Hedgehog antagonist GDC‐0449 is effective in the treatment of advanced basal cell carcinoma

Amin, Shivan; Tibes, Raoul; Kim, Ji Eon; Hybarger, C. Patrick

doi:10.1002/lary.21145

Cited by 28 publications

(20 citation statements)

References 13 publications

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“…Exogenous modulators of the pathway include Hh inhibitor GDC-0449 (Vismodegib) that acts directly on Smo [8–10]. The mechanism of action, pharmacokinetics, and pharmacodynamics of GDC-0449 have been studied extensively, mostly in the setting of cancer [9–13]. …”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing

Kazmers

McKenzie

Shen

et al. 2015

Bone

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Hedgehog (Hh) signaling is critical in developmental osteogenesis, and recent studies suggest it may also play a role in regulating osteogenic gene expression in the post-natal setting. However, there is a void of studies directly assessing the effect of Hh inhibition on post-natal osteogenesis. This study utilized a cyclic loading-induced ulnar stress fracture model to evaluate the hypothesis that Hh signaling contributes to osteogenesis and angiogenesis during stress fracture healing. Immediately prior to loading, adult rats were given GDC-0449 (Vismodegib - a selective Hh pathway inhibitor; 50mg/kg orally twice daily), or vehicle. Hh signaling was upregulated in response to stress fracture at 3d (Ptch1, Gli1 expression), and was markedly inhibited by GDC-0449 at 1d and 3d in the loaded and non-loaded ulnae. GDC-0449 did not affect Hh ligand expression (Shh, Ihh, Dhh) at 1d, but decreased Shh expression by 37% at 3d. GDC-0449 decreased woven bone volume (−37%) and mineral density (−17%) at 7d. Dynamic histomorphometry revealed that the 7d callus was composed predominantly of woven bone in both groups. The observed reduction in woven bone occurred concomitantly with decreased expression of Alpl and Ibsp, but was not associated with differences in early cellular proliferation (as determined by callus PCNA staining at 3d), osteoblastic differentiation (Osx expression at 1d and 3d), chondrogenic gene expression (Acan, Sox9, and Col2α1 expression at 1d and 3d), or bone resorption metrics (callus TRAP staining at 3d, Rankl and Opg expression at 1d and 3d). To evaluate angiogenesis, vWF immunohistochemistry showed that GDC-0449 reduced fracture callus blood vessel density by 55% at 3d, which was associated with increased Hif1α gene expression (+30%). Dynamic histomorphometric analysis demonstrated that GDC-0449 also inhibited lamellar bone formation. Lamellar bone analysis of the loaded limb (directly adjacent to the woven bone callus) showed that GDC-0449 significantly decreased mineral apposition rate (MAR) and bone formation rate (BFR/BS) (−17% and −20%, respectively). Lamellar BFR/BS in the non-loaded ulna was also significantly decreased (−37%), indicating that Hh signaling was required for normal bone modeling. In conclusion, Hh signaling plays an important role in post-natal osteogenesis in the setting of stress fracture healing, mediating its effects directly through regulation of bone formation and angiogenesis.

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Section: Introductionmentioning

confidence: 99%

Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing

Kazmers

McKenzie

Shen

et al. 2015

Bone

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“…3B; Table 1). To date, vismodegib has shown great promise in cancers associated with ligand-independent activation of the Hh pathway (18,(26)(27)(28). However, the drug has yet to show signs of clinical activity in tumors exhibiting ligand-dependent Hh pathway activation (29,30).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Targeted and Cytotoxic Agents in Murine Subcutaneous Tumor Models Correlates with Clinical Response

