Harnessing the Multipotency of Cancer Stem Cells for Differentiation Therapy

利用癌症干细胞的多能性进行分化治疗

• 批准号: 8929179
• 负责人: Alka Mansukhani
• 金额: $ 18.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929179
• 关键词: Adipocytes; Adolescent; Affect; Agonist; Automobile Driving; Benign; Biological Assay; Cell Lineage; Cell Proliferation; Cells; Child; Childhood; Clinic; Development; Diabetes Mellitus; Differentiation Therapy; Disease; Drug usage; FDA approved; Fatty acid glycerol esters; Genes; Growth; Health; Human; Incidence; Insulin; Lead; Malignant Bone Neoplasm; Malignant Neoplasms; Mesenchymal; Mesenchymal Cell Neoplasm; Mesenchymal Stem Cells; Metastatic Osteosarcoma; Mus; Operative Surgical Procedures; Osteoblasts; Outcome; PPAR gamma; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pioglitazone; Population; Proliferating; Property; Recurrence; Recurrent disease; Regimen; Relapse; Research; Safety; Staging; Stem cells; Survival Rate; Teenagers; Testing; Therapeutic; Thiazolidinediones; Tissues; Tumor Suppression; Tumorigenicity; Undifferentiated; Work; alternative treatment; base; bone; bone cell; cancer cell; cancer stem cell; clinically significant; improved; limb amputation; lipid biosynthesis; neoplastic cell; novel; novel strategies; novel therapeutics; osteoprogenitor cell; osteosarcoma; outcome forecast; progenitor; rosiglitazone; stem; stem cell differentiation; targeted treatment; tumor; tumor growth; tumorigenic

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.

描述（由适用提供）：骨肉瘤是一种影响儿童和青少年的侵略性骨癌。骨肉瘤被认为是一种破坏分化的疾病，其中肿瘤细胞无法分化为适当的骨形成成熟成骨细胞。骨肉瘤通常在表现上进行进展，目前的治疗主要由化学治疗方案和手术组成。骨肉瘤的复发率很高，并且经常导致年轻患者的肢体截肢。转移性骨肉瘤的存活率仍然约为30％，这种毁灭性疾病的替代治疗迫切需要替代治疗。在这项合作研究中，我们建议通过利用骨肉瘤癌症干细胞的内在多能特征来测试一种治疗骨肉瘤的新方法。骨肉瘤来自通常具有形成骨骼和脂肪细胞的能力的间充质干细胞。我们的分化治疗方法是使用优先抑制骨肉瘤干细胞生长的药物，同时使其成为脂肪细胞。我们将使用一类药物TZD，这些药物是脂肪形成的主要调节剂PPARγ的激动剂。几个TZD在胰岛素清除和糖尿病治疗中的无关效应批准。我们发现TZD可以抑制骨肉瘤细胞的生长并促进脂肪分化。我们将测试TZD对小鼠原代小鼠和人骨肉瘤细胞的影响，并检查它们对细胞和肿瘤的影响。特别是，我们将确定TZD是否可以激活脂肪形成所需的基因。如果成功，该提案将为治疗诊所中骨肉瘤的新策略提供基础。

项目成果

Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by Riluzole.

• DOI: 10.1371/journal.pone.0171256
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Liao S;Ruiz Y;Gulzar H;Yelskaya Z;Ait Taouit L;Houssou M;Jaikaran T;Schvarts Y;Kozlitina K;Basu-Roy U;Mansukhani A;Mahajan SS
• 通讯作者: Mahajan SS

Sox2 is required for tumor development and cancer cell proliferation in osteosarcoma.

• DOI: 10.1038/s41388-018-0292-2
• 发表时间: 2018-08
• 期刊: Oncogene
• 影响因子: 8
• 作者: Maurizi G;Verma N;Gadi A;Mansukhani A;Basilico C
• 通讯作者: Basilico C