Oncogenic Hedgehog Pathway Activation by a Putative Rho GTPase-Activating Protein
Aberrant Hedgehog (Hh) pathway activity during postnatal life contributes to a subset of medulloblastomas, the most common malignant brain tumors in children.
For this subset of cancer, drugs that inhibit the Hh pathway have demonstrated very promising anti-tumor effects in early clinical trials. However, the current generation of drugs primarily targets an upstream component of the pathway, rendering them ineffective in patients with mutations in downstream components and potentially inappropriate for use in child patients, due to the critical roles the Hh pathway plays in normal postnatal development. We have identified ARHGAP36, a novel positive regulator of the Hh pathway that is mutated in many cancers, including medulloblastoma.
Our preliminary data indicates that ARHGAP36 is either a downstream component of the Hh pathway or part of a non-canonical mechanism to activate Hh signal transduction and upregulate the expression of Hh target genes. These discoveries suggest ARHGAP36 is a promising drug target for a new generation of therapies. We propose to further characterize the molecular mechanism of ARHGAP36 function in Hh signal transduction, particularly in the context of tumorigenesis.