Wong¹,

Choo²,

Alicke³

et al. 2012

Clinical Cancer Research

117

118

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Purpose: Immunodeficient mice transplanted with subcutaneous tumors (xenograft or allograft) are widely used as a model of preclinical activity for the discovery and development of anticancer drug candidates. Despite their widespread use, there is a widely held view that these models provide minimal predictive value for discerning clinically active versus inactive agents. To improve the predictive nature of these models, we have carried out a retrospective population pharmacokinetic-pharmacodynamic (PK-PD) analysis of relevant xenograft/allograft efficacy data for eight agents (molecularly targeted and cytotoxic) with known clinical outcome.Experimental Design: PK-PD modeling was carried out to first characterize the relationship between drug concentration and antitumor activity for each agent in dose-ranging xenograft or allograft experiments. Next, simulations of tumor growth inhibition (TGI) in xenografts/allografts at clinically relevant doses and schedules were carried out by replacing the murine pharmacokinetics, which were used to build the PK-PD model with human pharmacokinetics obtained from literature to account for species differences in pharmacokinetics.Results: A significant correlation (r ¼ 0.91, P ¼ 0.0008) was observed between simulated xenograft/ allograft TGI driven by human pharmacokinetics and clinical response but not when TGI observed at maximum tolerated doses in mice was correlated with clinical response (r ¼ 0.36, P ¼ 0.34).Conclusions: On the basis of these analyses, agents that led to greater than 60% TGI in preclinical models, at clinically relevant exposures, are more likely to lead to responses in the clinic. A proposed strategy for the use of murine subcutaneous models for compound selection in anticancer drug discovery is discussed.

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“…However, its reactivation has been linked to many cancers, including BCC and medulloblastoma [6]. By inhibiting SMO, vismodegib hinders cancer cell growth and survival [8].…”

Section: Open Accessmentioning

confidence: 99%

Vismodegib Provides a Novel Treatment for Advanced Basal Cell Carcinoma

Kelm¹,

Magliaro²,

Anderson³

et al. 2014

JCT

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Objective: To review and evaluate vismodegib, the first US Food and Drug Administration (FDA) approved treatment for locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) that has recurred after surgery or for patients in which surgery or radiation is not an option. Data Sources: A literature search using PubMed was conducted through January 2013, using the terms vismodegib, GDC-0449, and Erivedge. Additional literature was found through the reference citations of identified articles. Study Selection and Data Extraction: Potential sources were limited to human studies published in English with a priority placed on those focused on laBCC or mBCC. Data Synthesis: Vismodegib is a selective inhibitor of the hedgehog (Hh) pathway approved for the treatment of laBCC or mBCC that has recurred after surgery, or for patients for whom surgery or radiation is contraindicated. Vismodegib inhibits cancer cell growth and survival by binding Smoothened, a transmembrane protein involved in the Hedgehog signal transduction. Vismodegib is administered orally at a dose of 150 mg daily. It is primarily eliminated through the feces unchanged but does have some oxidative metabolites produced from the recombinant cytochrome P450 (CYP) 2C9 and CYP3A4/5. Despite CYP450 involvement, it appears to have very few drug interactions. The most common adverse events reported with vismodegib include muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, anorexia, and diarrhea. FDA approval was based on a single arm phase II study that demonstrated an objective response rate of 30% in mBCC patients and 45% in laBCC patients. Vismodegib was approved by the FDA on January 30, 2012 for use in patients with advanced basal cell carcinoma, and continues to be studied in other patient populations for additional potential uses. Conclusions: Based on a review of current evidence, vismodegib provides an effective and well-tolerated treatment for otherwise untreatable basal cell carcinoma.

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Hedgehog antagonist GDC‐0449 is effective in the treatment of advanced basal cell carcinoma

Abstract: GDC-0449 showed significant inhibitory activity in the treatment of advanced basal cell carcinoma.

Cited by 28 publications

References 13 publications

Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing

Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing

Antitumor Activity of Targeted and Cytotoxic Agents in Murine Subcutaneous Tumor Models Correlates with Clinical Response

Vismodegib Provides a Novel Treatment for Advanced Basal Cell Carcinoma

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