A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-κB signaling in chordoma biology.
Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
Matteo M
MM
Trucco
Ola
O
Awad
Breelyn A
BA
Wilky
Seth D
SD
Goldstein
Ruili
R
Huang
Robert L
RL
Walker
Preeti
P
Shah
Varalakshmi
V
Katuri
Naheed
N
Gul
Yuelin J
YJ
Zhu
Edward F
EF
McCarthy
Ido
I
Paz-Priel
Paul S
PS
Meltzer
Christopher P
CP
Austin
Menghang
M
Xia
David M
DM
Loeb
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002817:Chordoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D016328:NF-kappa B