NOTCH inhibition in melanoma

描述(申请人提供)：转移性黑色素瘤是一种高度致命的人类恶性肿瘤。尽管该领域取得了进展，但黑色素瘤的分子遗传学尚未完全确定。癌症基因组图谱报告黑色素瘤的高突变负荷。“司机”基因的识别和新的治疗方法仍然是一个主要的焦点。值得注意的是，有必要根据具有治疗意义的分子特征对黑色素瘤进行分类。我们的主要目标是将新的治疗方法引入黑色素瘤的治疗领域，并根据基因图谱对患者进行分层治疗。我们通过转移性黑色素瘤的外显子组测序确定了FBXW7突变是一种新的遗传事件。Fbxw7是一种肿瘤抑制基因，编码F-box蛋白家族的成员。F-box蛋白是泛素蛋白连接酶复合体SCF(Skp1-cullin-F-box)的四个亚基之一，在依赖磷酸化的泛素化过程中发挥作用，并调节在细胞分裂、细胞生长和分化中起核心作用的蛋白质网络。FBXW7的底物包括具有良好特性的癌蛋白，其中之一是NOTCH1。对黑色素瘤样本的筛查发现了FBXW7的错义和无义突变，其中一些是复发的。我们发现，在人类黑色素瘤细胞系中沉默FBXW7会导致NOTCH1水平升高。此外，我们还发现FBXW7下调的异种移植瘤对Notch信号的抑制有反应。在这项建议中，我们旨在研究在人类黑色素瘤中发现的FBXW7突变的影响，以及在这种情况下抑制NOTCH1的治疗益处。这项建议中的研究旨在扩大我们关于影响黑色素瘤发展和转移的遗传事件的知识，目的是为未来的机制驱动的临床试验确定新的靶点。这些研究的最终目标是将从分子研究中获得的知识转化为可用于临床决策的工具。

DESCRIPTION (provided by applicant): Metastatic melanoma is a highly lethal human malignancy. Despite advances in the field, the molecular genetics of melanoma has not been fully characterized. The Cancer Genome Atlas reports high mutational load for melanoma. Identification of 'driver' genes and novel therapeutics remain as a major focus. Notably, there is a need to classify melanomas based on molecular signatures that has therapeutic relevance. Our main goal is to bring in new treatments to the therapeutic arena for melanoma and stratify patients for treatment based on genetic profiles. We identified FBXW7 mutations as a novel genetic event via exome sequencing of metastatic melanomas. FBXW7 is a tumor suppressor gene that encodes a member of the F-box protein family. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination and regulates a network of proteins with central roles in cell division, cell growth and differentiation. The substrates of FBXW7 include well-characterized oncoproteins, one of which is NOTCH1. Screening of melanoma samples revealed missense and nonsense mutations in FBXW7, some of which were recurrent. We found that silencing of FBXW7 in human melanoma cell lines result in elevated NOTCH1 levels. Moreover, we showed that xenograft tumors with FBXW7 down regulation respond to NOTCH signaling inhibition. In this proposal, we aim to study the impact of FBXW7 mutations found in human melanoma and the therapeutic benefit of NOTCH1 inhibition in this setting. The studies in this proposal are designed to expand our knowledge regarding genetic events that influence melanoma development and metastasis with the goal of identifying novel targets for future mechanism-driven clinical trials. The ultimate goal of these studies is to translate knowledge gained from molecular studies into tools that can be used in clinical decision-making.