Medulloblastoma is the most common malignant brain tumor in children, often involving the cerebellum. It is associated with aberrant activation of the hedgehog signaling pathway, particularly through loss of heterozygosity and somatic mutation of the PTCH1 gene. A 26-year-old man with metastatic medulloblastoma resistant to multiple therapies was treated with GDC-0449, a hedgehog pathway inhibitor. The treatment led to rapid tumor regression and symptom reduction. Molecular analysis of the tumor showed activation of the hedgehog pathway, with PTCH1 mutations. The hedgehog pathway is essential for stem-cell and progenitor-cell differentiation. SMO activates the pathway, while PTCH1 inhibits it. Hedgehog ligands inactivate PTCH1, derepressing SMO and promoting pathway activation. Medulloblastoma is thought to arise from cerebellar stem cells or progenitor cells. The hedgehog pathway regulates granule-cell precursor expansion, migration, and differentiation. Preclinical and clinical studies suggest that aberrant hedgehog pathway activation in granule-cell precursors promotes medulloblastoma. Heterozygous deletion of Ptc1 in mice leads to medulloblastoma. Inhibition of the hedgehog pathway with SMO inhibitors reduces tumor growth in Ptc1(+/-) mice. Approximately 30% of human medulloblastomas show constitutive hedgehog pathway activation. Medulloblastoma occurs in about 5% of patients with Gorlin's syndrome, a disorder with germ-line PTCH mutations. GDC-0449 is an orally available SMO inhibitor. It induces rapid tumor regression in the Ptc1(+/-) mouse model. Preliminary data from a phase 1 trial show acceptable safety and efficacy in patients with advanced solid tumors. GDC-0449 showed preliminary efficacy in patients with basal-cell carcinoma, another tumor with PTCH1 mutations. The patient with medulloblastoma was treated with GDC-0449 at 540 mg/day. After one week, his pain increased, but MRI showed tumor regression. Dexamethasone was used for pain management. Over the next few weeks, the patient's symptoms improved, and tumor markers decreased. A PET scan showed reduced FDG avidity at all disease sites. However, after three months, the tumor regrew, and the patient was removed from the trial. Despite subsequent therapies, the patient died of disease progression. Transcriptional profiling showed active hedgehog pathway signaling in the patient's tumor. Genomic analysis confirmed PTCH1 mutations. The patient's tumor showed specific pathway activation. The hedgehog pathway plays a critical role in medulloblastoma growth. Targeting the hedgehog pathway may offer a more effective treatment than current options, which have significant side effects. However, the long-term safety of hedgehog pathway inhibitorsMedulloblastoma is the most common malignant brain tumor in children, often involving the cerebellum. It is associated with aberrant activation of the hedgehog signaling pathway, particularly through loss of heterozygosity and somatic mutation of the PTCH1 gene. A 26-year-old man with metastatic medulloblastoma resistant to multiple therapies was treated with GDC-0449, a hedgehog pathway inhibitor. The treatment led to rapid tumor regression and symptom reduction. Molecular analysis of the tumor showed activation of the hedgehog pathway, with PTCH1 mutations. The hedgehog pathway is essential for stem-cell and progenitor-cell differentiation. SMO activates the pathway, while PTCH1 inhibits it. Hedgehog ligands inactivate PTCH1, derepressing SMO and promoting pathway activation. Medulloblastoma is thought to arise from cerebellar stem cells or progenitor cells. The hedgehog pathway regulates granule-cell precursor expansion, migration, and differentiation. Preclinical and clinical studies suggest that aberrant hedgehog pathway activation in granule-cell precursors promotes medulloblastoma. Heterozygous deletion of Ptc1 in mice leads to medulloblastoma. Inhibition of the hedgehog pathway with SMO inhibitors reduces tumor growth in Ptc1(+/-) mice. Approximately 30% of human medulloblastomas show constitutive hedgehog pathway activation. Medulloblastoma occurs in about 5% of patients with Gorlin's syndrome, a disorder with germ-line PTCH mutations. GDC-0449 is an orally available SMO inhibitor. It induces rapid tumor regression in the Ptc1(+/-) mouse model. Preliminary data from a phase 1 trial show acceptable safety and efficacy in patients with advanced solid tumors. GDC-0449 showed preliminary efficacy in patients with basal-cell carcinoma, another tumor with PTCH1 mutations. The patient with medulloblastoma was treated with GDC-0449 at 540 mg/day. After one week, his pain increased, but MRI showed tumor regression. Dexamethasone was used for pain management. Over the next few weeks, the patient's symptoms improved, and tumor markers decreased. A PET scan showed reduced FDG avidity at all disease sites. However, after three months, the tumor regrew, and the patient was removed from the trial. Despite subsequent therapies, the patient died of disease progression. Transcriptional profiling showed active hedgehog pathway signaling in the patient's tumor. Genomic analysis confirmed PTCH1 mutations. The patient's tumor showed specific pathway activation. The hedgehog pathway plays a critical role in medulloblastoma growth. Targeting the hedgehog pathway may offer a more effective treatment than current options, which have significant side effects. However, the long-term safety of hedgehog pathway inhibitors