DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets.
DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets.
复制标题
DOI：
10.1158/1078-0432.ccr-15-3011
复制
发表时间：
2016-08-01
期刊：
影响因子：
--
通讯作者：
Raabe EH
中科院分区：
文献类型：
--
作者：
Hanaford AR;Archer TC;Price A;Kahlert UD;Maciaczyk J;Nikkhah G;Kim JW;Ehrenberger T;Clemons PA;Dančík V;Seashore-Ludlow B;Viswanathan V;Stewart ML;Rees MG;Shamji A;Schreiber S;Fraenkel E;Pomeroy SL;Mesirov JP;Tamayo P;Eberhart CG;Raabe EH
我们使用人类干细胞和祖细胞来开发一种遗传上精确的MYC驱动的第3组髓母细胞瘤的新模型。我们还开发了一种新的信息学方法，即疾病模型特征与化合物-品种富集反应（“DiSCover”），以鉴定靶向这种特定疾病亚型的新型疗法。来自小脑原基的人神经干细胞和祖细胞被转导与侵袭性髓母细胞瘤相关的致癌元件。在多个药物敏感性数据集中使用了筛选药物敏感性数据库（DiSCoVER）的计算机分析方法。我们在体外和体内验证了来自该分析的最高命中。用c-MYC、显性阴性p53、组成型活性AKT和hTERT转化的人神经干细胞和祖细胞在小鼠中形成肿瘤，其在病理学和表达谱方面重现第3组成神经管细胞瘤。DiSCover分析预测，侵袭性MYC驱动的第3组髓母细胞瘤对CDK抑制剂敏感。CKD 4/6抑制剂palbociclib可降低原位髓母细胞瘤原位异种移植小鼠的增殖，增加凋亡，并显著延长其生存期。我们提出了一种新的方法来生成罕见肿瘤的遗传准确模型，以及一种伴随的计算方法来寻找针对它们的治疗干预措施。我们验证了MYC驱动的第3组髓母细胞瘤的人神经干细胞模型，并表明CDK 4/6抑制剂对该亚组具有活性。我们的研究结果表明，palbociclib是一种潜在的有效治疗方法，用于精心选择的患者中预后不良的MYC驱动的第3组髓母细胞瘤肿瘤。
We used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. We also developed a new informatics method, Disease-model Signature vs. Compound-Variety Enriched Response (“DiSCoVER”), to identify novel therapeutics that target this specific disease subtype. Human neural stem and progenitor cells derived from the cerebellar anlage were transduced with oncogenic elements associated with aggressive medulloblastoma. An in silico analysis method for screening drug sensitivity databases (DiSCoVER) was used in multiple drug sensitivity datasets. We validated the top hits from this analysis in vitro and in vivo. Human neural stem and progenitor cells transformed with c-MYC, dominant-negative p53, constitutively active AKT and hTERT formed tumors in mice that recapitulated Group 3 medulloblastoma in terms of pathology and expression profile. DiSCoVER analysis predicted that the aggressive MYC-driven Group 3 medulloblastoma would be sensitive to CDK inhibitors. The CKD4/6 inhibitor palbociclib decreased proliferation, increased apoptosis and significantly extended the survival of mice with orthotopic medulloblastoma orthotopic xenografts. We present a new method to generate genetically accurate models of rare tumors, and a companion computational methodology to find therapeutic interventions that target them. We validated our human neural stem cell model of MYC-driven Group 3 medulloblastoma and showed that CDK4/6 inhibitors are active against this subgroup. Our results suggest that palbociclib is a potential effective treatment for poor-prognosis MYC-driven Group 3 medulloblastoma tumors in carefully selected patients.