Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma

Hoff, Daniel D. Von; LoRusso, Patricia; Rudin, Charles M.; Reddy, Josina C.; Yauch, Robert L.; Tibes, Raoul; Weiss, Glen J.; Borad, Mitesh J.; Hann, Christine L.; Brahmer, Julie R.; Mackey, Howard M.; Lum, B.; Darbonne, Walter C.; Marsters, James C.; Sauvage, Frédéric J. de; Low, Jennifer A.

doi:10.1056/nejmoa0905360

Cited by 996 publications

(483 citation statements)

References 19 publications

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“…The adverse events that tended to be more prevalent among vismodegib-treated versus placebo-treated patients (i.e., vomiting, weight loss, decreased appetite, dehydration, muscle cramps, dysgeusia, and asthenia/fatigue), regardless of chemotherapy backbone, were primarily those previously reported in association with vismodegib (12). The frequent occurrence of low-grade toxicities associated with vismodegib, superimposed on toxicities associated with the FOLFOX-bevacizumab or FOLFIRI-bevacizumab treatment regimens, may have increased treatment discontinuation among vismodegibtreated patients.…”

Section: Discussionmentioning

confidence: 76%

“…In vismodegib-treated patients, levels of vismodegib (12), oxaliplatin (20,21), irinotecan (22), 5-FU (19,23), and bevacizumab (24) were within the expected ranges for the doses administered ( Supplementary Figs. SA1-SA5).…”

Section: Pharmacokineticsmentioning

confidence: 88%

“…Vismodegib was evaluated in a phase I study of patients with refractory solid tumors and advanced basal cell carcinoma (12)(13)(14). The most common toxicities were mild to moderate fatigue, anorexia, muscle spasms, alopecia, and dysgeusia.…”

Section: Introductionmentioning

confidence: 99%

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A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Berlin

Bendell

Hart

et al. 2013

Clinical Cancer Research

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158

120

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Purpose: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).Experimental design: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.Results: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P ¼ 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.Conclusions: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

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Section: Discussionmentioning

confidence: 76%

Section: Pharmacokineticsmentioning

confidence: 88%

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A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Berlin

Bendell

Hart

et al. 2013

Clinical Cancer Research

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158

120

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“…A recent clinical trial revealed that GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal cell carcinoma (Von Hoff et al 2009). …”

mentioning

confidence: 99%

Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

Ding²,

Rao³

et al. 2012

Endocrine-Related Cancer

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The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status of BRAF gene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown of SHH and GLI expression by miRNA constructs that target SHH or GLI mRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.

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“…The Hedgehog pathway has been implicated in the development of basal cell carcinoma (BCC) and other cancers 1, 2, 3, 4, 5, 6, 7, 8, 9. Vismodegib is well tolerated in clinical practice, with pharmacodynamic evidence of Hedgehog pathway inhibition via GLI1 suppression and tumor regression in BCC patients and medulloblastoma 10, 11, 12. Vismodegib was approved by the US Food and Drug Administration (FDA) in January, 2012, for the treatment of adults with metastatic BCC or with locally advanced BCC 13, 14…”

mentioning

confidence: 99%

Semi‐Mechanism‐Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib

Tong¹,

B²,

Gao³

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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Vismodegib, approved for the treatment of advanced basal cell carcinoma, has shown unique pharmacokinetic (PK) nonlinearity and binding to α1‐acid glycoprotein (AAG) in humans. A semi‐mechanism‐based population pharmacokinetic (PopPK) model was developed from a meta‐dataset of 225 subjects enrolled in five clinical studies to quantitatively describe the clinical PK of vismodegib and identify sources of interindividual variability. Total and unbound vismodegib were analyzed simultaneously, together with time‐varying AAG data. The PK of vismodegib was adequately described by a one‐compartment model with first‐order absorption, first‐order elimination of unbound drug, and saturable binding to AAG with fast‐equilibrium. The variability of total vismodegib concentration at steady‐state was predominantly explained by the range of AAG level. The impact of AAG on unbound concentration was clinically insignificant. Various approaches were evaluated for model validation. The semi‐mechanism‐based PopPK model described herein provided insightful information on the nonlinear PK and has been utilized for various clinical applications.

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Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma

Abstract: GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma. (ClinicalTrials.gov number, NCT00607724.)

Cited by 996 publications

References 19 publications

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

Semi‐Mechanism‐Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib

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