Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Tang, Jean Y.; Ally, Mina S.; Chanana, Anita M.; Mackay‐Wiggan, Julian; Aszterbaum, Michelle; Lindgren, Joselyn; Ulerio, Grace; Rezaee, Mehrdad; Gildengorin, Ginny; Marji, Jackleen; Clark, Charlotte; Bickers, David R.; Epstein, Ervin

doi:10.1016/s1470-2045(16)30566-6

Cited by 116 publications

(100 citation statements)

References 24 publications

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“…Treatment with Hedgehog signaling inhibitor vismodegib mediates differentiation of BCC cells from a hair follicle stem cell like phenotype to an interfollicular epidermis or isthmus cell fate, and thereby leads to tumor regression (Sánchez-Danés et al, 2018). However, BCC tumors always relapse after vismodegib withdrawal (Tang et al, 2016). It was found that a small population of LGR51 BCC cells with active Wnt signaling escape from vismodegib-induced differentiation and mediate tumor relapse after treatment discontinuation.…”

Section: Downloaded Frommentioning

confidence: 99%

Wnt Signaling and Drug Resistance in Cancer

2019

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Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptors, and the signaling transduction are tightly regulated and fine-tuned to keep the signaling output "just right." Hyperactivated Wnt signaling due to recurrent genetic alterations drives several human cancers. Elevated Wnt signaling also confers resistance to multiple conventional and targeted cancer therapies through diverse mechanisms including maintaining the cancer stem cell population, enhancing DNA damage repair, facilitating transcriptional plasticity, and promoting immune evasion. Different classes of Wnt signaling inhibitors targeting key nodes of the pathway have been developed and show efficacy in treating Wnt-driven cancers and subverting Wnt-mediated therapy resistance in preclinical studies. Several of these inhibitors have advanced to clinical trials, both singly and in combination with other existing US Food and Drug Administration-approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for patients with cancer. SIGNIFICANCE STATEMENTThe latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer, are reviewed. Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.

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Section: Downloaded Frommentioning

confidence: 99%

Wnt Signaling and Drug Resistance in Cancer

2019

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“…1a). [2][3][4][5][6] Small-molecule SMO inhibitors (SMOi) show striking therapeutic efficacy in patients with advanced and metastatic BCC, 7,8 though development of drug resistance and severe adverse effects leave many patients without proper treatment options. [9][10][11] Furthermore, noncanonical, SMO-independent GLI activation has been identified as critical factor contributing to the growth of malignant cells refractory to SMOi treatment (reviewed in Refs.…”

Section: What's New?mentioning

confidence: 99%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

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“…Treatment options for alopecia include 2-5% minoxidil, which can be used in addition to concealment measures such as wearing a wig [43,47]. However, a longer duration of vismodegib treatment and an increased degree of treatment-related alopecia can lead to impaired and/or incomplete hair growth after completion of treatment [48]. For dysguesia, identification of food that is more pleasant for the patient as well as dietician referral can be helpful as it is only temporary and typically resolved 2-6 months after stopping vismodegib.…”

Section: Management Of Hedgehog Pathway Inhibitor Associated Adverse mentioning

confidence: 99%

Treatment of Advanced Basal Cell Carcinoma with Sonidegib: Perspective from the 30-Month Update of the BOLT Trial

Chen¹,

Aria²,

Silapunt³

et al. 2017

Future Oncol.

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Sonidegib, a hedgehog pathway inhibitor, was approved by the US FDA for the treatment of locally advanced basal cell carcinoma which cannot be readily treated with surgery or radiotherapy. The pharmacology and pharmacokinetics of sonidegib will be discussed in this review. Additionally, an in-depth analysis of the BOLT trial and data from the 30-month update will be included. This will serve as an update to a previously published article which reported the 12-month update of the BOLT trial. BackgroundBasal cell carcinoma (BCC) is the most common skin cancer in humans. Annually, there are 2.8 million cases that result in approximately 3000 deaths [1]. The use of surgical excision for the treatment of BCC results in a 5-year cure rate close to 90% [2,3]. The 5-year recurrence rate decreases to 0.7-2.4% when Mohs micrographic surgery (MMS) is performed [4][5][6][7]. Alternative nonsurgical approaches include cryotherapy, electrodesiccation and curettage, photodynamic therapy, radiation, or topical agents such as imiquimod or 5-fluorouracil. These options usually confer a lower cure rate and lack confirmation of tumor clearance on histology. Although metastasis of BCC has a very low incidence of 0.0028-0.

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Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Cited by 116 publications

References 24 publications

Wnt Signaling and Drug Resistance in Cancer

Wnt Signaling and Drug Resistance in Cancer

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Treatment of Advanced Basal Cell Carcinoma with Sonidegib: Perspective from the 30-Month Update of the BOLT Trial

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