2023-09-20 ケンブリッジ大学
◆具体的には、既存の2つの承認済み薬、パルボシクリブとレチノイン酸を組み合わせています。神経芽腫は小児のがんであり、このアプローチは治療の新たな可能性を示唆しています。
<関連情報>
- https://www.cam.ac.uk/stories/potential-new-neuroblastoma-treatment
- https://www.sciencedirect.com/science/article/pii/S1534580723004434?via%3Dihub
パルボシクリブが神経芽腫細胞の潜在分化能力を解放する Palbociclib releases the latent differentiation capacity of neuroblastoma cells
Kirsty M. Ferguson, Sarah L. Gillen, Lewis Chaytor, Evon Poon, Daniel Marcos, Roshna Lawrence Gomez, Laura M. Woods, Lidiya Mykhaylechko, Louis Elfari, Barbara Martins da Costa, Yann Jamin, Jason S. Carroll, Louis Chesler, Fahad R. Ali, Anna Philpott
Developmental Cell Available online: 20 September 2023
DOI:https://doi.org/10.1016/j.devcel.2023.08.028
Highlights
•Palbociclib inhibits neuroblastoma cell proliferation and drives differentiation
•The transcriptome and epigenome are reprogrammed favoring neuronal differentiation
•Palbociclib inhibits tumor growth in in vivo mouse neuroblastoma models
•PB and RA together drive transcriptional changes associated with improved prognosis
Summary
Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.
