Effective Targeting of Hedgehog Signaling in a Medulloblastoma Model with PF-5274857, a Potent and Selective Smoothened Antagonist That Penetrates the Blood–Brain Barrier

Abstract

Inhibition of the Smoothened (Smo) represents a promising therapeutic strategy for treating malignant tumors that are dependent on the Hedgehog (Hh) signaling pathway. PF-5274857 is a novel Smo antagonist that specifically binds to Smo with a K i of 4.6 AE 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC 50 of 2.7 AE 1.4 nmol/L in cells. This Smo antagonist showed robust antitumor activity in a mouse model of medulloblastoma with an in vivo IC 50 of 8.9 AE 2.6 nmol/L. The downregulation of Gli1 is closely linked to the tumor growth inhibition in patched þ/À medulloblastoma mice. Mathematical analysis of the relationship between the drug's pharmacokinetics and Gli1 pharmacodynamics in patched þ/À medulloblastoma tumor models yielded similar tumor and skin Gli1 IC 50 values, suggesting that skin can be used as a surrogate tissue for the measurement of tumor Gli1 levels. In addition, PF-5274857 was found to effectively penetrate the blood-brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. The brain permeability of PF-5274857 was also confirmed and quantified in nontumor-bearing preclinical species with an intact blood-brain barrier. PF-5274857 was orally available and metabolically stable in vivo. These findings suggest that PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway. Mol Cancer Ther; 11(1); 57-65. Ó2011 AACR.

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

“…In these mouse models, including Ptch1 heterozygous null mutants, the absence of Ptch1 mRNA (and ensuing Shh-Ptch-pathway activation) is critical for both the initiation and growth of medulloblastoma. For example, Hedgehog pathway inhibitors cause tumor regression in mouse models of medulloblastoma (Yauch et al 2009;Buonamici et al 2010;Lee et al 2012;Rohner et al 2012), and the emergence of resistance to these inhibitors is always liked to downstream activation of Shh-Ptch signaling (Yauch et al 2009;Buonamici et al 2010;Dijkgraaf et al 2011). Although the Atoh1-Cre;Ptch1flox/flox mouse model used in the present study has previously been characterized (Yang et al 2008), Ptch1 recombination in the presence of the Dicer1flox allele was measured by semiquantitative PCR on genomic DNA isolated from Ptch1flox and Atoh1-Cre;Dicer1-flox/flox tumors.…”

Effect of MUC1/β-catenin interaction on the tumorigenic capacity of pancreatic CD133+ cells

“…CSCs are known to aberrantly activate canonical signaling pathways (31–33). Recently, a MUC1 spliced form was reported to be associated with the differentiation status of stem cells (34).…”

The MYCN Protein in Health and Disease

“…The relationship between these two regulators could be important to study further for therapeutic purposes. Targeting Smoothened, the positive regulator of the hedgehog pathway, resulted in tumor regression in medulloblastoma patients with SHH mutations [173,174]. The collaboration of SHH and MYCN may be pivotal in both medulloblastoma and basal cell carcinoma regulation, and further insights are necessary for the identification of potential novel therapeutics.…”