Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model

Lee, Michelle J., Hatton, Beryl A., Villavicencio, Elisabeth H., Khanna, Paritosh C., Friedman, Seth D., Ditzler, Sally, Pullar, Barbara, Robison, Keith, White, Kerry F., Tunkey, Chris, LeBlanc, Michael, Randolph-Habecker, Julie, Knoblaugh, Sue E., Hansen, Stacey, Richards, Andrew, Wainwright, Brandon J., McGovern, Karen and Olson, James M. (2012) Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proceedings of the National Academy of Sciences of the United States of America, 109 20: 7859-7864. doi:10.1073/pnas.1114718109


Author Lee, Michelle J.
Hatton, Beryl A.
Villavicencio, Elisabeth H.
Khanna, Paritosh C.
Friedman, Seth D.
Ditzler, Sally
Pullar, Barbara
Robison, Keith
White, Kerry F.
Tunkey, Chris
LeBlanc, Michael
Randolph-Habecker, Julie
Knoblaugh, Sue E.
Hansen, Stacey
Richards, Andrew
Wainwright, Brandon J.
McGovern, Karen
Olson, James M.
Title Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2012-05-01
Sub-type Article (original research)
DOI 10.1073/pnas.1114718109
Open Access Status Not Open Access
Volume 109
Issue 20
Start page 7859
End page 7864
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract 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.
Keyword Resistance
Otx2
Cyclopamine
Progression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
 
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