Harnessing the Multipotency of Cancer Stem Cells for Differentiation Therapy

描述（申请人提供）：骨肉瘤是一种侵袭性骨癌，影响儿童和青少年。骨肉瘤被认为是一种分化破坏的疾病，其中肿瘤细胞不能分化成适当的成骨成熟成骨细胞。骨肉瘤通常是晚期的，目前的治疗主要包括化疗方案和手术。骨肉瘤有很高的复发率，年轻患者常需截肢。转移性骨肉瘤的存活率保持在30%左右，对于这种毁灭性的疾病，迫切需要替代治疗。 在这项合作研究中，我们提出了一种新的方法来治疗骨肉瘤，利用骨肉瘤癌症干细胞的内在多能性特征。骨肉瘤是由间充质干细胞引起的，而间充质干细胞通常具有形成骨和脂肪细胞的能力。我们的分化治疗方法是使用优先抑制骨肉瘤癌干细胞生长的药物，同时引导它们成为脂肪细胞。 我们将使用一类药物TZD，它是脂肪生成的主要调节因子--PPAR γ的激动剂。几种TZD因其在胰岛素清除和糖尿病治疗中的不相关作用而被批准。我们发现TZDs可以抑制骨肉瘤细胞的生长，促进成脂分化。我们将测试TZD对小鼠和人骨肉瘤原代细胞的影响，并检查它们对细胞和肿瘤的影响。特别是，我们将确定TZDs是否可以激活脂肪形成所需的基因。如果成功的话，这一建议将为临床治疗骨肉瘤的新策略提供基础。

DESCRIPTION (provided by applicant): Osteosarcoma is an aggressive bone cancer that affects children and adolescents. Osteosarcoma is considered a disease of disrupted differentiation wherein tumor cells are unable to differentiate into proper bone-forming mature osteoblasts. Osteosarcoma is often advanced at presentation and current treatments consist primarily of chemotherapeutic regimens and surgery. Osteosarcoma has a high rate of recurrence and often leads to limb amputations in young patients. The survival rate for metastatic osteosarcoma remains around 30% and alternative treatments are badly needed for this devastating disease. In this collaborative study, we propose to test a novel approach for treating osteosarcoma by harnessing intrinsic multipotency features of the osteosarcoma cancer stem cells. Osteosarcomas arise from mesenchymal stem cells that normally have the ability to form bone and fat cells. Our differentiation therapy approach is to use agents that preferentially inhibit the growth of osteosarcoma cancer stem cells while steering them to become adipocytes. We will use a class of drugs, the TZDs, that are agonists for PPARγ, the master regulator of adipogenesis. Several TZDs are approved for their unrelated effect in insulin clearance and treatment of diabetes. We have found that TZDs can inhibit the growth of osteosarcoma cells and promote adipogenic differentiation. We will test the effects of TZD on primary mouse and human osteosarcoma cells in mice, and examine their effects on cells and tumors. In particular, we will determine whether the TZDs can activate genes needed for adipogenesis. If successful, this proposal will provide the basis for new strategies to treat osteosarcoma in the clinic.