Predictive biomarkers of efficacy to the hedgehog pathway inhibitor, GDC-0449, in advanced basal cell carcinoma and medulloblastoma in phase I studies

The Hedgehog (Hh) signaling pathway has been directly implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma (MB). Constitutive Hh signaling, most often due to underlying loss of function mutations in the inhibitory receptor Patched1 (PTCH1), has been demonstrated in a majority of common localized BCCs and approximately 25–30% of sporadic MB cases. In this study, we examined molecular correlatives of clinical efficacy in locally‐advanced / metastatic BCC and MB patients treated with GDC‐0449, an inhibitor of the Hh pathway that targets the serpentine receptor Smoothened (SMO). An analysis of Hh pathway transcriptional target gene expression in archival tissue biopsies provided evidence for active Hh signaling in patients exhibiting clinical benefit (objective response or disease stabilization) on therapy. This was further supported by the identification of either loss of function or activating mutations in PTCH1 or SMO, respectively. We were unable to provide evidence for active Hh signaling in 2 patients with progressive disease as best response, potentially underlying the reason for lack of efficacy in these patients. In addition to providing molecular support for Hh pathway activity in patients exhibiting treatment benefit, this is the first evidence for Hh pathway dysregulation in the previously uncharacterized, advanced BCC setting. Furthermore, the results begin to support the utility of transcriptional‐based tests as a strategy to potentially select the subset of MB patients with Hh‐driven disease that would likely benefit on GDC‐0449. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A44.