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.
Inhibitors of Hedgehog Signaling for Brain Cancer Chemotherapy Jeffrey D. Winkler, PI Nadia Dahmane, PI PROJECT NARRATIVE Our overarching goals are to design better therapies for the treatment of brain tumors. Medulloblastoma, a pediatric malignancy of the cerebellum with the highest incidence of all pediatric brain tumors, and glioma, the most malignant and invasive adult brain tumor, have no optimal therapies. New molecular targets and approaches for clinical intervention are thus desperately needed to increase the survival rate and reduce side effects. The Shh signaling pathway is activated in both types of brain cancer and is required for tumor growth, constituting an excellent target for therapy.
| Winkler, Jeffrey D; Twenter, Barry M; Gendrineau, Thomas (2012) A NEW APPROACH TO THE SYNTHESIS OF SUBSTITUTED PHENAZINES VIA PALLADIUM-CATALYZED ARYL LIGATION(i.) Heterocycles 84: |
| Winkler, Jeffrey D; Isaacs, Andre K; Xiang, Chaomei et al. (2011) Design, synthesis, and biological evaluation of estrone-derived hedgehog signaling inhibitors. Tetrahedron 67:10261-10266 |
| Haimowitz, Thomas; Fitzgerald, Mark E; Winkler, Jeffrey D (2011) STUDIES DIRECTED TOWARD THE SYNTHESIS OF NAKADOMARIN A. Tetrahedron Lett 52:2162-2164 |
| Isaacs, Andre K; Xiang, Chaomei; Baubet, Valerie et al. (2011) Studies directed toward the elucidation of the pharmacophore of steroid-based Sonic Hedgehog signaling inhibitors. Org Lett 13:5140-3 |
| Zhang, Zhihui; Baubet, Valerie; Ventocilla, Christian et al. (2011) Stereoselective synthesis of F-ring saturated estrone-derived inhibitors of Hedgehog signaling based on cyclopamine. Org Lett 13:4786-9 |
