 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Apr 20, 2012 |
| Title |
Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.
|
| |
|
| Overall design |
P21 to P36 PtcC/C mice were randomized to receive either saridegib (20 mg/kg per dose) for 6 weeks or vehicle control [5% (2-hydroxylpropyl)-β-cyclodextrin (HPBCD)] for 3 weeks administered via daily i.p. injection. Triplicate total RNA samples were collected for each of the two conditions.
|
| |
|
| Contributor(s) |
Lee MJ, Hatton BA, Villavicencio EH, Khanna PC, Friedman SD, Ditzler S, Pullar B, Robison K, White KF, Tunkey C, LeBlanc M, Randolph-Habecker J, Knoblaugh SE, Hansen S, Richards A, Wainwright BJ, McGovern K, Olson JM |
| Citation(s) |
22550175 |
| Submission date |
Apr 19, 2012 |
| Last update date |
Jan 16, 2019 |
| Contact name |
Michelle Lee |
| E-mail(s) |
mjlee@fhcrc.org
|
| Phone |
2066674033
|
| Organization name |
Fred Hutchinson Cancer Research Center
|
| Department |
Clinical Research Division
|
| Lab |
Olson Lab
|
| Street address |
1100 Fairview Avenue, D4-100
|
| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98109 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL6887 |
Illumina MouseWG-6 v2.0 expression beadchip |
|
| Samples (6)
|
|
| Relations |
| BioProject |
PRJNA160117 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE37417_RAW.tar |
15.8 Mb |
(http)(custom) |
TAR |
| GSE37417_non-normalized.txt.gz |
810.1 Kb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
|
|
|
|
 |
Less...
More...