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


METHODS
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.
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Mamata
M
Singh
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Justin M
JM
Leasure
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Christopher
C
Chronowski
Nationwide Children's Hospital, Columbus, OH.
Brian
B
Geier
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Kathryn
K
Bondra
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Wenrui
W
Duan
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Lauren A
LA
Hensley
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Miguel
M
Villalona-Calero
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Ning
N
Li
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Anthony M
AM
Vergis
Nationwide Children's Hospital, Columbus, OH.
Raushan T
RT
Kurmasheva
Nationwide Children's Hospital, Columbus, OH.
Changxian
C
Shen
Nationwide Children's Hospital, Columbus, OH.
Gary
G
Woods
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Nikhil
N
Sebastian
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Denise
D
Fabian
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Rita
R
Kaplon
Nationwide Children's Hospital, Columbus, OH.
Sue
S
Hammond
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Kamalakannan
K
Palanichamy
Authors' Affiliations: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute; and.
Arnab
A
Chakravarti
Nationwide Children's Hospital, Columbus, OH Peter.Houghton@nationwidechildrens.org.
Peter J
PJ
Houghton
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000502:physiology*; D005260:Female; D006801:Humans; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D011836:Radiation Tolerance; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009025:Morpholines; D015514:Oncogene Proteins, Fusion; C471563:PAX3-FOXO1A fusion protein, human; D051761:Paired Box Transcription Factors; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol