所属 医学部 医学科（東京女子医科大学病院） 職種 教授
|表題||Druggable targets in pediatric neurocutaneous melanocytosis: Molecular and drug sensitivity studies in xenograft and ex vivo tumor cell culture to identify agents for therapy.|
|著者・共著者||Ruan Y, Kovalchuk A, Jayanthan A, Lun X, Nagashima Y, Kovalchuk O, Wright JR Jr, Pinto A, Kirton A, Anderson R, Narendran A.|
|概要||BACKGROUND: Neurocutaneous melanocytosis (NCM) is a rare congenital disorder that
presents with pigmented cell lesions of the brain or leptomeninges in children
with large or multiple congenital melanocytic nevi. Although the exact
pathological processes involved are currently unclear, NCM appears to arise from
an abnormal development of melanoblasts or melanocyte precursors. Currently, it
has an extremely poor prognosis due to rapid disease progression and lack of
effective treatment modalities.
METHODS: In this study, we report on an experimental approach to examining NCM
cells by establishing subcutaneous tumors in nude mice, which can be further
expanded for conducting molecular and drug sensitivity experiments.
RESULTS: Analysis of the NRAS gene-coding sequences of an established NCM cell
line (YP-MEL) and NCM patient cells revealed heterogeneity in NRAS Q61K that
activated mutation and possibly consequential differential sensitivity to MEK
inhibition. Gene expression studies were performed to compare the molecular
profiles of NCM cells with normal skin fibroblasts. In vitro cytotoxicity screens
of libraries of targeted small-molecule inhibitors revealed prospective agents
for further evaluation.
CONCLUSIONS: Our studies provide an experimental platform for the generation of
NCM cells for preclinical studies and the production of molecular and in vitro
data with which to identify druggable targets for the treatment.