Prevention and treatment of lethal metastases in group 3 medulloblastoma

脑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)是儿童最常见的恶性脑肿瘤。甲基溴的传播(转移)导致 播种覆盖大脑和脊髓的软脑膜。在之前的工作中，我们演示了 转移瘤与其匹配的原发肿瘤在生物学上是不同的，在原发肿瘤中，转移是压倒性的原因。 患有MB儿童的死亡，以及治疗后经常发生的转移性疾病在克隆性方面高度分化 来治疗幼稚的转移瘤。第三组髓母细胞瘤(G3 MB)是MB死亡的主要原因 病人。虽然只有三分之一的G3MB患者在确诊时有明显的转移，但几乎100%的 复发的疾病有转移。MB幸存者的主要发病率来源是整个发育过程中的辐射 大脑和脊髓，进行手术以防止转移复发，但给幸存者留下认知延迟，生长 失败和继发性癌症。适度减少颅脑脊髓辐射剂量将显著提高质量 对幸存者来说是生活的一部分。了解软脑膜播散、进展和复发的生物学基础 因此，G3MB可以允许开发补充颅脊辐射的治疗方法，从而使辐射剂量 在不增加复发率的情况下减少。我们之前已经表明，尽管大多数SHH肿瘤复发 在当地，G3几乎总是以转移的方式复发。该提案利用了经过充分验证的G3 MB制造的GEMM模型 在PIS实验室合作，发现驱动早期转移启动/进展和转移的基因 放射治疗后复发。识别这些基因应该使我们能够在老鼠医院测试新的治疗方法 在减少脊髓辐射的情况下，防止转移复发。我们的目标是： 目的1.利用我们的基因和途径发现启动和驱动G3MB早期转移的基因和途径 动物模型(功能基因组学)，随后在人类样本(癌症基因组学)和功能基因组学中进行验证 使用活体小鼠模型进行验证。 目的2.发现启动和驱动G3MB细胞治疗后转移的基因和途径 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影像引导的多分割颅脑脊髓放射治疗。 目的3.启动小鼠临床试验以预防术后G3MB的转移复发，并减少 通过提供靶向mTOR、非整倍体和其他靶点的新型药物，进行剂量脊髓照射 在AIMS#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.