Targeting Tumors with NF1 Loss

 描述（由申请人提供）：基因组信息可以使研究人员设计针对患者癌症特异性分子病变的精确疗法。之一 许多恶性肿瘤中存在的分子损伤是NF 1肿瘤抑制因子的丧失，其是最常见的遗传性遗传疾病之一的1型神经纤维瘤病（NF 1）的驱动因子。NF 1表现出广泛的临床谱，包括称为神经纤维瘤的良性神经系统肿瘤、低级星形细胞瘤、嗜铬细胞瘤和青少年粒单核细胞白血病。丛状神经纤维瘤（PN）发生在深部神经，可退化为恶性外周神经鞘瘤（MPNST），化疗和放射抵抗性肉瘤，5年生存率仅为20%。在NF 1携带者中，终身风险是 PN为30%，MPNST为8-15%。NF 1突变也见于散发性肿瘤，包括多形性胶质母细胞瘤（GBM）、黑色素瘤、嗜铬细胞瘤、卵巢癌、子宫癌和肺癌。此外，在动物模型和人类肿瘤细胞系中，NF 1的丢失已被证明会驱动GBM。一种靶向分子疗法，旨在抑制肿瘤启动和促进细胞将大大提高我们的能力，治疗肿瘤的发展作为一个结果，NF 1的损失。 使用互补筛选平台，我们鉴定了选择性杀死或停止携带NF 1突变的细胞及其分子靶点生长的小分子。在本申请中，我们专注于我们的顶级小分子先导物和我们的模型系统的能力，以测试以下假设：已知由NF 1损失驱动并且不存在治愈方法的侵袭性神经系统癌症，包括PN，MPNST和GBM，将对我们确定为合成致死的NF 1损失分子作出反应。为此，我们将确定我们的顶级小分子先导化合物的药代动力学特性，并在需要时进行结构-活性关系研究，以改善动力学和/或降低毒性，以测试其在PN和GBM临床前模型中的疗效。我们将利用我们的模型系统来定义我们的小分子先导化合物的作用机制，并在临床试验中添加具有相同靶点的药物。除了突变失活，一些GBM肿瘤表现出NF 1蛋白的下调。我们的先导化合物还在体外停止了具有低NF 1蛋白的人GBM和神经母细胞瘤细胞的生长，支持了我们已经鉴定的小分子先导物的广泛应用。为了捕获通过任何机制丢失NF 1的肿瘤，我们构建了一个基于RNA的分类器，该分类器能够使用机器学习识别指示GBM中NF 1失活的下游转录组学效应。我们将应用基于RNA的分类器，沿着NF 1的靶向测序，以鉴定具有NF 1失活突变或NF 1缺失的分子特征的其他患者来源的异种移植（PDX）GBM肿瘤，并在临床前模型中测试它们对我们的先导化合物的反应。我们希望这项工作将为NF 1丢失驱动的侵袭性神经系统癌症提供新的靶点和治疗线索。

 DESCRIPTION (provided by applicant): Genomic information can allow investigators to devise precision therapies that target molecular lesions specific to a patient's cancer. One of the molecular lesions present in many malignant tumors is loss of the NF1 tumor suppressor, which is a driver in neurofibromatosis type 1 (NF1), one of the most frequently inherited genetic disorders. NF1 exhibits a broad clinical spectrum including benign nervous system tumors called neurofibromas, low-grade astrocytomas, pheochromocytoma, and juvenile myelomonocytic leukemia. Plexiform neurofibromas (PN) occur in deep nerves and can degenerate into malignant peripheral nerve sheath tumors (MPNSTs), chemo- and radiation-resistant sarcomas with a dismal 20% five-year survival rate. In NF1 carriers, the lifetime risk is 30% for PN and 8-15% for MPNST. NF1 mutations are also found in sporadic tumors including glioblastoma multiforme (GBM), melanoma, pheochromocytoma, ovarian, uterine, and lung cancers. Furthermore, in animal models and human tumor lines NF1 loss has been shown to drive GBM. A targeted molecular therapy designed to inhibit tumor-initiating and -promoting cells would substantially advance our ability to treat tumors that develop as a result of NF1 loss. Using complementary screening platforms, we identified small molecules that selectively killed or stopped the growth of cells carrying a mutation in NF1 as well as their molecular targets. In this application we focus on our top small molecule leads and the power of our model systems to test the hypothesis that aggressive neurological cancers that are known to be driven by NF1 loss and for which no cure exists, including PN, MPNST and GBM, will respond to molecules that we identified as synthetic lethal with NF1 loss. For this, we will determine pharmacokinetic properties of our top small molecule leads and, where needed, conduct structure-activity relationship studies to improve kinetics and/or reduce toxicity in order to test their efficacy in pre-clinical models of PN and GBM. We will leverage our model systems to define the mechanisms of action of our small molecule leads and add to our pipeline drugs in clinical trials that share the same targets. In addition to mutational inactivation, some GBM tumors exhibit down-regulation of the NF1 protein. Our lead compounds also stopped the growth of human GBM and neuroblastoma cells with low NF1 protein in vitro, supporting the broad application of the small molecule leads that we have identified. To capture tumors that have lost NF1 by any mechanism, we constructed an RNA-based classifier, which is capable of identifying downstream transcriptomic effects that indicate NF1 inactivation in GBM, using machine learning. We will apply the RNA-based classifier, along with targeted sequencing of NF1, to identify additional patient derived xenograft (PDX) GBM tumors that have an inactivating mutation of NF1 or molecular signatures of NF1 loss and test their response to our lead compounds in pre-clinical models. We expect that this work will provide new targets and therapeutic leads for aggressive neurological cancers driven by NF1 loss.