title: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.
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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Lee
authors.forename: Beryl A
authors.initials: BA
authors.lastname: Hatton
authors.forename: Elisabeth H
authors.initials: EH
authors.lastname: Villavicencio
authors.forename: Paritosh C
authors.initials: PC
authors.lastname: Khanna
authors.forename: Seth D
authors.initials: SD
authors.lastname: Friedman
authors.forename: Sally
authors.initials: S
authors.lastname: Ditzler
authors.forename: Barbara
authors.initials: B
authors.lastname: Pullar
authors.forename: Keith
authors.initials: K
authors.lastname: Robison
authors.forename: Kerry F
authors.initials: KF
authors.lastname: White
authors.forename: Chris
authors.initials: C
authors.lastname: Tunkey
authors.forename: Michael
authors.initials: M
authors.lastname: LeBlanc
authors.forename: Julie
authors.initials: J
authors.lastname: Randolph-Habecker
authors.forename: Sue E
authors.initials: SE
authors.lastname: Knoblaugh
authors.forename: Stacey
authors.initials: S
authors.lastname: Hansen
authors.forename: Andrew
authors.initials: A
authors.lastname: Richards
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Wainwright
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D055028:Comparative Genomic Hybridization; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D010865:Pilot Projects; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D016019:Survival Analysis; D014704:Veratrum Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000075746:Zinc Finger Protein Gli2
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; C000618551:Gli2 protein, mouse; C541444:IPI-926; D051741:Kruppel-Like Transcription Factors; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000075746:Zinc Finger Protein Gli2