Using genetically engineered mouse models of brain tumors to develop therapeutic nanoparticles & biomaterials

 描述(申请人提供)：我们已经开发了一套人类胶质瘤和室管膜瘤的基因工程小鼠模型，我们已经使用它来为临床药物的治疗选择提供信息。高级别胶质瘤在几乎所有病例中都是致命的，因为无法完全切除它们，以及剩余的肿瘤细胞对可用的治疗方法具有抵抗力。胶质瘤有两种主要的分子亚型，一种是侵袭性较弱的肿瘤，具有IDH1突变和甲基化表型CIMP；另一种是侵袭性较强的非CIMP胶质瘤，通常是4级胶质瘤。这些肿瘤的治疗是对高级别胶质瘤进行手术后再进行放疗和化疗，复发几乎一致，中位生存期不到2年。我们显然需要改进治疗这些脑瘤的策略，部分是通过加强放射治疗，部分是通过让免疫系统更好地攻击这些肿瘤细胞。在这笔赠款中，我们将通过纳米颗粒和生物聚合物在小鼠身上开发这些方法。这项赠款申请是一个机会，可以聚集这些领域的领先专家团队，使用这些肿瘤类型的GEMM模型来推动这些领域的发展。在每一种情况下，我们都将在这些模型中开发技术，这些技术可以在几年内转化为人体试验。

 DESCRIPTION (provided by applicant): We have developed a suite of genetically-engineered mouse models of human gliomas and ependymomas that we have used to inform treatment options for clinical agents. High-grade gliomas are fatal in nearly all cases because of the inability to fully resect them, and the resistance of the remaining tumors cells to available therapy. There are two main molecular subtypes of glioma, those less aggressive tumors with IDH1 mutation and a methylator phenotype designated CIMP, and the more aggressive non-CIMP gliomas that are frequently grade 4 GBMs. The treatment of these tumors is surgery followed by radiation and chemotherapy for high-grade gliomas, with almost uniform recurrence and a median survival of less than 2 years. We clearly need improved strategies for treating these brain tumors, partly by enhancing radiation therapy and partly by getting the immune system to work better at attacking these tumor cells. In this grant we will develop these methods in mice via nanoparticles and biopolymers. This grant application is an opportunity to gather a team of leading experts in these fields to use GEMM models of these tumor types to advance these areas. In each case we will be developing technology in these models that can be translated to human trials within a few years.