FANCD2 is a potential therapeutic target and biomarker in alveolar rhabdomyosarcoma harboring the PAX3-FOXO1 fusion gene

Mamata Singh, Justin M. Leasure, Christopher Chronowski, Brian Geier, Kathryn Bondra, Wenrui Duan, Lauren A. Hensley, Miguel Villalona-Calero, Ning Li, Anthony M. Vergis, Raushan T. Kurmasheva, Changxian Shen, Gary Woods, Nikhil Sebastian, Denise Fabian, Rita Kaplon, Sue Hammond, Kamalakannan Palanichamy, Arnab Chakravarti, Peter J. Houghton

Producción científica: Articlerevisión exhaustiva

9 Citas (Scopus)

Resumen

Purpose: Alveolar rhabdomyosarcoma that harbors the PAX3-FOXO1 fusion gene (t-ARMS) is a common and lethal subtype of this childhood malignancy. Improvement in clinical outcomes in this disease is predicated upon the identification of novel therapeutic targets. Experimental Design: Robust mouse models were used for in vivo analysis, and molecular studies were performed on xenografts treated in parallel. Two independent patient sets (n = 101 and 124) of clinically annotated tumor specimens were used for analysis of FANCD2 levels and its association with clinical and molecular characteristics and outcomes. Results: Our xenograft studies reveal a selective suppression of FANCD2 by m-TOR kinase inhibition and radiosensitization of the t-ARMS line only. In the initial patient set, we show that FANCD2 transcript levels are prognostic in univariate analysis, and are significantly associated with metastatic disease and that the copresence of the translocation and high expression of FANCD2 is independently prognostic. We also demonstrate a significant and nonrandom enrichment of mTOR-associated genes that correlate with FANCD2 gene expression within the t-ARMS samples, but not within other cases. In the second patient set, we show that on a protein level, FANCD2 expression correlates with PAX3-FOXO1 fusion gene and is strongly associated with phospho-P70S6K expression in cases with the fusion gene. Conclusions: Our data demonstrate that FANCD2 may have a significant role in the radiation resistance and virulence of t-ARMS. Indirectly targeting this DNA repair protein, through mTOR inhibition, may represent a novel and selective treatment strategy.

Idioma originalEnglish (US)
Páginas (desde-hasta)3884-3895
Número de páginas12
PublicaciónClinical Cancer Research
Volumen20
N.º14
DOI
EstadoPublished - jul 15 2014
Publicado de forma externa

ASJC Scopus subject areas

  • General Medicine

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