Prevention and treatment of lethal metastases in group 3 medulloblastoma

脑肿瘤是最常见的实体肿瘤，也是儿童癌症相关死亡的主要原因。 髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤。MB的播散（转移）导致 植入覆盖大脑和脊髓的软脑膜在之前的工作中，我们证明了 转移瘤在生物学上不同于其匹配的原发性肿瘤， MB儿童死亡，治疗后经常发生的转移性疾病具有高度的克隆性差异 治疗初治的转移瘤第3组髓母细胞瘤（G3 MB）是造成MB中大多数死亡的原因 患者虽然只有三分之一的G3 MB患者在诊断时有可见的转移，但几乎100%的G3 MB患者在诊断时有可见的转移。 复发性疾病有转移。MB幸存者发病率的主要来源是整个发育期的照射。 脑和脊髓，进行预防转移复发，但留下的幸存者与认知延迟，生长 失败和继发性癌症。适度降低颅脊髓放射剂量将显著改善质量 幸存者的生命。了解脑膜炎患者软脑膜播散、进展和复发的生物学基础 因此，G3 MB可以开发补充颅脊髓放射的疗法，使放射剂量 减少而不增加复发率。我们以前已经表明，虽然大多数SHH肿瘤复发， 在局部，G3几乎总是转移性复发。该提案利用了G3 MB的经过充分验证的GEMM模型， 在PI实验室合作，发现驱动前期转移启动/进展和转移的基因， 放疗后复发。识别这些基因应该使我们能够在小鼠医院中测试新疗法 设置，以防止转移复发的设置减少颅脊髓辐射。我们的目标是： 目标1.利用我们的研究，发现启动和驱动G3 MB前期转移进展的基因和途径。 动物模型（功能基因组学），然后在人类样品中验证（癌症基因组学）和功能基因组学。 使用体内小鼠模型进行验证。 目标2.发现启动和驱动G3 MB治疗后转移进展的基因和途径， 对辐射的反应。我们将在人性化的小鼠医院环境中使用功能基因组学和癌症基因组学， 提供显微神经外科手术和图像引导的多分割颅脊髓放射治疗。 目标3：启动小鼠临床试验，以预防手术后G3 MB的转移性复发， 通过递送靶向mTOR、非整倍体和其他靶点的新型药剂进行的大剂量颅脊髓照射 在目标#1和#2中发现。

Brain tumors are the most common solid tumor and the leading cause of cancer-related death in children. Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Dissemination (metastasis) of MB results in seeding the leptomeningeal membranes that cover the brain and spinal cord. In prior work, we demonstrated that metastases are biologically distinct from their matched primary tumor that metastases are the overwhelming cause of death in children with MB, and that metastatic disease which frequently develops post-therapy is highly clonally divergent to therapy naïve metastases. Group 3 medulloblastoma (G3 MB) is responsible for the majority of deaths among MB patients. While only a third of G3 MB patients have visible metastases at diagnosis, almost 100% of patients with recurrent disease have metastases. The major source of morbidity in MB survivors is irradiation of the entire developing brain and spinal cord, performed to prevent metastatic recurrence, but leaving survivors with cognitive delay, growth failure, and secondary cancers. Modest decreases in the dose of craniospinal radiation would significantly improve quality of life for survivors. Understanding the biological basis of leptomeningeal dissemination, progression, and recurrence in G3 MB could therefore allow the development of therapies to supplement craniospinal radiation, enabling radiation dose reductions without an increased rate of recurrence. We have shown previously that, whereas most SHH tumors recur locally, G3 almost always recurs metastatically. This proposal leverages a well-validated GEMM model of G3 MB made collaboratively in the PIs labs, to discover genes that drive up-front metastatic initiation/progression and metastatic recurrence after radiation therapy. Identifying these genes should enable us to test novel therapies in a mouse hospital setting, to prevent metastatic recurrence in the setting of reduced craniospinal radiation. Our aims are to: Aim 1. Discover genes and pathways that initiate and drive progression of up-front metastases in G3 MB utilizing our animal model (functional genomics), followed by validation in human samples (cancer genomics) and functional validation using in vivo mouse models. Aim 2. Discover genes and pathways that initiate and drive progression of post-treatment metastases in G3 MB in response to radiation. We will use functional genomics and cancer genomics in a humanized mouse hospital setting, delivering both microneurosurgery and image guided multifractionated craniospinal radiotherapy. Aim 3. Initiate murine clinical trials to prophylactically prevent metastatic recurrence of G3 MB after surgery and reduced dose craniospinal irradiation, through delivery of novel agents targeting of mTOR, aneuploidy, and additional targets discovered in Aims #1 and #2.