Blockade of p53 and Aurora A in Therapy Resistant Neuroblastoma

描述（由申请人提供）：神经母细胞瘤是一种起源于神经嵴的肿瘤，是儿童最常见的颅外实体瘤。MYCN（MYC家族个体发生）扩增发生在约25%的神经母细胞瘤中，标志着高危疾病。神经母细胞瘤在实体瘤中是独特的，因为所有患者通常对初始化疗有反应。因此，风险与复发有关，复发通常是耐药的。促成这种耐药性的是，大部分复发性肿瘤在p53通路基因中具有治疗诱导的突变，这在初始呈现时并不明显。神经母细胞瘤的TH-MYCN小鼠模型是人类疾病的奇迹，对化疗有反应。为了提供化疗抗性、复发性疾病的小鼠模型，我们将TH-MYCN小鼠与敲入p53 ER的小鼠杂交，这些小鼠在基线时是p53缺陷的。暴露于羟基他莫昔芬允许快速和可逆的p53恢复。所产生的神经母细胞瘤肿瘤在基线时显示出增加的潜伏期和减少的潜伏期。当p53恢复时，小鼠表现出最初改善的存活率，随后复发。在目标1中，我将描述肿瘤如何逃避p53的重新激活，以使。然后，我将描述p53在现有常规和靶向治疗的化疗耐药性中的重要性，为临床前开发新型治疗药物（包括Aim 2中产生的药物）建立基线。MYCN蛋白在神经母细胞瘤中的稳定性受到通过PI 3 K/mTOR通路的上游信号传导以及Aurora A蛋白的激酶非依赖性支架功能的严格调节。在目标2中，我将描述一类新的II型Aurora A激酶抑制剂，专门设计用于改变Aurora A的二级结构并破坏MYCN的激酶独立稳定性。在初步研究中，我已经确定了候选抑制剂，显着减少MYCN蛋白在神经母细胞瘤细胞，似乎这样做的不稳定机制提出。我将完成构效关系的研究，以进一步完善这些候选化合物。成功完成将导致化学抗性神经母细胞瘤的改进模型以及一类新的靶向Aurora A抑制剂，预计对神经母细胞瘤具有高度有效和特异性。

DESCRIPTION (provided by applicant): Neuroblastoma, a tumor of neural crest origin, is the most common extra-cranial solid tumor of childhood. Amplification of MYCN, a MYC family ontogeny, occurs in ~25% of neuroblastoma and marks high-risk disease. Neuroblastoma is unique among solid tumors in that all patients typically respond to initial chemotherapy. Risk is thus associated with relapse, which is typically therapy-resistant. Contributing to this resistance a large proportion of relapsed tumors have therapy-induced mutations in p53 pathway genes, not evident at initial presentation. Mirroring human disease, the TH-MYCN mouse model of neuroblastoma is responsive to chemotherapy. In order to provide a mouse model of chemotherapy resistant, relapsed disease, we have crossed TH-MYCN mice to mice knocked-in for p53ER, which are p53 deficient at baseline. Exposure to hydroxytamoxifen allows rapid and reversible p53 restoration. Resulting neuroblastoma tumors show increased penetrance and decreased latency at baseline. When p53 is restored, mice show initially improved survival followed by relapse. In Aim 1, I will characterize how tumors evade reactivation of p53 to enable. I will then characterize the importance of p53 in chemotherapy resistance to existent conventional and targeted therapies, establishing a baseline for pre-clinical development of novel therapeutic agents, including those generated in Aim 2. The stability of MYCN protein in neuroblastoma is tightly regulated by upstream signaling through the PI3K/mTOR pathway as well as by a kinase-independent scaffolding function of the Aurora A protein. In Aim 2, I will characterize a novel class of Type II inhibitors of Aurora A kinase designed specifically to alter the secondary structure of Aurora A and disrupt the kinase-independent stabilization of MYCN. In pilot studies I have identified candidate inhibitors that dramatically decrease MYCN protein in neuroblastoma cells and that appear to do so by the destabilization mechanism proposed. I will complete structure activity relationship studies to further refine these candidate compounds. Successful completion will result in both an improved model of chemo-resistant neuroblastoma as well as a new class of targeted Aurora A inhibitors, predicted to be both highly potent and specific against neuroblastoma.