Department of Stem Cell and Regenerative Medicine, Harvard University, Boston, MA, USA.
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Cell Rep Med. 2023 Dec 19;4(12):101309. doi: 10.1016/j.xcrm.2023.101309. Epub 2023 Dec 11.
Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1 and NF1 hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1 but not NF1 cell proliferation. We identify econazole nitrate as being effective against NF1 hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1 murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.
皮肤神经纤维瘤（cNFs）是在超过 99%的神经纤维瘤病 1 型（NF1）患者中发展的肿瘤。它们在真皮中发展，可以达到数千个。cNFs 可能会瘙痒和疼痛，并对自尊心产生负面影响。目前还没有美国食品和药物管理局（FDA）批准的药物用于治疗。在这里，我们使用源自 NF1 患者的诱导多能干细胞（hiPSC）衍生的 cNF 细胞模型筛选了 FDA 批准的药物库。我们在第二个等位基因中设计了 NF1 突变，以模拟杂合性丢失，将 NF1 和 NF1 hiPSC 分化为雪旺细胞前体（SCP），并使用它们筛选药物库，以评估 NF1 但不 NF1 细胞增殖的抑制作用。我们确定硝酸益康唑对 NF1 hiPSC-SCP 有效。硝酸益康唑乳膏选择性地诱导 Nf1 鼠神经根神经球细胞和人 cNF 异种移植物中的细胞凋亡。这项研究支持进一步测试益康唑治疗 cNF。
