ABT-199 based therapies to treat neuroblastoma

高危神经母细胞瘤占儿童癌症死亡的第二位。 MYCN的扩增解释了其中许多情况，而其他不太了解的机制解释了这些情况。 非MYCN扩增的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BCL-2抑制剂维奈托克（ABT-199）具有合成致死性。在这里，我们发现了几个 维奈托克在MYCN扩增神经母细胞瘤治疗中的合理应用，旨在临床前测试 他们此外，我们提供了合理的和证据，证明维奈托克可以有效地联合在高风险 MYCN-野生型神经母细胞瘤，基于这些癌症中新发现的凋亡阻滞。最后， 通过高通量药物筛选，我们发现了一类新的药物，具有强效，特异性和广泛的 活性的神经母细胞瘤，并结合维奈托克，以消除几乎所有的神经母细胞瘤细胞。 目的：高危神经母细胞瘤对目前的治疗方案是难治的。通过研究 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， 高风险的神经母细胞瘤，总体目标是为临床测试做好准备。 具体目标#1。测定标准化疗和维奈托克的抗癌活性 针对分子异质性神经母细胞瘤细胞系和动物模型。 在此，我们将评估维奈托克与标准化疗在多个小鼠中的疗效。 神经母细胞瘤模型。 具体目标2：描述维奈托克/MDM 2抑制剂联合治疗的疗效和安全性 在细胞系和动物模型中的p53野生型神经母细胞瘤中。 在这里，我们将确定MDM 2抑制剂与维奈托克联合使用的体外疗效机制 在p53野生型神经母细胞瘤中，并确定了体内功效和安全性。 具体目标3：表征H3 K27 me 3抑制单独和组合的有效性和安全性 用维奈托克 我们已经确定了一类新的药物，在神经母细胞瘤中具有强效和特异性活性。我们将进一步 在体外和体内定义这种敏感性的机制。 研究设计/方法：利用创新的药物基因组学方法， 对于已经或即将进入临床试验的新型靶向治疗，我们将评估其他新药 与维奈托克联合治疗神经母细胞瘤的疗效。使用神经母细胞瘤的多种体外模型， 我们将研究特定药物的脆弱性与其分子基础之间的关系， 灵敏度最后，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 在神经母细胞瘤的多种和不同的动物模型中的组合。

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.