Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449

Abstract

Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling.

Figure 1. Tumor Response on Positron-Emission Tomographic (PET) Scanning

Whole-body projections from ¹⁸F-fluorodeoxyglucose (FDG)–PET scans are shown. Panel A shows the pretreatment scan; Panel B, the repeat scan after 2 months of therapy with the hedgehog pathway inhibitor GDC-0449; and Panel C, the repeat scan after 3 months of therapy.

Figure 2. Tumor-Specific Hedgehog Pathway Activation

Panel A shows the expression of GLI family zinc finger 1 (GLI1) and patched homologue 1 (PTCH1) messenger RNA in the patient’s tumor (red dot) relative to the expression in a panel of 55 banked medulloblastoma samples (gray dots). GLI1 and PTCH1 expression levels were assessed with the use of real-time polymerase-chain-reaction assays, and results are presented as normalized gene expression (2^−ΔCt). Panel B shows the nucleotide sequence of the PTCH1 gene in specimens of the patient’s skin and tumor. In the tumor specimen, both forward and reverse reactions show a homozygous mutation at position 2720, resulting in a G→C change (arrow).