ABT-199 based therapies to treat neuroblastoma

高危神经母细胞瘤是导致儿童癌症死亡的第二大原因。 MYCN的扩增可以解释其中的许多情况，而其他鲜为人知的机制可以解释 非MYCN基因扩增了高危神经母细胞瘤。我们最近证明了扩增的MYCN是 对FDA批准的bcl2抑制剂ventoclax(ABT-199)的合成致死作用。在这里，我们揭示了几个 万乃馨在MYCN扩增神经母细胞瘤治疗中的合理应用及临床前试验 他们。此外，我们还提供了合理的证据，证明万乃馨联合应用在高危人群中是有效的。 MYCN-野生型神经母细胞瘤，基于在这些癌症中新发现的凋亡阻断。最后， 通过高通量药物筛选，我们发现了一类有效、特异和广泛的新药 在神经母细胞瘤中的活性，并与万乃馨联合使用，几乎消除所有神经母细胞瘤细胞。 目的：高危神经母细胞瘤对目前的治疗方案难以奏效。通过研究分子 针对这些癌症的脆弱性，我们提出了几种新的有希望的治疗方法来专门对抗亚群 高危神经母细胞瘤，总体目标是为临床测试做好准备。 具体目标#1.确定标准护理化疗和万乃馨的抗癌活性 对抗分子异质性神经母细胞瘤细胞系和动物模型。 在这里，我们将评估万乃馨在多只小鼠身上的疗效。 神经母细胞瘤模型。 具体目标2：评价万乃馨/MDM2抑制剂联合治疗的有效性和安全性 在p53野生型神经母细胞瘤的细胞系和动物模型中。 在这里，我们将确定mdm2抑制剂与万乃馨联合的体外疗效机制。 在p53野生型神经母细胞瘤中，明确活体疗效和安全性。 具体目标3：表征单独和联合使用H3K27me3抑制剂的有效性和安全性 用维尼托克拉克斯。 我们已经确定了一类在神经母细胞瘤中具有有效和特定活性的新药物。我们将进一步 确定这种敏感性的机制(S)在体外和体内。 研究设计/方法：利用一种创新的药物基因组学方法，发现了几种 已经达到或即将进行临床试验的新靶向疗法，我们将评估其他新药 联合万乃馨治疗神经母细胞瘤的疗效。使用多种神经母细胞瘤体外模型， 我们将研究特定的药物脆弱性与其分子基础之间的关系。 敏感度。最后，我们将严格评估我们的新型靶向治疗的临床前有效性和安全性。 多种不同的神经母细胞瘤动物模型的组合。

High-risk neuroblastoma accounts for the second most pediatric cancer deaths. Amplification of MYCN accounts for many of these cases, while other less-understood mechanisms account for non-MYCN amplified high-risk neuroblastoma. We have recently demonstrated that amplified MYCN is synthetic lethal to the FDA-approved BCL-2 inhibitor, venetoclax (ABT-199). Herein, we uncover several rational implementations of venetoclax in MYCN-amplified neuroblastoma therapy and aim to preclinically test them. In addition, we provide rational and evidence that venetoclax can be effective in combination in high-risk MYCN-wild-type neuroblastoma, based on a newly discovered apoptotic block in these cancers. Lastly, through high-throughput drug screening, we uncover a novel class of drug that has potent, specific and broad activity across neuroblastoma, and combines with venetoclax to eliminate virtually all neuroblastoma cells. Objectives: High-risk neuroblastoma is refractory to current treatment regimens. By studying the molecular vulnerabilities of these cancers, we propose several new promising treatments to specifically combat subsets of high-risk neuroblastoma, with the overall goal to ready these for clinical testing. Specific Aim #1. Determine anti-cancer activity of standard-of-care chemotherapy and venetoclax against molecularly heterogeneous neuroblastoma cell lines and animal models. Here, we will evaluate the efficacy of venetoclax with the standard-of-care chemotherapy in multiple mouse models of neuroblastoma. Specific Aim 2: Characterize the efficacy and safety of venetoclax/ MDM2 inhibitor combination therapy in p53 wild-type neuroblastoma in cell lines and animal models. Here, we will determine the mechanisms of in vitro efficacy of MDM2 inhibitors in combination with venetoclax in p53 wild-type neuroblastoma, and define vivo efficacy and safety. Specific Aim 3: Characterize the efficacy and safety of H3K27me3 inhibition alone and in combination with venetoclax. We have identified a novel class of drug with potent and specific activity in neuroblastoma. We will further define the mechanism(s) of this sensitivity in vitro and in vivo. Study Design/Methods: Utilizing an innovative pharmacogenomics approach that has uncovered several novel targeted therapies that have reached or are headed to clinical trials, we will evaluate other novel drugs for efficacy in neuroblastoma in combination with venetoclax. Using multiple in vitro models of neuroblastoma, we will study the relationship between particular drug vulnerabilities and the molecular underpinnings of that sensitivity. Lastly, we will rigorously evaluate preclinical efficacy and safety of our novel targeted therapy combinations in multiple and diverse animal models of neuroblastoma.