Targeting Tumors with NF1 Loss

 描述(由申请人提供)：基因组信息可以让研究人员设计出针对患者癌症特定分子损害的精确治疗方法。其中一个 在许多恶性肿瘤中存在的分子损害是NF1肿瘤抑制基因的缺失，NF1是神经纤维瘤病1型(NF1)的驱动因素，NF1是最常见的遗传性疾病之一。NF1表现出广泛的临床范围，包括称为神经纤维瘤的良性神经系统肿瘤、低级别星形细胞瘤、嗜铬细胞瘤和幼年粒单核细胞白血病。丛状神经纤维瘤(PN)发生在深部神经，可退化为恶性周围神经鞘瘤(MPNSTs)，耐化疗和放射的肉瘤，5年生存率低达20%。在NF1携带者中，终身风险是 PN为30%，MPNST为8-15%。在散发性肿瘤中也发现NF1突变，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系中，NF1的缺失已被证明是推动GBM的原因。一种旨在抑制肿瘤启动和促进细胞的靶向分子疗法将极大地提高我们治疗因NF1缺失而发展的肿瘤的能力。 使用互补筛选平台，我们确定了选择性地杀死或阻止携带NF1突变的细胞生长的小分子以及它们的分子靶标。在这项应用中，我们将重点放在我们的顶级小分子先导和我们的模型系统的能力上，以测试这一假设，即已知由NF1缺失驱动且没有治愈方法的侵袭性神经癌症，包括PN、MPNST和GBM，将对我们确定为具有NF1缺失的合成致命分子做出反应。为此，我们将确定我们的顶级小分子先导的药代动力学特性，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，以便在PN和GBM的临床前模型中测试它们的有效性。我们将利用我们的模型系统来定义我们的小分子先导的作用机制，并在共享相同靶点的临床试验中添加我们正在进行的药物。除了突变失活外，一些GBM肿瘤还表现出NF1蛋白的下调。我们的先导化合物还在体外阻止了低NF1蛋白的人GBM和神经母细胞瘤细胞的生长，支持了我们已经确定的小分子先导的广泛应用。为了捕获通过任何机制丢失NF1的肿瘤，我们构建了一个基于RNA的分类器，它能够使用机器学习识别指示GBM中NF1失活的下游转录效应。我们将应用基于RNA的分类器以及NF1的定向测序，来识别其他患者来源的异种移植(PDX)GBM肿瘤，这些肿瘤具有NF1的失活突变或NF1丢失的分子特征，并在临床前模型中测试它们对我们的先导化合物的反应。我们期待这项工作将为由NF1缺失驱动的侵袭性神经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.