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1.
Fig. 2.

Fig. 2. From: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

Saridegib improves survival in the PtcC/C medulloblastoma model. Kaplan–Meier analysis demonstrates that all PtcC/C mice receiving daily saridegib (20 mg/kg, dashed line) survived, whereas all vehicle-treated mice (solid line) succumbed to their disease before the 6-wk time point (P < 0.001).

Michelle J. Lee, et al. Proc Natl Acad Sci U S A. 2012 May 15;109(20):7859-7864.
2.
Fig. 3.

Fig. 3. From: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

In-skull tissue processing preserves intracranial integrity, enabling accurate 3D tumor volume rendering and analysis of pathology. Image panel summarizing a comparison of tissue sections from brains processed outside of (first column) or from within (second column) the skull and the related H&E-based 3D renderings (third column) of cerebellar or tumor volume. H&E-based 3D tumor models are matched to the MRI-generated volume model (fourth column) for the same sample.

Michelle J. Lee, et al. Proc Natl Acad Sci U S A. 2012 May 15;109(20):7859-7864.
3.
Fig. 1.

Fig. 1. From: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

The Smo inhibitor saridegib causes regression of mouse medulloblastoma and resolution of advanced clinical symptoms. Three-week-old mice symptomatic for medulloblastoma were randomized to receive daily i.p. saridegib (20 mg/kg per dose, n = 3) or vehicle (n = 2) for 19 d. (A) Compared with a representative vehicle-treated mouse with a large tumor (Left) and a WT littermate with no tumor (Right), a representative mouse treated with saridegib (Center) showed complete resolution of clinical symptoms after 19 d of saridegib treatment. Arrow denotes the bulging skull caused by tumor. (B–D) Response to saridegib was apparent by gross pathology (B), imaging with Tumor Paint (chlorotoxin:Cy5.5) (C), and H&E staining (D).

Michelle J. Lee, et al. Proc Natl Acad Sci U S A. 2012 May 15;109(20):7859-7864.
4.
Fig. 4.

Fig. 4. From: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

MRI scans demonstrate decreasing tumor volumes at multiple treatment time points during daily saridegib administration but indicate tumor progression despite prolonged therapy. (A) A representative T2-weighted MRI image demonstrates the enlarged ventricles (yellow arrow) and transependymal CSF flow (red arrow) resulting from cerebellar tumor progression in a vehicle-treated mouse. Saridegib-treated mice demonstrate a significant reduction in ventricle size and a resolution of transependymal CSF flow. (B) Tumor volume was estimated from MRI scans taken at enrollment, after 3 wk, and after 6 wk of treatment. Representative images of 3D-reconstructed tumors are shown, with an untreated WT cerebellum (shown in yellow) displayed for reference. (C) Tumor volumes (mm3) were estimated at each time point for vehicle-treated (n = 5) and saridegib-treated (n = 7) PtcC/C mice. None of the vehicle-treated mice survived until the 6-wk imaging time point.

Michelle J. Lee, et al. Proc Natl Acad Sci U S A. 2012 May 15;109(20):7859-7864.
5.
Fig. 6.

Fig. 6. From: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

Mechanisms of resistance in saridegib-treated PtcC/C tumors. (A) The pharmacodynamic activity of saridegib in PtcC/C tumors was confirmed by analysis of Gli1 mRNA by RT-PCR. Result shows a substantial decrease in Gli1 expression after 4 d of saridegib treatment (P = 0.05). The initial reduction in Gli1 expression seen in response to daily saridegib (20 mg/kg per dose) was diminished after 6 wk of therapy. Drug resistance to saridegib was partially reversed by cotreatment with the Pgp inhibitor verapamil. Bars represent the average fold change in Gli1 expression normalized to vehicle-treated controls (n = 3). (B) The expression of Pgp was quantified via Western blotting at enrollment, after 4 d, and after 6 wk of treatment. Bars represent the average fold change in Pgp normalized to Gapdh (n = 3). (C) Efflux activity of Pgp in saridegib-treated PtcC/C tumors was evaluated by measuring the intracellular fluorescence of calcein by flow cytometry. Compared with vehicle controls, saridegib-treated tumors had lower calcein accumulation. Inhibiting the Pgp activity with 100 μM verapamil increased calcein fluorescence, as indicated by a small shift of the peak to the right. Gray line indicates autofluorescence of the cells that were not exposed to calcein-AM. (D) Percentage of cells appearing within the FITC+ gate was quantified. Pgp-mediated efflux activity was significantly increased in PtcC/C tumors treated with saridegib (n = 3). (Error bars: SEM.)

Michelle J. Lee, et al. Proc Natl Acad Sci U S A. 2012 May 15;109(20):7859-7864.
6.
Fig. 5.

Fig. 5. From: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

Saridegib maintenance administration prolongs survival in mice bearing intracranial medulloblastomas, whereas continued saridegib administration induces regression of flank allografts from drug-resistant donors. (A) Three- to five-week-old PtcC/C mice symptomatic for medulloblastoma were randomized to receive vehicle (blue line) or saridegib (purple lines). Mice were initially given daily saridegib (20 mg/kg per dose) for 6 wk (n = 19) and then taken off the drug (n = 6; pink line) or given maintenance dosing (20 mg/kg twice per week) for an additional 6 wk (n = 13; purple line). Daily saridegib followed by twice-weekly dosing provided a significant survival benefit compared with vehicle controls (P < 0.001) and to mice taken off of the drug (P = 0.001). (B) Flank allografts were established in 43% of recipients from drug-naïve PtcC/C donors. Only 23% of recipients developed flank tumor when donors were treated with saridegib daily for 6 wk (20 mg/kg) before transplantation. (C) Recipient mice bearing drug-naïve and saridegib-treated allograft tumors were then treated with daily saridegib (20 mg/kg). Dotted line indicates beginning of treatment. Tumors were undetectable in both allograft groups by day 15. Two of five tumors became unresponsive during the 9-wk trial despite initial responses to saridegib. (D) The average Gli-luciferase reporter activity was measured in C3H10T1/2 cells transfected with WT SMO (gray) or the D473H SMO mutant (green) after treatment with various doses of saridegib. Saridegib inhibited reporter activity at an IC50 of 9 nM in C3H10T1/2 cells transfected with WT SMO and also showed activity against the D473H SMO mutant at an IC50 of 244 nM. Reporter activity is normalized to untreated C3H10T1/2 cells. (Error bars: SEM.)

Michelle J. Lee, et al. Proc Natl Acad Sci U S A. 2012 May 15;109(20):7859-7864.

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