Hedgehog Pathway as the Target in Rhabdomyosarcoma with Gli1 Gene Amplification

INTRODUCTION: Hedgehog (Hh) pathway inhibition is being actively investigated in clinical trials for metastatic colorectal cancer, ovarian cancer, medulloblastoma and other solid tumors. One such inhibitor, GDC-0449 (Vismodegib), has shown positive results in phase II clinical trial on advanced basal cell carcinoma. Response to Hh pathway inhibition has been shown for both GDC-0449 and GANT61 for in vitro, non-Gli gene amplified RMS models. Our interest lies in the potential use of Hh pathway inhibition for rhabdomyosarcoma, in which Gli gene amplification has been reported in ~25% of human cases [1]. The Objective of this study was to evaluate the effects of hedgehog (Hh) pathway inhibition at two different levels in the alveolar rhabdomyosarcoma (ARMS) cell line RMS-13 harboring Gli1 gene amplification. Pathway inhibition was conducted at the level of Smoothened (Smo) with the drug GDC-0449 and downstream at the target Gli with GANT61. Our Hypothesis was that in this Gli-amplified model, Hh inhibition would only be possible at the downstream target Gli, not at Smo.