Next-Generation Therapies for Hedgehog Pathway-Dependent Tumors
Inappropriate activation of the Hedgehog signaling pathway can promote the onset and/or progression of several pediatric cancers, including medulloblastoma, rhabdomyosarcoma, diffuse intrinsic pontine glioma, and Ewing's sarcoma. Hedgehog pathway inhibitors therefore provide new hope to children afflicted with these diseases, and drugs that target the transmembrane signaling protein Smoothened have induced dramatic tumor regressions in the clinic.
However, Smoothened inhibitors are not a 'silver bullet' for Hedgehog pathway-related cancers. Certain tumors are inherently insensitive to these drugs and even those that initially respond can be come resistant. In addition, there are significant risks associated with the use of Smoothened antagonists in children. Hedgehog signaling plays important roles in post-natal growth, and Smoothened blockade is likely to cause permanent developmental deficits.
To overcome these challenges, we recently completed a 325,120-compound screen for new Hedgehog pathway antagonists, leading to the discovery of a small molecule we have named "glimidazole." Unlike other Hedgehog pathway inhibitors, glimidazole selectively abrogates the function of Gli1, a signaling protein that promotes tumorigenesis but is dispensable for normal physiology. In principle, Gli1-specific drugs could cure Hedgehog pathway-dependent cancers in children, including those that are resistant to Smoothened inhibitors, without compromising pediatric health. We now seek to determine how glimidazole blocks Gli1 function and the efficacy of glimidazole-based drugs in mouse tumor models.
Our studies will provide new insights into how Gli1 function is controlled and could lead to a new class of pediatric-specific chemotherapies.