An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer

Abstract

Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models.

Therapeutic strategies targeting cancer stem cells

“…16 Hedgehog inhibitor cyclopamine, a combination with cyclopamine and gemcitabine or a triplet combination with cyclopamine/CUR199691, rapamycin and chemotherapy can all inhibit Hedgehog signaling pathway, decrease the proportion of CSCs and induce tumor regression in pancreatic cancer xenograft models. [61][62][63] In brain tumor cells, cyclopamine treatment decreased CSCs proportion or even eliminated CSCs and deprived the tumorigenicity of the tumor cells. 64 In breast CSCs, activation of the Notch signaling pathway is significantly higher than in bulk cancer cells.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Studies also indicate that Hh signaling may be involved in different stages of carcinogenesis in different tumors. In pancreatic and esophageal cancers for example, activation of this pathway is found in both early tumors and metastatic cancer (Bailey et al, 2009;Feldmann et al, 2008;Ma et al, 2006;Pasca di Magliano and Hebrok, 2003), suggesting that Hh signaling has a significant role in carcinogenesis of these tumors. In support of these findings, transgenic mice with pancreatic-specific expression of SHH or (Sheng et al, 2004).…”

Activation of the hedgehog pathway in gastroesophageal cancers

“…22 Activation of the Hh pathway is detected in stem cell-like subpopulation in pancreatic adenocarcinoma. [23][24][25] Hh pathway inhibitors cyclopamine, 26 IPI-269609 27 have effect in pancreatic cancer mouse model. Combination of Hh pathway inhibitor IPI-926 and gemcitabine, 28 SMO antagonist SANT-1 and histone deacetylase inhibitor SAHA, 29 Hh pathway inhibitor cyclopamine and inhibitor of epidermal growth factor receptor (EGFR) Iressa 30 inhibit tumor cells in pancreatic cancer.…”