Hedgehog Inhibitors

Hedgehog (Hh) Pathway in Cancer

  • The Hedgehog signaling pathway plays a key role in embryonic development, but it’s usually inactive in adults.
  • In certain cancers, the pathway becomes abnormally activated, driving tumor growth, survival, and angiogenesis.
  • Common malignancies with aberrant Hh signaling:

Key Pathway Components

  • PTCH1: Tumor suppressor that inhibits SMO
  • SMO (Smoothened): GPCR-like protein, critical for signal transduction
  • GLI transcription factors: Drive expression of target genes promoting cell proliferation

Mechanism of Hedgehog Inhibitors

  • Most Hh inhibitors target SMO, blocking downstream activation of GLI.
  • Result: ↓ Tumor cell proliferation, ↓ survival signals

FDA-Approved Hedgehog Inhibitors

Drug Brand Indication Notes
Vismodegib Erivedge Advanced/metastatic BCC Oral; CYP substrate (interactions)
Sonidegib Odomzo Locally advanced BCC Oral; similar profile to vismodegib
Glasdegib Daurismo AML (with low-dose Ara-C) Targets SMO; oral; used in elderly/unfit AML

Pharmacist Considerations

  • Adverse Effects: Muscle spasms, dysgeusia, alopecia, fatigue, nausea
  • BBW: Embryo-fetal toxicity – strict pregnancy prevention (REMS-like precautions)
  • DDIs: CYP3A4 substrates; caution with inhibitors/inducers
  • Resistance: Can occur via SMO mutations or downstream activation of GLI