The ASPIRE Path in Molecular Medicine

The hedgehog signaling pathway plays an essential role in developmental pattern formation, and its constitutive activation through oncogenic mutations has been linked to basal cell carcinomas, medulloblastomas, small cell lung cancers, pancreatic cancers, and rhabdomyosarcomas. Signaling functions through the key transmembrane receptor Smoothened (Smo) to effect downstream gene transcription through an as yet fully elucidated mechanism. Vismodegib, an FDA-approved treatment for advanced basal cell carcinoma, represents the canonical hedgehog inhibitor by antagonizing Smo; however, drug-resistant mutations in Smo and downstream oncogenic activation have limited this and other clinical successes. Therefore, the ability to inhibit hedgehog signaling downstream of Smo holds immense therapeutic potential. Through a high-content zebrafish screen for small molecules that perturb embryonic patterning, we identified the small molecule eggmanone (EGM) as a potent and selective inhibitor of hedgehog signaling through a novel mechanism downstream of Smo, and our interests lie in the application of EGM to hedgehog-dependent cancers.

Despite the tremendous clinical potential, modulation of the molecular target of EGM has been associated with severe dose-limiting side effects such as headache, nausea, vomiting, and in rare cases serious cardiovascular events such as myocardial infarction. Therefore, in designing next-generation EGM analogs and optimizing assays for their evaluation, we must apply an extensive knowledge of the underlying cancer pathophysiology in and its interplay with broad systems biology. Most concerning for the future of EGM and its clinical implementation remains its potential to cause severe cardiotoxicity, and the field of cardio-oncology has partly emerged out of necessity for those oncology patients experiencing this life-threatening side effect. With this in mind and in conjunction with Dr. Madan Jagasia in the Vanderbilt-Ingram Cancer Center, the opportunity to gain essential clinical insights into the complications arising from chemotherapy treatment will aid our development and translation of EGM into a clinical treatment for hedgehog-dependent cancers.