Angling Downstream For Next-Generation Hedgehog Pathway Antagonists
James Chen,
Associate Professor,
Stanford University
Uncontrolled Gli transcription factor activity has been associated with several human cancers, including basal cell carcinoma, medulloblastoma, small-cell lung cancer, and pancreatic adenocarcinoma. Oncogenic Gli function frequently stems from Hedgehog (Hh)
pathway dysregulation, and inhibitors of the Hh signaling protein Smoothened (Smo) have been developed as targeted anti-cancer therapies. Smo antagonists have been transformative for many patients, inducing dramatic tumor regressions. However, the initial excitement surrounding Smo-targeting therapies has given way to concerns about drug-resistant tumors and on-target side effects in children and
adults. Using high-throughput genetic and chemical screens, we have pursued the
mechanisms of chemoresistance and new small-molecules that can restore Gli suppression. I will discuss our discovery that the Rho GAP family member Arhgap36 can activate Gli-dependent transcription in a non-canonical manner and may contribute to Smo inhibitor-resistance in medulloblastoma. I will also
describe our discovery of novel chemical antagonists of Gli function that act
downstream of Smo and can block Gli-dependent tumor growth in-vitro and in-vivo.
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