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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-05, Vol.109 (20), p.7859-7864
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: allografting; Animal models; Animals; Antineoplastics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Base Sequence; Biological Sciences; Blotting, Western; Brain; Brain cancer; Brain neoplasms; Cancer; Comparative Genomic Hybridization; Cytotoxicity; DNA Primers - genetics; Donors; Dosage; Drug resistance; Drug Resistance, Neoplasm; drugs; Flow Cytometry; Gene Expression Profiling; Genetic mutation; Glycoproteins; Hedgehog protein; Homologous transplantation; Immunohistochemistry; Kruppel-Like Transcription Factors - genetics; Life span; longevity; Magnetic Resonance Imaging; Medulloblastoma; Medulloblastoma - drug therapy; Medulloblastoma - pathology; Mice; Molecular Sequence Data; Molecules; natural products; neoplasms; P-Glycoprotein; patients; Pilot Projects; Point mutation; Real-Time Polymerase Chain Reaction; Receptors, G-Protein-Coupled - antagonists & inhibitors; remission; resistance mechanisms; Rodents; Sequence Analysis, DNA; Signal transduction; Signal Transduction - drug effects; Smoothened Receptor; Survival; Survival Analysis; Tumor burden; Tumors; Veratrum Alkaloids - pharmacology; Veratrum Alkaloids - therapeutic use; Zinc Finger Protein Gli2
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1114718109

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.