. To determine the rates of radioiodine efflux from myeloma deposits infected with viruses that code for NIS, plus or minus a shRNA that suppresses CLC(N)2 chloride channel expression. The hypothesis is that radioiodine escapes from most mammalian cells via the chloride channel, CLC(N)2 and can be retained more efficiently in myeloma cells by constraining the expression of this channel. Aim 2. To determine whether dexamethasone can ameliorate the bone marrow toxicity of I-131. The hypothesis is that dexamethasone, administered with radiovirotherapy will significantly decrease the bone marrow toxicity of the treatment without retarding the propagation of the virus or the expression of NIS in myeloma cells, and will thereby lead to improved treatment outcome. Aim 3. To determine whether the proteasome inhibitor bortezomib, an approved antimyeloma drug that sensitizes myeloma cells to the lethal effects of ionizing radiation, can enhance the oncolytic potency of radiovirotherapy using MV-NIS or VSV-NIS. The hypothesis is that bortezomib, administered with radiovirotherapy will significantly enhance the radiosensitivity of the tumor without retarding the propagation of the virus or the expression of NIS in myeloma cells, and will thereby lead to improved treatment outcome. Despite the introduction of new treatments, multiple myeloma remains incurable. The studies to be pursued in this grant combine the promising novel approach of oncolytic virotherapy with the use of radioactive iodine for the treatment of this disease.