Inhibitors of Hedgehog Signaling For Brain Cancer Chemotherapy

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The overarching goal of this research program is the development of new chemotherapeutic agents for the treatment of brain cancer. Approximately 10,000 cases of glioma are diagnosed each year in the United States and only about half of those patients survive one year. For adults, high-grade glioma or glioblastoma multiforme (GBM) is the most malignant and invasive brain tumor. Treatments include surgery, radiotherapy, and chemotherapy, yet survival rarely exceeds one year after diagnosis. New molecular targets and approaches for clinical intervention are thus desperately needed to increase the survival rate and reduce side effects. Glioblastoma multiforme (GBM) requires Sonic Hedgehog (SHH) signaling for its growth. Our hypothesis is that blockade of SHH signaling constitutes a promising strategy for brain cancer chemotherapy. Cyclopamine, a naturally occurring alkaloid that inhibits the SHH pathway, reduces growth of tumors with activated SHH signaling in vivo, and has been shown to cross the blood brain barrier. However, the metabolic instability of cyclopamine precludes its use as a chemotherapeutic agent. We propose that structurally simplified, metabolically stable cyclopamine-like SHH signaling inhibitors can be prepared from commercially available steroidal precursors (estranes, androstanes and cholanes). The steroidal framework enables the facile synthesis of analogs for in vitro biological testing and for the optimization of biological potency and selectivity. Importantly, our preliminary results have established the validity of this scenario. The studies outlined herein therefore hold the promise of developing important new tools in cancer biology and new drug candidates for the treatment of brain cancers.