Abstract PL04-03: Targeting the hedgehog pathway in meduloblastoma and basal cell carcinoma

Abstract

Abstract The hedgehog (Hh) pathway is an ancient signaling cascade that directs patterning in most animals and is crucial for proper development. While Hh signaling is very active during embryogenesis, it remains relatively quiet in adult life. However, aberrant reactivation of the pathway in adult tissues can lead to the development of cancer. Hh pathway activation in tumors such as basal cell carcinoma (BCC) and medulloblastoma is the result of inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED (SMO) mutations. Targeting the Hh pathway with small molecule antagonists therefore provides a new therapeutic opportunity for the treatment of these tumor types. GDC-0449, an oral Hedgehog (Hh) pathway inhibitor, was tested in a first-in-human, first-in-class, phase I study in BCC patients. Strong antitumor activity was observed in patients with locally advanced and metastatic BCC, thereby highlighting the potential benefit of inhibiting aberrant Hh signaling in tumors where the pathway is mutated. While most BCC tumors display Hh pathway activity, only a subset of medulloblastoma tumors are caused by mutations in the Hh pathway. Early evidence of clinical benefit of GDC-0449 in a medulloblastoma patient selected for Hh pathway activity was demonstrated. However, as is the case for most targeted therapies used in cancer, mechanisms of resistance to Hedgehog pathway inhibitors have started to emerge in man and mouse models, highlighting the importance of this pathway for these tumors. Characterization of various resistance mechanisms such as SMO mutations or amplification of downstream pathway components suggests potential for therapeutic strategies for the treatment of HPI resistant tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL04-03. doi:10.1158/1538-7445.AM2011-PL04-03