Hedgehog pathway inhibitors

• Definition

• Hedgehog pathway inhibitors are targeted anticancer agents that block abnormal activation of the Hedgehog (Hh) signaling pathway.

• This pathway plays a key role in embryonic development, tissue regeneration, and stem cell maintenance, but its aberrant activation is implicated in certain cancers, particularly basal cell carcinoma (BCC) and medulloblastoma.

• Inhibitors are mainly designed to target Smoothened (SMO), a critical transmembrane protein in the Hh signaling cascade.

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• Mechanism of Action

• The normal Hh pathway involves ligands (Sonic Hedgehog, Desert Hedgehog, Indian Hedgehog) binding to the Patched-1 (PTCH1) receptor, which removes suppression on SMO, allowing downstream activation of GLI transcription factors.

• In cancers with PTCH1 mutations or SMO activating mutations, the pathway is constitutively active, leading to uncontrolled cell growth.

• Hedgehog pathway inhibitors (e.g., vismodegib, sonidegib) bind directly to SMO, preventing activation of downstream GLI-mediated transcription and halting tumor cell proliferation.

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• Common Agents

1. Vismodegib

   • Indication: Metastatic BCC or locally advanced BCC not amenable to surgery/radiation.

   • Route: Oral, once daily.

   • Targets SMO to inhibit downstream signaling.

2. Sonidegib

   • Indication: Locally advanced BCC not suitable for surgery/radiation.

   • Route: Oral, once daily.

   • Similar SMO inhibition, but with different pharmacokinetic and tissue distribution profiles compared to vismodegib.

3. Glasdegib

   • Indication: Acute myeloid leukemia (AML) in combination with low-dose cytarabine for newly diagnosed elderly or unfit patients.

   • Route: Oral, once daily.

   • Also targets SMO but used in hematologic malignancies due to stem cell pathway modulation.

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• Therapeutic Uses

• Oncology:

  • Basal cell carcinoma (most common)

  • Acute myeloid leukemia (glasdegib)

  • Investigational use in medulloblastoma, pancreatic cancer, and other solid tumors with Hh pathway mutations or activation.

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• Dosage Examples

• Vismodegib: 150 mg orally once daily, with or without food.

• Sonidegib: 200 mg orally once daily, on an empty stomach.

• Glasdegib: 100 mg orally once daily, combined with low-dose cytarabine.

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• Contraindications

• Pregnancy (Category D/X – teratogenic; strict contraception required for both sexes during and after treatment).

• Known hypersensitivity to the drug or excipients.

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• Adverse Effects

1. Common

   • Muscle spasms

   • Alopecia

   • Dysgeusia (taste changes)

   • Weight loss

   • Fatigue

   • Nausea, vomiting, diarrhea or constipation

2. Serious

   • Severe teratogenicity

   • Amenorrhea

   • Hepatotoxicity (rare)

   • Electrolyte disturbances (especially with prolonged use)

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• Precautions

• Mandatory pregnancy prevention programs for both male and female patients (similar to REMS in the US).

• Monitor for muscle toxicity (especially creatine kinase with sonidegib).

• Regular liver function tests if indicated.

• Evaluate for potential drug interactions before initiation.

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• Drug Interactions

• Metabolized primarily via CYP3A4 (especially sonidegib and glasdegib) – strong inhibitors/inducers can alter plasma concentrations.

• Proton pump inhibitors may reduce absorption of vismodegib.

• Avoid concomitant use with other QT-prolonging agents when using glasdegib.

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• Clinical Considerations

• In BCC, these agents are usually given continuously until disease progression or unacceptable toxicity occurs.

• Tumor resistance can develop due to secondary SMO mutations or activation of downstream GLI factors; alternative approaches may be needed in refractory cases.

• Combination strategies (Hh inhibitor + chemotherapy or immunotherapy) are under investigation to improve outcomes in resistant disease.