saridegib

Overview

Saridegib (IPI-926) is an oral small-molecule inhibitor of SMO (Smoothened), a key signal transducer in the Hedgehog (Hh) pathway. By antagonizing Smoothened, saridegib blocks downstream GLI-mediated transcription, suppressing Hedgehog-dependent tumor-cell proliferation and stromal remodeling. It was developed by Infinity Pharmaceuticals and entered clinical trials in solid tumors including pancreatic ductal adenocarcinoma (PAAD). Saridegib is not currently in the OncoKB or cBioPortal canonical drug list (corpus-grown, unverified).

Evidence in the corpus

  • A co-clinical review describes the combination of gemcitabine + saridegib in PAAD as a cautionary case study: preclinical GEM mouse data (Olive et al., Science 2009) showed extended survival with the combination, but the parallel human phase II trial NCT01130142 was halted by Infinity Pharmaceuticals after interim analysis revealed inferior survival in the experimental arm; post-trial mouse experiments suggested that long-term continuous Smoothened targeting may induce a more aggressive phenotype in early-stage disease PMID:23999436.

Resistance mechanisms

  • Post-clinical murine studies in pancreatic adenocarcinoma suggested that chronic (as opposed to acute) Smoothened inhibition may paradoxically promote a more aggressive tumor phenotype, implicating dosing schedule as a critical variable in Hedgehog-pathway targeting PMID:23999436.

Cancer types (linked)

  • PAAD — phase II co-clinical trial (NCT01130142) in combination with gemcitabine; trial halted for inferior survival in experimental arm PMID:23999436.

Sources

  • PMID:23999436 — Herter-Sprie et al. co-clinical trial review (2013); saridegib + gemcitabine PAAD co-clinical case study.

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