Shh Pathway Activity Is Down-Regulated in Cultured Medulloblastoma Cells: Implications for Preclinical Studies

Sasai, Ken; Romer, Justyna T.; Lee, Youngsoo; Finkelstein, David; Fuller, Christine; McKinnon, Peter J.; Curran, Tom

doi:10.1158/0008-5472.can-05-4505

Cited by 139 publications

(143 citation statements)

References 29 publications

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“…In addition, other downstream pathway activation mechanisms have been revealed, such as REN deletions (15), GLI gene amplifications (24)(25)(26), GLI1 chromosomal translocations (27), or GLI2 protein stabilization (28). Moreover, reports on frequent cyclopamine-insensitivity of GLI1-positive cell lines derived from pancreatic adenocarcinoma can be found in the literature (6).…”

mentioning

confidence: 99%

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Lauth

Bergström²,

Shimokawa³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

733

693

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The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.

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mentioning

confidence: 99%

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Lauth

Bergström²,

Shimokawa³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

733

693

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show abstract

“…shown that vismodegib could induce complete regression of tumors (40,41). Importantly, in both the autochthonous and allograft models, it was demonstrated that the near complete (39,42).…”

Section: Preclinical Efficacy Modelsmentioning

confidence: 94%

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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“…Таким образом, культивирование клеток на среде с сывороткой может приводить к инактивации пути HH [50,51,57]. Аналогичные данные получены и для клеток медуллобластомы, теряющих GLI активность в экспериментах in vitro [58].…”

Section: изменения сигнального пути Hedgehog при глиомахunclassified

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

et al. 2015

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The review summarizes current knowledge on the Hedgehog signaling pathway, its role in normal embryogenesis and/or initiation and progression of neuro-oncological diseases, especially of high-grade gliomas, the most malignant neuroepithelial tumors. The main proteins forming the Hedgehog signaling pathway include Shh, PTCH1, SMO, HHIP, SUFU and GLI1 isoforms. Effects of other signaling pathways on the family of transcription factors GLI and other proteins are described. The review summarizes modern data about the impact of the Hedgehog signaling pathway on proliferation, migration activity and invasiveness, and also on tumor neoangiogenesis and tumor cell chemoresistance. The role of the Hedgehog signaling pathway in origin of cancer stem cells and epithelial-mesenchymal transition is also analyzed. Some prospects for new anticancer drugs acting on components of the Hedgehog signaling pathway inhibitors are demonstrated.

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Shh Pathway Activity Is Down-Regulated in Cultured Medulloblastoma Cells: Implications for Preclinical Studies

Cited by 139 publications

References 29 publications

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

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