Resolution of Odontogenic Keratocysts of the Jaw in Basal Cell Nevus Syndrome With GDC-0449

Goldberg, Leonard Harry; Landau, Jennifer M.; Moody, Megan N.; Kazakevich, N. V.; Holzer, Aton M.; Myers, A. T.

doi:10.1001/archdermatol.2011.50

Cited by 33 publications

(36 citation statements)

References 5 publications

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“…, 100 101 Gastric epithelial stem cells may be the cellular origin of gastric cancer. 102,103 Under mucosal injury and inflammation, mature gastric chief cells act as cryptic progenitors and reacquire the ability of proliferation. 104 Study of Hh signaling in gastric cancer stem cells has just begun.…”

Section: Hh Signaling In Gastroesophageal Cancer Stem Cellsmentioning

confidence: 99%

Activation of the hedgehog pathway in gastroesophageal cancers

Yang

Xie²,

Su³

2011

JST

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The hedgehog pathway is a major regulator for cell differentiation, tissue polarity and cell proliferation in embryonic development and homeostasis in adult tissue. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas, medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last two years in our understanding of hedgehog signaling activation in human gastroesophageal cancer, and their potential in clinical treatment with hedgehog pathway inhibitors.

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Section: Hh Signaling In Gastroesophageal Cancer Stem Cellsmentioning

confidence: 99%

Activation of the hedgehog pathway in gastroesophageal cancers

Yang

Xie²,

Su³

2011

JST

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“…Another hypothesis is that higher doses of vismodegib are required to induce shrinkage. Indeed, the dose used in our study was almost half of that used in Goldberg et al’ s case report 3 and, cyclopamine (another HH pathway inhibitor) has been found to significantly arrest the growth of KCOT cells in a dose-dependent manner in vitro 10 . However, since all our patients received the same FDA-approved dose of vismodegib, we were not able to assess any dose-dependent response.…”

Section: Discussionmentioning

confidence: 73%

“…In one case report, Goldberg et al 3 incidentally noted resolution of KCOTs in one BCNS patient treated with vismodegib (270mg/day) for 2 years. This dose was used in phase 1-studies before the data demonstrated 150mg/day to be the most efficacious.…”

Section: Discussionmentioning

confidence: 99%

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The Use of Vismodegib to Shrink Keratocystic Odontogenic Tumors in Patients With Basal Cell Nevus Syndrome

et al. 2014

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Importance Keratocystic odontogenic tumors of the jaw (KCOTs) affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog (HH) signaling pathway. Observations We examined the effect of vismodegib (an oral HH-pathway inhibitor) on KCOT size in BCNS patients enrolled in a clinical trial testing vismodegib for BCC prevention (NCT00957229), using pre and post-treatment MRIs. Four men and 2 women had pretreatment KCOTs, mean longest diameter 2.0cm (range: 0.7–3.3cm), occurring primarily in the mandible. Subjects were treated with vismodegib (150mg/day) for a mean 18 months (SD: 4.8, range: 11–24). Four subjects experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all subjects by 1.0cm (95% CI: 0.03, 1.94, p= 0.02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development. Conclusions and relevance Vismodegib shrinks some KCOTs in BCNS patients and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.

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“…Interestingly, palmoplantar pits of BCNS disappeared during vismodegib treatment. In addition, vismodegib treatment reduced the size of odontogenic cysts by at least 50% from baseline and could represent an alternative to surgery for some patients (52).…”

Section: Preclinical Efficacy Modelsmentioning

confidence: 99%

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Basset-Séguin

Sharpe

Sauvage

2015

Molecular Cancer Therapeutics

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Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated antitumoral activity, but treatment may be limited in duration by a number of side effects, and it is not yet established whether these agents are truly curative or whether continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability, as well as neoadjuvant use of Hh pathway inhibitors, are currently under investigation. Here, we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC.

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Resolution of Odontogenic Keratocysts of the Jaw in Basal Cell Nevus Syndrome With GDC-0449

Cited by 33 publications

References 5 publications

Activation of the hedgehog pathway in gastroesophageal cancers

Activation of the hedgehog pathway in gastroesophageal cancers

The Use of Vismodegib to Shrink Keratocystic Odontogenic Tumors in Patients With Basal Cell Nevus Syndrome

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

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